Professional Documents
Culture Documents
of Rectal Cancer
Vincenzo Valentini
Hans-Joachim Schmoll
Cornelis J.H. van de Velde
Editors
Multidisciplinary
Management of Rectal
Cancer
Questions and Answers
Editors
Vincenzo Valentini Cornelis J.H. van de Velde
Department of Radiation Therapy Leiden University
Università Cattolica S.Cuore Medical Center
Rome Leiden
Italy Netherlands
Hans-Joachim Schmoll
Klinik und Poliklinik Innere Medizin IV
Abt. Hämatologie und Onkologie
Universitätsklinikum Halle-Wittenberg
Halle, Sachsen-Anhalt
Germany
During the past few decades there have been many advances in the
management of rectal cancer. Building on a more comprehensive
understanding of anatomy and patterns of local recurrence, new surgical
techniques such as total mesorectal resection and sphincter sparing coloanal
anastomosis have become standards. The move toward preoperative adjuvant
therapy has been facilitated by more effective chemoradiation programs.
Advances in radiation planning, delivery, and fractionation techniques
coupled with new cytotoxic and targeted chemotherapeutic agents hold the
promise of reduced toxicity and increased tumor response and control rates.
New diagnostic modalities such as high resolution MRI have helped identify
which therapeutic approaches and modalities are best suited to an individual
tumor, allowing a more selective approach. Lastly, a renewed focus on expert
pathologic analysis coupled with the evolving field of prognostic and
predictive molecular markers has facilitated the development of surrogate
endpoints of response.
Although each discipline has made their individual diagnostic and
therapeutic contributions, the cornerstone of success has been the unified
movement toward multidisciplinary management. It is the collaborative
efforts of surgeons, radiation oncologists, medical oncologists, radiologists,
and pathologists which have truly had the most significant impact on
outcome.
This exciting new book is a unique contribution to the field of rectal cancer.
In contrast to the traditional didactic approach, each chapter directly engages
the reader with timely questions and answers. Building on the value of
multidisciplinary management, Professors Valentini, Schmoll, and Van de
Velde have assembled an internationally known group of contributors from a
number of European centers of excellence. Broad areas of expertise include
risk factors, imaging, radiotherapy, chemotherapy, surgery, and pathology.
The advances of the past three decades as well as new emerging controversies
are discussed.
The editors have succeeded in providing us with the foundation, relevant
data, and guidance to multidisciplinary management of rectal cancer. This
team approach sets the standard for modern cancer management.
v
Preface
In an era where all patients are entitled to access healthcare systems that
enable the highest quality of treatment delivered within a safe healthcare
environment, and access to appropriate advice, support and long term follow-
up, the multidisciplinary team is of central importance and a critical require-
ment in the development of modern oncology.
Joint efforts of different specialists involved in the diagnosis, staging,
treatment and evaluation of outcomes in rectal cancer throughout Europe to
promote mutual understanding and collaboration by managing multidisci-
plinary consensus conferences (EURECA-CC1-2) and the publication of
their recommendation were undertaken.
This was extended to a multidisciplinary teaching course (5 editions across
Europe and 1 in China) and culminated to the endorsement of these activities
by European cancer societies like ESTRO, ESSO and ESMO and hence cre-
ating the background to the holistic approach in promoting the multidiscipli-
narity of this book.
The aim of this book is to report the most common questions that arose in
the practice of a multidisciplinary team, devoted to address the health request
of patients with rectal cancer. A recognised group of clinicians, mostly
involved in the management of the more significant trials published in Europe
in the last decade, were requested to provide simple and focused answers to
support the best choices in a multidisciplinary setting. We are very grateful to
their enthusiastic and fully supportive participation to this project.
With this book we hope to contribute to improve the overall care of the
patient, supporting the multidisciplinary teams in their unique responsibility
for patient’s on-going care and wellbeing.
Vincenzo Valentini
Hans-Joachim Schmoll
Cornelius J.H. van de Velde
vii
Contents
Part I Introduction
ix
x Contents
Fig. 1.1 Sagittal and transversal illustration of the male rectal artery (red), seminal vesicles (purple) (Illustrated
pelvis. Sympathetic and parasympathetic nerves (green), by J.F.M. Lange)
mesorectum (yellow), mesorectal fascia (blue), middle
Fig. 1.2 Three-dimensional reconstruction of the male pelvis. The levator ani nerve, running just cranially to the pelvic
floor (green), is closely related to the mesorectum (light blue)
its vessels, fat and most of its lymph glands, are mesenteric nodes and then the para-aortic nodes.
embryologically derived together as a single unit. The lower lymph drainage is variable both proxi-
The anatomy and embryological origin is respected mally and laterally along the middle rectal ves-
by the current golden standard for rectal cancer sels towards nodes at the internal iliac vessels.
resection (total mesorectal excision, TME) as it The nerve supply to the pelvic organs, i.e., the
involves en bloc resection of the rectum and the rectum, vagina, uterus, vestibular bulbs, clitoris,
mesorectal tissue to the level of the levator muscles bladder, urethra, penis, prostate and pelvic floor,
within the embryologically determined, avascular are closely related to the rectum. From the supe-
plane outside the mesorectum between the parietal rior hypogastric plexus (at level L4-S1, at the level
and visceral rectal fascia [12]. This allows for radi- of the promontory) within the aorta bifurcation,
cal resection of the tumour and preservation of the the two sympathetic hypogastric nerves descend
pelvic autonomic nerves which are essential for dorsally to the mesorectum, parallel to the ureters
urogenital and anorectal functions [6, 7]. towards the inferior hypogastric plexuses (plexi
The mesorectum is suspended to the pelvic pelvini), where they join the parasympathetic pel-
wall by: (1) the ‘lateral ligaments’ which are vic splanchnic nerves (nervi erigentes) coming
strands of condensed tissue, located ventrolater- from S2–4 (Fig. 1.1). The levator ani nerve, which
ally to the rectum, at the level of the seminal ves- is responsible for the innervation of the levator ani
icles in men, containing the middle rectal blood muscle, also arises from S3–4 and runs over the
vessels and lymphatics [13]—these adhere close surface of the pelvic floor muscles, only covered
to the sympathetic and parasympathetic inferior by the parietal fascia [14] (Fig. 1.2).
hypogastric plexuses—(2) the rectosacral fascia,
just cranially to the pelvic floor, at the anorectal
junction at level S4; (3) levator ani complex, cov- 1.2.2 Function
ered by fat and the parietal rectal fascia.
The arterial supply of the rectum is supported The anorectum is responsible for maintaining
by the superior rectal (haemorrhoidal) artery, rep- faecal continence and, when socially appropriate,
resenting the inferior mesenteric artery after defaecation. This is possible as the rectum has a
spring-off of the left colic and sigmoid arteries. capacity to store an amount of faeces, acting as a
The inferior haemorrhoidal arteries from the reservoir [15]. Furthermore, the anal canal con-
internal iliac and the middle rectal artery also tains a rich network of nerve endings sensitive to
contribute blood to the rectum. Venous return fol- pain, temperature and touch, which is used to dif-
lows the arteries. The lymphatic drainage mirrors ferentiate solid or liquid stool from flatus, and
its vasculature. The first nodal level is located in allows for selective passage of flatus. The anal
the mesorectum, draining mostly to the inferior sphincters keep the anal canal closed in a resting
6 M.M. Lange and C.J.H. van de Velde
state. In addition to the resting anal pressures, the entiated and with an unusual histologic type
mesenteric plexus of the internal anal sphincter (mucinous and marked intra- and peritumoural
enables the recto-inhibitory reflex, which implies lymphocytic infiltration). It is also the hallmark
relaxation of the internal anal sphincter in of hereditary nonpolyposis colorectal cancer,
response to increased pressure in the rectum. And HNPCC (Lynch syndrome). It has been observed
finally, the pelvic floor (levator ani muscles) is that MSI is most common in (right-sided) colon
responsible for the anorectal angle, flattening cancer and rare in rectal carcinoma [19].
during defaecation [16]. Nevertheless, compared with colon cancer, the
number of mutations detected is significantly
higher in rectal cancer [20]. Furthermore,
1.3 Pathophysiology cyclooxygenase-2 (COX2) is overexpressed in
90% of rectal tumours but in only 20% of colonic
The majority of rectal cancers develop from tumours [21]. These genetic characteristics
benign preneoplastic lesions: the adenomatous confirm that rectal cancer is a different entity in
polyps or adenomas. Polyps are histologically colorectal cancer.
classified as tubular (5% malignant), villous In the progression of rectal cancer microenvi-
(40% malignant) or mixed (20% malignant), ronmental interactions are important. Loss of
depending on glandular structure. Degree of cell adhesion leads to reorganisation of epithe-
dysplasia (atypical cells) is graded: chance of lial cells to make invasion and metastasis possi-
malignancy varies from about 5% (low grade) to ble [22]. Angiogenesis is vital for tumour growth
about 35% (high grade). Risk of malignancy is and is mediated by multiple molecules, such as
also collated with size: 90% of adenomas are less vascular endothelial growth factor (VEGF),
than 1 cm (1% risk of malignancy), 10% are big- which are released by tumour cells [23]. For a
ger than 1 cm (about 10% malignant). Progression full understanding of the process of normal cells
from a benign adenoma to a malignant carcinoma becoming malignant tumours, all the genetic
passes through a series of well-defined histologi- pathways and mechanisms need to be
cal stages, which is referred to as the adenoma- identified.
carcinoma sequence. Two major mechanisms of Direct spread of rectal cancer occurs intramu-
genomic instability lead to colorectal carcinoma rally and radially, resulting in invasion of adjacent
development and progression: chromosomal tissues or organs. Indirect spread through lymph
instability (CIN) and microsatellite instability and blood vessels was first described by Harrison
(MSI). The former mechanism is associated with Cripps in 1890 [24]. Consequently, his pupil,
a series of genetic changes that involve the acti- William Ernest Miles stretched the importance of
vation of oncogenes (uncontrolled cell growth; resecting the rectal tumour en bloc with its
k-ras gene) and inactivation of tumour suppres- mesorectum, lymph nodes and blood supply,
sor genes (uninhibited growth; APC gene, p53 introducing the first curative resection for rectal
gene, DCC/SMAD4 gene) and contributes pre- cancer [25]. Lymphatic spread occurs in stepwise
dominantly to carcinogenesis in the rectum [17, progression. Skip metastases appear in less than
18]. Familial adenomatous polyposis (FAP) and 5%. Haematogenous spread is the most important
its attenuated variant (AFAP) represents the pattern of spread, most commonly involving the
(hereditary) syndrome dealing with APC muta- liver. However, rectal cancer may also metastasise
tion. The MSI-pathway, in which mutations in initially to the lungs because the inferior rectal
DNA mismatch repair (MMR) genes result in a vein drains into the inferior vena cava rather than
failure to repair errors that occur during DNA into the portal venous system. Other infrequent
replications in repetitive sequences (microsatel- sites are the adrenal glands, kidneys, bones and
lites), results in an accumulation of frameshift brain. In addition, spread within the peritoneal
mutations. This failure leads to an MSI type of cavity happens, initially close to the tumour with
tumour, which is more frequently poorly differ- small nodules arising from cells shed from the pri-
1 What Do We Consider Cancer of the Rectum? 7
1.5 Diagnosis
7. Lange MM, van de Velde CJ (2011) Urinary and sex- 18. Vogelstein B et al (1988) Genetic alterations during
ual dysfunction after rectal cancer treatment. Nat Rev colorectal-tumor development. N Engl J Med 319:
Urol 8:51–57 525–532
8. Martling A, Holm T, Johansson H, Rutqvist LE, 19. Nilbert M, Planck M, Fernebro E, Borg A, Johnson A
Cedermark B (2001) The Stockholm II trial on preoper- (1999) Microsatellite instability is rare in rectal carci-
ative radiotherapy in rectal carcinoma: long-term follow- nomas and signifies hereditary cancer. Eur J Cancer
up of a population-based study. Cancer 92:896–902 35:942–945
9. Kapiteijn E et al (1999) Total mesorectal excision 20. Frattini M et al (2004) Different genetic features asso-
(TME) with or without preoperative radiotherapy in ciated with colon and rectal carcinogenesis. Clin
the treatment of primary rectal cancer. Prospective Cancer Res 10:4015–4021
randomised trial with standard operative and histo- 21. Dimberg J, Samuelsson A, Hugander A, Soderkvist P
pathological techniques. Dutch ColoRectal Cancer (1999) Differential expression of cyclooxygenase 2 in
Group. Eur J Surg 165:410–420 human colorectal cancer. Gut 45:730–732
10. Czito BG, Willett CG (2010) Rectal cancer: interna- 22. Takeichi M (1991) Cadherin cell adhesion receptors as
tional perspectives on multimodality management. a morphogenetic regulator. Science 251:1451–1455
Humana Press, New York 23. Sinicrope FA et al (1996) Increased apoptosis accom-
11. Lange JF, Kleinrensink GJ (2002) Surgical anatomy panies neoplastic development in the human colorec-
of the abdomen. Elsevier, Maarssen tum. Clin Cancer Res 2:1999–2006
12. Heald RJ (1979) A new approach to rectal cancer. Br 24. Cripps H (1890) On diseases of the rectum and the
J Hosp Med 22:277–281 anus. J&A Churchill, London
13. Kusters M et al (2010) Origin of presacral local recur- 25. Miles WE (1971) A method of performing abdomino-
rence after rectal cancer treatment. Br J Surg perineal excision for carcinoma of the rectum and of
97:1582–1587 the terminal portion of the pelvic colon (1908). CA
14. Wallner C et al (2008) The contribution of the levator Cancer J Clin 21:361–364
ani nerve and the pudendal nerve to the innervation of 26. MacKay GJ, Dorrance HR, Richard GM, O’Dwyer PJ
the levator ani muscles; a study in human fetuses. Eur (2010) Colorectal surgery. Oxford University Press,
Urol 54:1136–1142 Oxford
15. Lange MM et al (2007) Risk factors for faecal incon- 27. Wibe A et al (2002) Prognostic significance of the cir-
tinence after rectal cancer treatment. Br J Surg cumferential resection margin following total
94:1278–1284 mesorectal excision for rectal cancer. Br J Surg
16. Wallner C et al (2008) Causes of fecal and urinary 89:327–334
incontinence after total mesorectal excision for rectal 28. Lahaye MJ et al (2005) Imaging for predicting the risk
cancer based on cadaveric surgery: a study from the factors – the circumferential resection margin and
cooperative clinical investigators of the Dutch total nodal disease – of local recurrence in rectal cancer: a
mesorectal excision trial. J Clin Oncol 26:4466–4472 meta-analysis. Semin Ultrasound CT MR 26:259–268
17. Conlin A, Smith G, Carey FA, Wolf CR, Steele RJ
(2005) The prognostic significance of K-ras, p53, and
APC mutations in colorectal carcinoma. Gut
54:1283–1286
What Is the Ongoing
Recommendation in the 2
Management of Rectal Cancer?
Vincenzo Valentini, Hans-Joachim Schmoll,
and Cornelis J.H. van de Velde
In the last decade, several European phase III times a web-based document customized for the
trials evaluating the role of radiotherapy and che- consensus process. A meeting was openly held to
motherapy in rectal cancer have been published. debate by attendees the more controversial sen-
From these trials, the efficacy of both short-course tences. The total number of voted sentences was
preoperative radiotherapy and preoperative con- 207. Of the 207, 86% achieved large consensus,
current chemoradiotherapy was determined [1–7]. 13% achieved moderate consensus, and only 3 (1%)
Anyway, although the findings of large random- resulted in minimum consensus. The document
ized trials have addressed important questions, addresses a wide range of topics relating to the man-
there remain patient care issues that cannot be agement of rectal cancer and, of equal importance,
addressed by subgroup analyses of existing trials identifies areas where future research is a priority.
and large areas of controversies are still in place. A second document was addressed by ESMO
To support physicians to deliver more tailored inside their program of organ oriented guide-
choices—as the oncology profession moves into lines. A group of experts invited by ESMO
the era of individualized medicine—some debated in a 2-day meeting the key issues about
European Consensus guidelines were proposed the management of rectal and colon cancer and a
under the collaboration of the major Oncology document circulated between them till a final
Society ESTRO (European SocieTy of Radio- approval [9].
therapy and Oncology), ESSO (European Society To get more information about the different
of Surgical Oncology), and ESMO (European strategies regarding staging and treatment of rec-
Society of Medical Oncology) [8, 9]. tal cancer, we recommend the reading of these
Two papers summarized these efforts: The two documents as well as the different answers to
EURECA project elaborated the Consensus the main questions, which arose in a multidisci-
document using the Delphi method [8]. A group plinary group in the daily management of rectal
of experts delegated by the three Oncology cancer patients, reported in this book (Figs. 2.1–2.10
Societies voted sentence by sentence for three and Tables 2.1–2.3). In this chapter, we tried to
T stage
MRF Sphincter
Aim Location N stage Metastases
involvement involvement
T1 T2–3 T4
1° Abdomen MDCT
Choice ERUS MRI MRI MRI MRI MRI +
MRI
Exam chest –X ray or
CT (to be preferred)
MDCT
IF 1° Rigid ERUS MDCT MDCT high
choice ERUS slow ERUS mid ERUS
proctocopy high
exam is rectum mid rectum rectum
not
available
Flexible
2°
endoscopy MDCT Multidetector CT ERUS Endorectal US MRF Mesorectal Fascia
choice
Clinical cT1 N0 M0
stage
Local
TME
Primary excision
treatment
pT1NX
Pathological pT1NX high risk > pT2 or pN + pT1–2 N0
report Margin - features
or > pT1N0
Adjuvant Chemotherapy
Observation Observation
treatment + radiochemotherapy
(see table 20.1)
Clinical cT2 N0 M0
stage
TME
Primary
treatment
Preoperative
RT chemotherapy
Preoperative long course
Primary RT short course (see Table 2.1)
treatment
TME TME
Pathological
report CRM− CRM+ CRM− CRM+
Clinical
cT3 (MRF+) N0−2−M0 or cT4 any N M0
stage
Preoperative
RT chemotherapy
long course
Primary (see Table 2.1)
treatment
6–8 weeks
TME
Adjuvant
Adjuvant chemotherapy
treatment (see Table 2.2)
6−8 weeks
Preoperative
Preoperative
RT chemotherapy
RT short course
long course
TME
Primary
treatment 6−8 weeks
Preoperative
Restaging
CRM + chemotherapy
CRM− > clinical response?
or PN +
Pathological
report
Local excision TME
pT0 Nx pT1–2–3
CHEMO+
RT Chemo Adjuvant chemotherapy
Adjuvant Observation Observation TME (see Table 2.2)
(see Table 2.1)
treatment
pT0–2 N0 pT3 N+
Observation Adjuvant
Chemotherapy (seeTable 2.2)
No previous RT Previous RT
for the primary for the primary
RT chem Resecability
Primary
treatment Resecability
Yes No
Yes No
Surgery RT chem Chemotherapy RT chem
Chemotherapy B
Resection + IORT Surgery
(see Table 2.2) Adjuvant Resecability
Chemotherapy
(see Table 2.2)
Yes No
adjuvant
chemotherapy
Adjuvant – Adjuvant (see Table 2.2) Surgery Chem
maintenance Chemotherapy B
treatment
Chem
or
Preop RT (5 × 5) 3 months preop
3 months preop
Primary Or CRT FOLFOX
FOLFOX
treatment
Primary
Resectability of mets achieved?
treatment
Yes No
< T3 N0 ≥ T3 or N+
Continue/change chemotherapy
Yes No
Resection of primary +
resection of metastases
Avoid radical and mutilating
Adjuvant – Resume initial treatment for a surgery
maintenance total of 6 months RCT or short course RT or brachiterapy
treatment for locally advanced tumors
Intensive chemotherapy
Single, <2 cm FOLFOX
3−4(−6) months
Primary liver met 3 months preop
(see Table 2.3)
treatment
Resection No resection
Table 2.1 Chemotherapy-options and doses for concomitant chemotherapy during radiation
Regimen References
5FU 325–350 mg/m2 + LV 20 mg/m2 iv bolus, d1–5, week 1 and 5 [3, 10]
5FU 400 mg/m2 + LV 100 mg iv bolus, d1, 2, 11, 12, 21, 22 [7]
5FU 225 mg/m2 iv continuous infusion, 5 days per week, together [11, 12]
with radiotherapy
5FU 1,000 mg/m2 iv continuous infusion, d1–5, week 1 and 5 [1]
Capecitabine 800–825 mg/m2 bid po continuously, 5–7 days per week, [11, 13, 14]
together with radiotherapy
UFT (300–350 mg/m2/day) and LV (22.5–90 mg/day) po continu- [15–18]
ously, 5–7 days per week, together with radiotherapy
5FU 250 mg/m2 iv continuous infusion on days 1–14 and 22–35 and [19]
oxaliplatin 50 mg/m2 iv d1, 8, 22, 29, only preoperatively
Table 2.2 Standard adjuvant chemotherapy regimens in rectal cancer (number of cycles without chemoradiation are
given in brackets)
Regimen Cycles References
5FU 350–370 mg/m2, + LV 20–25 mg/m2 iv 4 (−6) [3, 20]
bolus, d1–5, q 4 weeks
5FU 500 mg/m2 iv, continuous infusion, d1–5, 4 [1]
q 4 weeks
5FU 500 mg/m2 + LV 100 mg, iv Bolus, d1, 2, 8 [7]
q 2 weeks
Capecitabine 2,000–2,500 mg/m2, po, d1–14, 5–6 (−8) [13, 21]
q 3 weeks
16 V. Valentini et al.
the phase III trial ACCORD 12/0405-Prodige 2. radiotherapy (60 Gy) and UFT/l-leucovorin in patients
J Clin Oncol 28:1638–1644 with non-resectable locally advanced rectal cancer
15. Bystrom P, Frodin JE, Berglund A, Wilking N, (LARC). Acta Oncol 47:428–433
Glimelius B (2004) Phase I study of UFT plus leuco- 19. Roedel C, Becker H (2011) Preoperative chemoradio-
vorin with radiotherapy in patients with inextirpable therapy and postoperative chemotherapy with
non-rectal gastrointestinal cancer. Radiother Oncol 5-fluorouracil and oxaliplatin versus 5-fluorouracil
70:171–175 alone in locally advanced rectal cancer: first results of
16. Schiebe ME, Reese T, Wenz F et al (2002) Phase I the German CAO/ARO/AIO-04 randomized phase III
study of oral uracil and Tegafur plus leucovorin and trial. J Clin Oncol 29:abstract LBA3505
pelvic radiation in patients with recurrent rectal can- 20. Gray R, Barnwell J, McConkey C, Hills RK, Williams
cer. Anticancer Drugs 13:1005–1009 NS, Kerr DJ (2007) Adjuvant chemotherapy versus
17. Jakobsen A, Appelt AL (2011) The dose-effect rela- observation in patients with colorectal cancer: a ran-
tionship in preoperative chemoradiation of locally domised study. Lancet 370:2020–2029
advanced rectal cancer: preliminary results of a phase 21. Twelves C, Wong A, Nowacki MP et al (2005)
III trial. J Clin Oncol 29:abstract 3512 Capecitabine as adjuvant treatment for stage III colon
18. Vestermark LW, Jacobsen A, Qvortrup C et al (2008) cancer. N Engl J Med 352:2696–2704
Long-term results of a phase II trial of high-dose
Part II
Q&As on Risk Factor Identification
What Prognostic Clinical Factors
Must Be Considered Before 3
Treatment?
Claus Rödel
in women treated with 5-fluorouracil-based CRT. patients, who may require aggressive supportive
Furthermore, an increased risk of dyspareunia management to complete therapy.
and vaginal dryness was observed in women fol- An increased body mass index, particularly in
lowing surgery combined with (chemo-)radio- males, was associated with a decreased likelihood
therapy compared with women treated with of sphincter preservation and an increased risk of
surgery alone. local recurrences in a pooled analysis of 1,688
There is limited information on how elderly rectal cancer patients treated within postoperative
patients tolerate radiotherapy or combined CRT 5-fluorouracil-based CRT trials. Interestingly,
for rectal cancer. Recent analyses of the Dutch obese patients – both women and men – had a
TME trial and two large Dutch population-based significantly lower rate of grade 3–4 acute toxic-
registries showed that, unlike younger patients, ity (mainly leucopenia, stomatitis) when com-
patients >75 years of age did not benefit in terms of pared to normal-weight individuals, indicating
overall survival from the introduction of preopera- that actual body weight dosing of 5-fluorouracil
tive radiotherapy and TME surgery [2]. Randomized may be justified in obese patients [3].
trials in rectal cancer commonly include few
patients more than 75 years of age. Data from the
pooled analysis of the five European trials 3.2 Tumor-Related Characteristics
(Table 3.1) do not indicate worse outcome in terms
of local and distant control in the age cohorts from 3.2.1 Tumor Size and Location
below 50 years to above 70 years, respectively.
However, several nonrandomized and population- Through digital rectal examination (DRE, the
based datasets indicate higher rates of toxicity and average finger can reach approximately 8 cm
treatment deviation during CRT among elderly above the anal verge), tumors can be assessed for
3 What Prognostic Clinical Factors Must Be Considered Before Treatment? 23
Table 3.2 Impact of distance from anal verge by univariate analysis on local failure rates
Swedish rectal cancer trial
Local failure rate at 5 years (%)
Preop. RT Surgery P value
High >11 cm 8 12 n.s.
Middle 6–10 cm 9 26 <0.001
Low £5 cm 10 27 0.03
Dutch trial
High >10 cm 3.7 6.2 0.12
Middle 5.1–10 cm 3.7 13.7 <0.001
Low £5 cm 10.7 12 0.58
Medical Research Council MRC CR07
High >10–15 cm 1.2a 6.2a HR 0.19 (0.07–0.47)
Middle >5–10 cm 5.0a 9.8a HR 0.50 (0.28–0.9)
Low 0–5 cm 4.8a 10.4a HR 0.45 (0.23–0.88)
a
Three-year data
size, ulceration, and fixation to surrounding struc- randomized trials which were not stratified by
tures. DRE also permits a cursory evaluation of distance. These trials used short-course preopera-
the patient’s sphincter function, which is critical tive radiation and included patients with cT–
when determining whether a patient is a candi- –2N0 disease (Swedish Rectal Cancer Trial from
date for a sphincter-sparing procedure. Several the pre-TME era, Dutch Trial, Medical Research
studies identified the pretreatment tumor size Council MRC CR07) [4–6]. As seen in Table 3.2,
(<3 cm) as a significant factor for pathologic by univariate analysis, “high” tumors generally
complete response after preoperative chemora- had a lower incidence of local recurrence com-
diotherapy (CRT) in rectal cancer. Other known pared with mid and lower tumors. On multivari-
risk factors include circumferential lesions, teth- ate analysis, tumor location was an independent
ered or fixed tumors on palpation, near-obstruct- prognostic variable in the Dutch trial. The MRC
ing lesions, and low-lying tumors. Rigid CR07 trial also identified tumors involving the
proctosigmoidoscopy allows direct visualization anterior quadrant as an independent risk factor
of the lesion and provides an estimation of the for time to local recurrence, whereas distal extent
size of the lesion and degree of obstruction. This was not significantly associated with local recur-
procedure is used to obtain biopsies and gives an rence on multivariate analysis.
accurate measurement of the distance of the It is interesting to note that radiation did
lesion from the anal verge. significantly decrease local recurrence for all
The rectum is subdivided into three parts tumor positions in the MRC CR07 trial, whereas
according to the distance of the lower margin of this effect was significant only for middle and
the tumor from the anal verge: upper third low tumors in the Swedish and for middle
12–16 cm, middle third 6–£12 cm, and lower tumors only in the Dutch trial, respectively. If
third <6 cm. Alternative definitions (0–5 cm, analyzed as a continuous factor (rather than with
>5–10 cm, >10–15 cm) have also been used. The arbitrary cutoff points), the benefit of radiother-
anterior peritoneal reflexion represents the point apy in the Dutch trial became significant as the
at which the rectum exits the peritoneal cavity distance from anal verge increased. However, if
and becomes retroperitoneal (approximately patients with positive circumferential resections
8–12 cm from the anal verge, extremely variable margins (which occurs more often in distal rec-
between females and males). There are no pro- tal cancer) were excluded, the effect of radio-
spective randomized data examining the impact therapy on reduction of local recurrences was
of the distance from the anal verge on local recur- independent of the distance of the tumor from
rence. The available data are subset analysis from the anal verge.
24 C. Rödel
3.2.2 Clinical T- and N-Stage presence of mixed signal intensity and irregular-
ity of the borders of the lymph nodes may be more
The primary imaging modalities to assess the reliable. However, adequate clinical detection of
extent of the primary tumor (cT-, cN-status) are lymph node involvement remains a challenge that
endorectal ultrasound (ERUS), multidetector 4–16 is critically important with respect to the increas-
slice CT, and phased-array MRI. ERUS is the most ing use of preoperative treatment strategies.
accurate tool in predicting T stage of rectal can- It is clear that the most important prognostic
cers, especially T1 versus T2. Thus, ERUS has factors for survival are the extent of disease as
been recommended as the investigation of choice determined histopathologically after surgery
in selection of potentially curative local excision (with or without neoadjuvant treatment) by the
which should be restricted to patients with T1 degree of bowel wall penetration; the presence or
tumors without further risk factors, as well as in absence of lymph node metastases or distant
selection of patients with early T3 tumors (vs. T2) metastases, i.e., the (y)pTNM stage, as well as
for neoadjuvant treatment. ERUS cannot be reli- the tumor resections margins (R0, R1, R2; cir-
ably used in patients with high or stenosing tumors. cumferential resection margin £1 mm). The prog-
Of note, overestimation of staging with this tech- nostic value of the clinically determined cT- and
nique occurs more often than understaging. In the cN-stage is less validated. Figure 3.1a depicts the
German CAO/ARO/AIO-94 study, 18% of patients association of the pretreatment, clinical T- and
in the immediate surgery arm – clinically staged N-stage with disease-free survival within the
by ERUS to have cT3–4 and/or cN + disease – had German Rectal Cancer Study [8]. In this trial,
lymph node negative tumors confined to the rectal staging procedures included DRE, proctoscopy,
wall (pT1/2 pN0) on pathologic assessment of the endorectal ultrasound, and a pelvic CT scan (MRI
resected specimen. This probably is due to the was not mandatory). Only patients with cT3–4
inflammatory and desmoplastic processes caused and/or cN + disease were eligible. Interestingly,
by the tumor (or by taken tumor biopsy within clinical T and N staging was not significantly
1 week before ERUS was performed) but is also associated with long-term outcomes in this trial,
operator dependent. Endorectal coil MRT is an reflecting the inaccuracy of pretreatment staging,
alternative to ERUS but appears to be not superior especially with respect to lymph node involve-
to ERUS for T staging. Because of limited acous- ment. Data from the pooled analysis of the five
tic penetration by ERUS, invasion of bulky tumors European trials (Table 3.1), however, indicate
into the perirectal fat and adjacent organs and pel- that cT-stage and cN-stage are significantly asso-
vic side walls is better evaluated by multislice-CT ciated with the risk of local and distant failure,
scan and phased-array MRI. The involvement of respectively, albeit the absolute difference in out-
the anal sphincter and levator ani muscles cannot comes was only small. Conversely, positive
be truly seen on CT scans, whereas high-resolu- lymph nodes after preoperative CRT indicate
tion MRI techniques using phased-array coils have both an aggressive potential of the malignant
led to better spatial resolution and particularly cells to spread to the regional lymph nodes and
have been shown to identify the anal sphincter, the resistance of these cells toward CRT. As a
puborectalis, and particularly the mesorectal fas- result, these patients have a very unfavorable
cia. This latter is an important feature to predict prognosis and ypN0 versus ypN1–2 largely sepa-
negative circumferential margins between the rates different prognostic groups (Fig. 3.1b).
tumor and the mesorectal fascia and makes phase
array MRI superior to CT especially for lower
third rectal tumors [7]. 3.2.3 Distance of the Tumor
The identification of positive lymph nodes is to Mesorectal Fascia
more difficult. Involvement is mainly assessed by
size criteria (>8 mm), although enlarged lymph Histopathologic tumor involvement of the mesorec-
nodes are not pathognomonic of tumor involve- tal resection margin is a well-established indepen-
ment, and morphological features such as the dent predictor of local and distant metastases
3 What Prognostic Clinical Factors Must Be Considered Before Treatment? 25
Disease-free survival
survival after preoperative
.6 cT4 cT3 .6
chemoradiotherapy (Data from cN0 (n=154)
the German Rectal Cancer (n=24) (n=268)
Study)
.4 .4
.2 .2
P=0.92 P=0.34
0 0
0 20 40 60 80 100 0 20 40 60 80 100
Months Months
b
1.0 ypT1 1.0
ypT0
ypNO
.8 ypT2 .8
Disease-free survival
ypT3 ypN1
.6
ypT4 .6
.4
.4
ypN2
.2
P=0.001 .2
P<0.0001
0
0
0 20 40 60 80 100 0 20 40 60 80 100
Months Months
both after primary surgery and after preoperative prognostic tumors (e.g.,T4; predicted CRM
CRT/RT plus surgery. High-resolution phased- £1 mm, cN2; extramural venous invasion).
array MRI techniques are highly accurate for the
prediction of the circumferential resection margin
(CRM), especially CRM £1 mm versus >1 mm. 3.3 Histopathology on
Moreover, substaging of T3 tumors (T3a/b with Pretreatment Biopsies
tumor spread £5 mm into the mesorectal compart-
ment) has been validated prospectively by the The majority (over 90%) of rectal cancers are ade-
MERCURY study group and has shown direct nocarcinomas. Some adenocarcinomas have mucin
agreement between pretreatment imaging and which can be extracellular (colloid) or intracellular
corresponding pathology [9]. Both information (signet ring cell). Colloid cancer, which occurs in
may help to stratify patients for preoperative treat- 15–20% of adenocarcinomas, is not an indepen-
ment alternatives, including omission of RT in dent prognostic factor, whereas signet ring cell,
good prognostic tumors (e.g., cT3a/b, cN0, mid- which occurs in 1–2% of adenocarcinomas, is an
dle/upper part of rectum, predicted CRM >1 mm) independent poor prognostic factor for survival.
or short-course RT versus CRT in intermediate Other histological types are rare and include carci-
(e.g., >cT3a/b, predicted CRM >1 mm) and poor noid tumors, leiomyosarcomas, lymphoma, and
26 C. Rödel
over the other when assessing rectal cancer pre- Patients with synchronous metastatic disease now
operatively; rather, they are complimentary tech- receive systemic chemotherapy and may be con-
niques [1]. Local staging and the usefulness of sidered for metastasectomy with consequent
EAUS is discussed below. High spatial resolution of improvements in overall survival.
EAUS images is particularly suited to identification Limitations of CT include poor spatial resolu-
of the structure of the bowel wall. However, whilst tion which makes identification of the individual
MRIs drawbacks relate to tolerance and compatibil- layers of the bowel wall difficult. Tumour depth is
ity with the magnet, EAUS is not reliable for certain an important consideration in decision making as
types of tumour morphology. For example, the regards neoadjuvant therapy, and accurate local
endoanal technique produces inaccuracy with staging is a must. Recent studies have investigated
stenosing tumours, polypoidal tumours and high the use of multi-detector CT as an alternative to
rectal cancer. In addition, it does not demonstrate MRI for local staging of rectal cancer [3, 4].
fully the mesorectal fascia and thus the proximity of However, results of these studies have not favoured
tumour to the potential circumferential resection CT. Although for “higher” rectal tumours CT is
margin. Peritumoral inflammation, fibrosis and fae- accurate in identifying a potentially involved
cal material can give the appearance of artefact or CRM, it has poor accuracy for low rectal cancer.
overcall tumour. Accuracy may be further reduced
due to a combination of technical and user errors
including incorrect field alignment, improper bal- 4.3 Local Factors Which Influence
loon inflation, physical or refraction artefacts and if Treatment Decisions
the tumour is close to the anal verge [2].
Therefore, EUS is severely limited in support- The main risk factors for local recurrence in
ing preoperative treatment decisions on the fol- rectal cancer are histopathological involvement
lowing basis: of the circumferential resection margin (CRM)
1. Inability to identify patients at risk of local and height of tumour from anal verge. More
recurrence based on predicted CRM status recently, the presence of extramural venous inva-
2. Limited assessment of bulky and stricturing sion (EMVI) has been shown to be a prognostic
tumours and of identifying disease remote factor for poor outcome in terms of both local
from the lumen within mesorectum and distant failure [5]. In patients undergoing
3. Poor accuracy in reassessment of tumour stage TME surgery, nodal status no longer predicts
and safety of surgical margins following local failure but remains a risk factor for distant
chemoradiotherapy or radiotherapy metastases as well as increasing depth of tumour
spread. All these factors can be most accurately
assessed with MRI, although there may be some
4.2.3 Computed Tomography (CT) role for CT and endoanal ultrasound (EAUS).
TME is the “gold standard” as CRM involvement basis for neoadjuvant therapy for CRM positive
is a positive predictive factor for local recurrence. tumours reduced the need for CRT by 35% with-
Whereas histopathological analysis of the resec- out compromising outcome [11].
tion specimen provides confirmation of oncolog-
ically successful surgery, knowledge of the
relationship between the tumour and the mesorec- 4.3.2 Height of Tumour
tum is a mandatory in treatment planning. MRI
has been shown to accurately predict the rela- Rectal cancer is defined in terms of distance from
tionship between tumour and mesorectal fascia the anal verge. The rectum is measured as
with a high degree of concordance (92%) with 12–15 cm from the anal verge, and tumours found
histology [6]. within the distal 6 cm are classified as “low” rec-
Tumour spread which threatens the potential tal cancers. The distance from the anal verge or
CRM has been shown to be a predictive factor of height of the tumour is important due to its ana-
local recurrence [7]. It is now generally accepted tomical relationships as the rectum leaves the
that tumour spread within 1 mm of the potential peritoneal cavity. It is prognostically significant
CRM is a strong influence in local recurrence. for local recurrence [12, 13] and anastomotic leak
Recent work by Taylor et al. has shown that rates following surgery [14, 15].
of local recurrence decreased from 53% with Traditional assessment of the height of tumour
tumour less than 1 mm from the potential CRM was done using a combination of digital rectal
to less than 8% when the tumour distance from examination and rigid sigmoidoscopy. Both these
the mesorectal fascia was between 1 and 5 mm methods can be greatly inaccurate. The level of the
[8]. Knowledge of the proximity of the tumour to tumour has implications on surgical planning and
the mesorectal fascia at an early stage is impor- may be the difference between performing an
tant when planning treatment. anterior resection or abdominoperineal resection
Involvement of the potential circumferential or deciding to create a defunctioning stoma. In this
resection margin may be subdivided and appears regard, demonstrating the relationship between the
as distinct entities on imaging (Fig. 4.2). It is tumour and pelvic floor as well as the sphincter
therefore important to define the type of threat to complex is vital. In the era of laparoscopic surgery,
the potential CRM as not all subtypes may be many surgeons find laparoscopic rectal cancer
prognostic. For example, a local well-encapsu- resection for low tumours inappropriate, so accu-
lated lymph node lying close to the mesorectal rate objective identification of tumour height is
fascia is not associated with an increased risk in important, particularly the distance between the
local recurrence [9] (Table 4.1). distal edge of the tumour and the puborectal sling.
Being able to accurately identify tumour Axial images on MRI can clearly demonstrate
proximity to the mesorectal fascia within a mil- the level and longitudinal spread of the tumour
limetre on MRI has been a challenge. A mea- (Fig. 4.1). However, correct field alignment is
sured distance of 5 mm on MRI has been shown imperative and taking images through a plane
to strongly correlate with negative CRM on his- which is not exactly 90° to the long axis of the
tology, which led to patients being offered rectum and over- or under-call tumour height.
chemoradiotherapy when tumours are within
5 mm of the mesorectal fascia. However, this
results in substantial overtreatment of patients 4.3.3 Extramural Venous
with safe margins. More recently, the MERCURY Invasion (EMVI)
Study Group showed that margins could be
identified more accurately and reproducibly Invasion of extramural veins has been identified
using a 1-mm cut-off [10]. One recent study has as a poor prognostic factor for overall survival
shown that using MRI-based measurement as a and, more recently, local recurrence [1, 2]. This
4 What Are the Relevant Imaging Factors to Optimize Treatment Decisions? 31
a b
Fig. 4.2 (a) Grade 2 EMVI on MRI. (b) Grade 3 EMVI. (c) Grade 4 EMVI. The red arrows indicate the extent of
venous invasion
is independent of tumour stage. The definition be identified pre-operatively on MRI with great
of EMVI is the presence of malignant cells accuracy [3]. Knowledge of the appearances
within the endothelial-lined blood vessels and position of normal rectal vasculature is
beyond the muscularis propria. It can occur in important to be able to accurately identify
up to 50% of rectal cancer patients. EMVI can EMVI.
32 M. Chand and G. Brown
Table 4.1 Subtypes of histopathology CRM involvement of the UICC TNM classification. Depth of extra-
Type of spread Frequency (%) mural invasion is recognized as an independent
Direct tumour spread 18–29 prognostic factor [1, 2]. Within the broad T-stage
Discontinuous spread 14–67 classification, there are certain groups of patients
Lymph node metastases 12–14 who are considered high risk and thus may benefit
Venous invasion 14–57 from adjuvant therapy. This has led to a sub-
Lymphatic invasion 9 classification of T-stage. For example, T3 tumours
Perineural spread 7–14 can be further classified according to maximal
tumour invasion beyond the outer border of the
Table 4.2 MRI classification of EMVI muscularis propria – into the mesorectum. T4
MRI- tumours can be further classified depending on
EMVI the presence of invasion into adjacent organs with
score EMVI status Description or without perforation of visceral peritoneum [3].
0 Negative No vessels adjacent to areas A more detailed discussion of T sub-staging will
of tumour penetration be addressed in further chapters.
1 Negative Minimal stranding but well
Accurate assessment of this relies on the
away from vessels
2 Negative Stranding within vicinity of
identification of the layers of the bowel wall. A
vessel but no definite tumour meta-analysis of almost 5,000 patients compar-
signal ing accuracy of T-staging between MRI, CT and
3 Positive Intermediate signal within EAUS showed 84%, 73% and 87%, respectively
slightly expanded vessel [4]. Although this would suggest greater accu-
4 Positive Irregular contour of vessel by racy with EAUS, MRI techniques have improved
definite tumour signal
since, and it has the advantage in being able to
evaluate the peri-rectal structures and not be lim-
Using high spatial resolution MRI, veins are ited by access or user problems. EAUS may be
identified as serpiginous or tortuous linear struc- more useful for T1 and T2 tumours where accu-
tures on T2-weighted images. The depth of inva- rate identification of the mesorectal fascia has
sion of the tumour bears relevance as a tumour less importance, particularly if the lesion is ame-
limited to the muscularis propria will not be able to nable to local resection.
spread into extramural veins. Essentially, this An understanding of the MRI appearances of
means that EMVI positive tumours will be T-stage normal rectal anatomy is essential to appreciate
3 or 4. Assessment of EMVI using MRI must con- tumour depth and spread. MRI can readily iden-
sider the following components: pattern of tumour tify the layers of mucosa and muscle through dis-
margin which gives the appearance of nodularity, tinct signal characteristics. T2-weighted images
location of tumour to relevant vessels which makes are particularly useful for this. The mucosal layer
tumour invasion more likely, calibre of vessel as is seen as a very fine line of low signal intensity
tumour infiltration can cause an increase in lumi- overlying the much thicker and higher signal of
nal size, and vessel border if the tumour disrupts the submucosa (Fig. 4.3). Outside this, the mus-
the vessel itself [4]. Table 4.2 shows classification cularis propria can be seen as a dual layer repre-
of EMVI in rectal cancer. Extension of the primary senting the inner circular and the outer longitudinal
tumour into a vascular structure indicates EMVI. muscle layers. The latter has a typically irregular
appearance due to vessels traversing the rectal
wall. The peri-rectal fat is identified as a high sig-
4.3.4 T-Staging nal with signal void areas surrounding the rela-
tively low signal intensity of the muscularis. This
Staging of rectal cancer involves determining the is all enveloped by the fine layer of low signal
depth of invasion of the tumour in relation to the intensity representing the mesorectal fascia – the
composition of the bowel wall and makes up part defining plane of the TME.
4 What Are the Relevant Imaging Factors to Optimize Treatment Decisions? 33
70.5
4.4.1.2 MRI
Fig. 4.7 CT and PET-CT of liver metastases
MRI assessment includes T1- and T2-weighted
images with a contrast medium such as gadolin-
It is important to appreciate that it is unlikely ium providing sufficient anatomical detail, delin-
that a single imaging modality will be able to eating perfusion defects seen on CT images from
satisfy all the above questions; however, it is impor- fatty infiltration. Differentiating benign liver
tant to select an appropriate combination of sequen- lesions from malignant ones is an important abil-
tial imaging techniques to optimize outcome. ity of MRI. Specific contrast agents are taken up
by functioning Kupffer cells and are seen as dark-
4.4.1.1 CT ened areas on MR imaging. Mangafodipir triso-
CT exploits the relative hypovascularity of dium (Mn-DPDP) is taken up by functioning
hepatic metastases compared with normal liver hepatocytes and leads to an elevation in signal
parenchyma and has accuracy rates of up to 85% intensity of T1-weighted images of normal liver
[14]. The use of multi-detector CT can be highly parenchyma within 10 min of injection. There is
accurate in demonstrating liver lesions (Fig. 4.7). a 400% increase in conspicuity between the
The entire liver can be imaged within 10 s during hypointense hepatic metastases and the surround-
several phases of hepatic enhancement. Liver ing normal liver tissue [17]. It is important to be
metastases are seen as hypodense lesions with able to distinguish metastases from haeman-
complimentary rim enhancement. Larger lesions giomas, fatty infiltration and cysts (Fig. 4.8).
may exhibit signs of central necrosis such as a
central low density ‘cystic nidus’.
Differentiating metastases from benign lesions 4.4.2 Extra-hepatic Disease
is more straightforward for larger lesions as they
are well defined and lack rim enhancement. Smaller Patients who demonstrate single metastases in
lesions, particularly less than 10 mm, are more one lobe only are much less likely to have
difficult to characterize, but the same principles of unrecognized irresectable disease when
38 M. Chand and G. Brown
compared with those patients with multi-lobar tumour features being identified, thus giving cli-
metastases [18]. Although laparoscopy may be nicians more information to base treatment deci-
a useful tool in assessing the presence of extra- sions. This also highlights the advantages of a
hepatic disease, a combination of CT and PET multi-disciplinary approach to cancer.
scanning are more common.
PET imaging with 18-fluoro-2-deoxyglucose
(FDG) has been shown to have the greatest poten-
tial in detecting extra-hepatic disease not found
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What Biochemical and Molecular
Biological Factors Have Greater 5
Relevance to Treatment Decisions?
treatment decisions leading to probably unneces- The percentage of patients developing a patho-
sary toxicities and subsequently impact on quality logical complete response (pCR) varies, but lies
of life [8, 26]. However, rectal cancer is a biologi- typically around 20%. In treatment decision mak-
cal tumour, characterized by several biological ing, it would be very helpful to identify good and
features, which are nowadays better and better poor responders in order to give a tailored treat-
understood. Dramatic technical improvements in ment. Until now, the predictive value of several
detection assays have made it possible to charac- biomarkers has been studied. In these studies,
terize more and more biochemical and biological various endpoints have been used, but the most
features and phenotypes related to individual rec- common endpoints are overall survival, tumour
tal cancer patients. Thus, biological markers regression grade (TRG), pCR and downstaging.
might be able to better tailor the treatment of rec- Kuremsky et al. published a review evaluating
tal cancer, thereby minimizing the risk for over- the potential of genetic biomarkers in predicting
and undertreatment with also an improvement in the outcome of locally advanced rectal cancer
outcome and quality of life. However, this needs patients treated with chemoradiation [9]. In their
prospective evaluation and stringent validation. It review, they focused on gene products with more
is clear that there is a biological basis for the dif- than five studies in the literature. The six bio-
ferent responses of individual tumours to certain markers that met this criterion were p53, epider-
treatments, like CRT, RT and CT. The tumour mal growth factor receptor (EGFR), thymidylate
microenvironment, e.g. angiogenesis and hypo- synthase (TYMS), Ki-67, p21 and bax/bcl-2.
xia, repopulation and the intrinsic radiosensitivity The most studied marker is p53, a gene that
are currently the best known biological tumour plays a key role in apoptosis, tumorigenesis and
phenotypes, which undoubtedly have an impor- sensitivity to chemotherapeutic agents. Twenty-
tant impact on the degree of response to anti- one studies studying the predictive value of p53
tumour treatments [11]. status were identified. Seventeen of these stud-
This chapter will focus on the question where ies could not identify a correlation between p53
we are now in the detection and analysis of bio- expression and tumour response. Of the four
chemical and biological factors influencing treat- studies that did show a relationship between
ment decisions and how far we have already p53 and outcome, three identified a p53 muta-
come in our attempts to better individualize treat- tion as a predictor of poor response, whereas the
ment based on biomarkers. other study found a positive predictive value for
Section 5.2 will give an update on the current mutated p53. Therefore, p53 does not seem to
knowledge on biomarkers in treatment deci- be a good predictor for tumour response to
sions for neoadjuvant RT and CRT. Section 5.3 chemoradiation.
will focus on biomarkers for surgical treatment EGFR is important in the regulation of various
decisions, while Sect. 5.4 will discuss the bio- cellular responses, like proliferation, apoptosis
markers known to influence decisions for the and differentiation. Overexpression of EGFR has
adjuvant and systemic treatment of rectal can- been shown in 60–80% of all colorectal cancers
cer. Finally, Sect. 5.5 will provide a conclusion and has been associated with a poor prognosis
and a perspective. independent of lymph node status. Five studies
have been published studying the value of EGFR
expression as response predictor. These were
5.2 Biochemical and Molecular studies looking at chemoradiation only, without
Biological Factors for addition of EGFR inhibitors. Although these
Radiochemotherapy studies looked at different endpoints, the studies
that found a correlation all point towards a better
The combination of chemotherapy and radiother- response to chemoradiation in tumours with low
apy leads to some degree of pathological down- EGFR expression. It seems to be more important
staging in approximately 40–60% of patients. to quantify the level of EGFR expression rather
5 What Biochemical and Molecular Biological Factors Have Greater Relevance to Treatment Decisions? 43
Good-risk group
TYMS
Surgical Resection
*2/*2,*2/*3, RT 45 Gy
*2/*4 FU 225 mg/m2/day
T3/T4
Rectal TYMS genotyping
Cancer RT 45 Gy
FU 225 mg/m2/day
TYMS Cpt-11 50 mg/m2
*3/*3,*3/*4 q wk × 5
Staging
Poor-risk group
(TRUS, CT, MRI) Staging
Biopsy (TRUS, CT, MRI)
Fig. 5.1 Design of a phase II trial stratifying rectal cancer patients in good- and poor-risks according to TYMS status
than divide tumours into positive or negative. One group (TYMS overexpression) (Fig. 5.1) [31].
study identified a single nucleotide polymorphism The good-risk group was treated with standard
that may be useful as a biomarker for response. chemoradiation consisting of radiotherapy and
Thymidylate synthase is an important enzyme continuous 5-FU infusion, while the poor-risk
in DNA synthesis and is the main target of patients received weekly irinotecan in addition to
5-fluorouracil (5-FU). Overexpression of this standard chemoradiation. A pCR and tumour
enzyme leads to 5-FU resistance. Nine studies downstaging was found in 18.9% and 64.4% of
were identified in the Kuremsky review analysing good-risk patients, respectively, and in 35.5%
the influence of TYMS expression and SNPs in and 64.5% of poor-risk patients. However, the
the TYMS enhancer region on tumour response, combination with irinotecan turned out to cause
and very recently, two additional studies have more toxicity. RFS and OS were comparable
been published. Four studies used immunohis- between both risk groups. This study is the first
tochemical staining, and five studies used PCR attempt to stratify the treatment of rectal cancer
for genotyping. Three studies did not show a cor- patients according to TYMS status. Although
relation between TYMS and tumour response. further phase III trials are needed, it was remark-
The remaining six studies found in general a bet- able that the proportion of patients showing
ter response to chemoradiation in tumours with downstaging was comparable between the good-
low TYMS expression. Two studies also included and poor-risk group and the percentage that
a group of patients treated with radiotherapy only, developed a pCR was higher in the poor-risk
and as could be expected in this group, no corre- group.
lation between TYMS expression and response Ki-67 is a proliferation marker which has not
was observed. Only one study found an inverse shown a clear relationship with chemo- or radio-
correlation; however, this was a small study with sensitivity. Thirteen articles have been published
only 19 patients, who received both 5-FU and about the predictive value of Ki-67, of which
oxaliplatin, which could have confounded the only 2 showed a correlation. One study found a
results. Recently, however, two studies found a better response in tumours with high Ki-67 stain-
correlation between high expression of TYMS ing; the other showed an association between low
and better response after CRT for rectal cancer Ki-67 expression and response. Therefore, Ki-67
[10, 17]. Although there is not enough evidence is not a good biological marker in rectal cancer.
to use TYMS in daily practice, incorporation of The tumour suppression gene p21 is activated
TYMS expression measurements in chemoradio- by DNA damage and causes cell cycle arrest. Four
therapy trials would be worthwhile. Recently, the of eight studies found a correlation between p21
results of a phase II study have been published in expression and response to chemoradiation.
which patients were stratified in a good-risk However, the results of these four studies are
group (no TYMS overexpression) and a poor-risk conflicting. Two studies found better responses or
44 G. Lammering and J. Buijsen
survival in patients with low or negative p21 shown to have a predictive role in radiosensitivity
expression, while the other two studies found the of malignant tumours. The first study included 81
opposite. Based on in vitro studies, one would patients with locally advanced rectal cancer
expect better results in tumours with low p21 treated with chemoradiation. Of the patients with
expression because p21 suppresses apoptosis in an AG phenotype, 47% showed a major response,
case of DNA damage. The two studies which as compared to 22% in the AA and GG pheno-
showed better results in positive p21 tumours used type group. The second study analysed 93 patients
other treatments in addition to radiotherapy and treated with chemoradiation for rectal cancer.
5-FU which may have confounded the results. Genotyping was done on peripheral blood mono-
The bax and Bcl-2 proteins are involved in cytes. They found a better response in G/G carri-
apoptosis. Loss of bax function is correlated with ers as compared with G/A carriers (OR 4.180;
chemoresistance in colorectal cancer, and Bcl-2 p = 0.003). In the third study, DNA from mono-
overexpression has been linked with resistance to cytes of 128 rectal cancer patients was analysed.
different chemotherapeutic agents and inhibition In this study, no statistical significant association
of radiation-induced apoptosis. Three studies with tumour response was found. In conclusion,
evaluated the role of bax expression in response results of XRCC1 as a predictor of response in
to chemoradiation. Only one study found a rectal cancer are conflicting.
significant correlation. In that study, the percent- Another protein that attracted interest in the
age of bax-positive tumours was significantly past years is survivin, an inhibitor of apoptosis
higher in the complete-response group than in the [7, 16, 25]. Again, results are conflicting. Two
partial-response group (54% vs. 29%). Bcl-2 was recent studies reported a correlation between sur-
analysed in 12 studies, but a correlation with vivin expression and tumour response. Higher
response was found in only one study including survivin expression correlated with worse
only 17 patients. response to chemoradiation. One of these studies
Two rather small studies have tested the value compared survivin expression in pretreatment
of microarray in prediction of response. The first biopsies and surgical resection specimens and
study tested 54 genes in 23 patients. A different found a worse survival in patients with tumours
expression pattern was found between respond- expressing high levels of survivin after chemora-
ers and non-responders based on downstaging, diation. However, other studies could not find a
but this difference was no longer significant if correlation between survivin expression and clin-
response evaluation was based on TRG. The neg- ical outcome, which underlines the need for fur-
ative predictive value (NPV) was 86%, and the ther studies.
positive predictive value (PPV), 78%. The second
study included 43 patients and found 42 genes that
were differentially expressed between respond- 5.3 Biochemical and Molecular
ers and non-responders based on TRG. The PPV Biological Factors
using this gene set was 71% and the NPV 86%. for Surgical Decisions
Although these studies show for the first time
that gene expression profiles may be helpful in The surgical treatment strategy for rectal cancer
response prediction, they certainly need further has dramatically changed over the last years.
validation with larger patient groups. Coming from a standard radical surgical proce-
Quite recently, X-ray repair cross-comple- dure performed in strictly defined TME protocols
menting 1 (XRCC1) has been identified in three with only radicality being the primary goal, it
studies as a potential useful marker for response nowadays changes to a more tailored approach
prediction in rectal cancer [4, 10, 17]. XRCC1 with also the aim to reduce toxicity with better
plays an important role in DNA repair as it is quality of life. The surgical treatment usually
involved in the base excision repair (BER) path- takes place initially after diagnosis in early stage
way. One polymorphism, A399G, has been cancer or after a neoadjuvant treatment consisting
5 What Biochemical and Molecular Biological Factors Have Greater Relevance to Treatment Decisions? 45
of either radiotherapy alone (5 × 5 Gy) or RCT. In higher in earlier stages [23]. This however has
case of a neoadjuvant treatment, a short-course not been validated yet and warrants further evalu-
radiotherapy will usually be followed within ation. Generally, the only molecular markers
1–3 days by an immediate surgical resection of being currently prognostically relevant in rectal
the TME, as has been published by the DUTCH cancer are the deficient mismatch repair and pos-
TME trial [6]. Thus, the short-course radiother- sibly the KRAS mutation and the BRAF muta-
apy does not induce any downsizing or down- tions. All else, like expression assays, copy
staging, since the timing of the followed surgical number variation tests and even proteomics is
replacement of the rectum tumour does not allow experimental and have not shown any validated
any tumour shrinkage [15]. However, newer trials correlation with prognosis yet. The recently
have suggested that the short-course preoperative published analysis of the QUASAR study, which
radiotherapy indeed could be used to also down- mainly analysed stage II cases, showed MMR,
size and downstage the tumour, if the surgical KRAS or BRAF abnormalities in rectal cancer in
treatment is postponed by at least 6–8 weeks after 1–4%, 30–35% and 2–3%, respectively [5]. All
radiotherapy [19, 22]. This strategy might three abnormalities had prognostic impact at dif-
increase the potential for better sphincter- and ferent levels, with MMR being the strongest
even organ-sparing surgical treatment techniques, marker for prognostic impact. The defective
etc., as has been already proposed after neoadju- MMR genes were hMLH-1, hMSH-2 PMS-2 and
vant chemoradiotherapy in selected patients [14]. hMSH-6, detected by either immunohistochem-
However, accurate tumour response assessment istry or microsatellite testing. However, up until
is crucial in these modern adaptive surgical strat- now, no biomarkers have reached the level of
egies after neoadjuvant radio- or radiochemo- clinical relevance which would allow inclusion in
therapy. Biomarkers could help in the treatment surgical decision making. Recently, the first
decisions for less aggressive conservative surgi- cohort analysis of 20 patients selected for a non-
cal treatments, beside modern imaging and clini- surgical wait-and-see strategy after RCT has been
cal examinations. This applies not only for published with very promising local and distant
preoperatively pretreated rectal cancer patients controls [14]. The decision making for such a
but also for initially diagnosed patients, in which non-surgical approach in patients with good to
early stage disease is suggested. These patients complete clinical response after RCT, which is
could benefit from conservative surgery (e.g. currently only based on clinical and imaging
TEM) instead of radical surgery, if accurate bio- parameters due to the lack of sufficient biomark-
markers associated with disease progression, par- ers, should be stepwise improved with also bio-
ticularly mesorectal nodal metastasis, would chemical and molecular markers, as soon as they
become available. have been approved and validated.
One recently published study compared pat-
terns of gene-specific hypermethylations in radi-
cally excised rectal cancers with histopathological 5.4 Biochemical and Molecular
stage and came to the conclusion that locus- Biological Factors for Adjuvant
specific hypermethylation was more prevalent in and Systemic Therapy
early- than late-stage disease and that the hyper-
methylation of two or more of a panel of five The value of adjuvant chemotherapy in node-pos-
tumour suppressor genes was associated with itive colon cancer is clear. Since rectal tumours
localized disease [13]. Another study by Rasheed originate in an organ that is in anatomic continuity
et al. assessed the microvessel density (MVD) with the colon and tumours show a similar histol-
and the CA9 expression in more than 100 rectal ogy, it is often argued that results of adjuvant trials
cancer specimen and came to the conclusion that in colon cancer can be translated to rectal can-
the MVD was higher in more advanced T and N cers. However, until now, randomized trials in
stages, whereas the CA9 expression was generally rectal cancer have failed to show a clear benefit of
46 G. Lammering and J. Buijsen
adjuvant chemotherapy [3]. Especially in patients confirmed for metastatic colorectal cancer in a
who have a good response after preoperative recent meta-analysis [1].
chemoradiation, the expected gain of adjuvant
treatment is small. Recently, data of five large rec- Conclusion and Perspective of Biomarkers for
tal cancer trials including chemoradiation have Treatment Decisions
been pooled to build nomograms for the prediction Biochemical and molecular biological factors
of local and distal recurrence as well as survival. could help in treatment decision making along
This analysis confirms that in patients showing a the different treatment steps in the treatment of
good response after chemoradiation, the added rectal cancer. This would allow more tailored
benefit of adjuvant chemotherapy is small [32]. treatment approaches, thereby improving qual-
Biomarkers could be helpful to identify ity of life with even the benefit of more effec-
patients who are at higher risk for recurrent dis- tive treatments. When analysing the current
ease. When looking at the value of biomarkers, it value of these biomarkers in treatment decision
is important to distinguish prognostic from pre- making, it is important to identify markers as
dictive factors. A prognostic factor gives infor- being prognostic or predictive or even both. In
mation about the risk of recurrence of disease rectal cancer, the only markers reaching clini-
irrespective of a certain treatment, while a predic- cal relevance in prognosis so far are deficient
tive factor predicts the chance that a patient will MMR, KRAS and BRAF; however, its fre-
benefit from a treatment. Of course, a marker can quency in rectal cancer is rather low with only
be both prognostic and predictive. 1–4% deficient MMR, 30–35% KRAS muta-
In colorectal cancer, most evidence is available tion and 2–3% BRAF mutation (QUASAR).
for the prognostic value of mismatch repair (MMR) The defective MMR genes hMLH-1, hMSH-2,
gene status. Tumours that are MMR deficient have PMS-2 and hMSH-6, detected by immunohis-
a better prognosis. There is some debate whether tochemistry or by microsatellite testing,
MMR status also has a predictive value. However, showed a prognostic value in a meta-analysis
the proportion of rectal tumours that is MMR [20], in the PETACC trial [24], the QUASAR
deficient is small (around 1%). Therefore, it is not and numerous single-centre studies, which
a useful marker for rectal cancer. might lead to MMR-related treatment deci-
The role of BRAF status seems to have a pre- sions in the near future. KRAS status has also
dictive value, but the debate is going on about a been shown to be of prognostic value. KRAS
possible predictive role. Because the proportion of mutation tumour has a worse prognosis and a
rectal tumours carrying a BRAF mutation is very higher chance of recurrence. For EGFR-
low, BRAF does not seem to be a very important inhibitor therapy, the KRAS status even reaches
biomarker in rectal cancer. a predictive value.
KRAS status also has been shown to be of prog- With regard to prediction, six genetic bio-
nostic value. In about 40% of all rectal tumours, markers were identified with the potential of
KRAS is mutated. KRAS mutant tumours have a being predictive in the outcome of locally
poor prognosis and a higher chance of recurrence. advanced rectal cancer after CRT. These were
In the QUASAR trial, this difference was even p53, EGFR, TYMS, Ki-67, p21 and bax-bcl-2.
more pronounced for tumours located in the rec- While EGFR expression levels seem to pro-
tum as compared to tumours in other parts of the vide some prediction to CRT response, p53
colon. In this trial, the reduced risk of recurrence does not seem to serve as a good predictor, nei-
with chemotherapy was comparable between ther does Ki-67 or p21 nor bax and Bcl-2.
KRAS wild-type and KRAS-mutated tumours. TYMS expression measurements are worth-
Other studies also found that KRAS has a prognos- while to further study in future trials, while
tic but not predictive value [30]. However, for the survivin showed mostly conflicting results and
prediction of response to EGFR inhibitors, KRAS gene expression profiles with microarrays need
status has a predictive value. This has been further validation with larger patient groups.
5 What Biochemical and Molecular Biological Factors Have Greater Relevance to Treatment Decisions? 47
Taken together, the current value of bio- 10. Lamas MJ, Duran G, Gomez A et al (2012) X-ray
chemical and molecular biological factors in cross-complementing group 1 and thymidylate syn-
thase polymorphisms might predict response to
treatment decision making is rather low, how- chemoradiotherapy in rectal cancer patients. Int J
ever, with many promising developments in Radiat Oncol Biol Phys. Jan 1;82(1):138–144
the pipeline. Especially whole genome DNA 11. Lammering G (2005) Molecular predictor and prom-
or RNA analysis with copy number variation, ising target: will EGFR now become a star in radio-
therapy? Radiother Oncol 74:89–91
multiple mutation testing, full sequencing and 12. Lange MM, Maas CP, Marijnen CA et al (2008)
the association of genotype with phenotype, Urinary dysfunction after rectal cancer treatment is
will ultimately lead to more biomarker-based mainly caused by surgery. Br J Surg 95:1020–1028
treatment decisions in rectal cancer. However, 13. Leong KJ, Wei W, Tannahill LA et al (2011)
Methylation profiling of rectal cancer identifies novel
successful biomarker development needs col- markers of early-stage disease. Br J Surg 98:724–734
laboration, external validation and meta-analy- 14. Maas M, Beets-Tan RG, Lambregts DM et al (2011)
ses to reach the level of accuracy necessary to Wait-and-see policy for clinical complete responders
base treatment decisions on these markers. after chemoradiation for rectal cancer. J Clin Oncol.
Dec 10;29(35):4633–4640
15. Marijnen CA, Nagtegaal ID, Klein Kranenbarg E et al
(2001) No downstaging after short-term preoperative
radiotherapy in rectal cancer patients. J Clin Oncol
19:1976–1984
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Do Different Populations of Rectal
Cancer Exist? 6
Vincenzo Valentini, Francesco Cellini,
Maria Cristina Barba, and Ruud van Stiphout
mobile lesion was 59% (95% CI 49–70%), for that of each evidence, understanding not only its
with partially fixed it was 33% (95% CI 21–54%), specific strength but also how the main evidences
and for the fixed tumour presentations was 9% mutually correlate. A detailed analysis is reported
(95% CI 4–20%). Even if tumour spread through in the chapter dealing with this issue [7].
rectal wall is prognostically significant for sur-
vival, each of the tumour presentation reported
subset (i.e., mobile, partially fixed and fixed) 6.2 Is It Possible to Obtain an
showed a rate of long-surviving patients (varying Adequate Characterization
according to the extension of the tumour): for the of Tumour Heterogeneity,
locally advanced lesions, up to 33% were cured by Based on Clinical Observation?
only intermediate dose of radiotherapy. This
behaviour highlights a different sensibility to the On the basis of the data reported by a recent study
same treatments that is irrespective of the macro- on pooled data from five large European random-
scopic initial presentation and based on intrinsic ized trials about the clinical behaviour of the differ-
tumour heterogeneity, supporting the concept that ent populations in locally advanced rectal cancer,
biological tumour heterogeneity leads to different the four subgroups [8] identified are as follows:
clinical patterns of responses and tumour progres- • Very good (15–20%): curable patients, highly
sion. As Mohiuddin et al. highlighted, indeed rec- sensible to radiation, in whom organ preserva-
tal cancer represents a broad spectrum of diseases tion is to be pursued
requiring tailored treatment regimens to maximize • Good (40–50%): curable patients, who require
the outcome [5]. It aims to use the most aggressive good local treatment and could have some
therapies only for the high-risk-featured presenta- benefit by adjuvant chemotherapy
tions, avoiding the less biologically aggressive • Bad (10%): patients with late recurrent dis-
tumours from the more intense treatment sched- ease, who require radical treatment when
ules. To tailor treatments, there are some questions tumour recurs
which have to be considered in the multidisci- • Ugly (15–20%): patients with early metasta-
plinary management of rectal cancer. ses onset, whom ongoing chemotherapy has
still not been able to cure
The analysis of overall risk ratio between DM
6.1 Is It Possible to Obtain an rate and LR rate (Fig. 6.1) reveals that at the start
Adequate Characterization
of Tumour Heterogeneity, 6
Based on Biological Evidences?
5.5
There is nowadays a great expectation about the
5
likelihood to determine tumour heterogeneity bas-
DM rate/LR rate [−]
LR [% of total LR]
20
10
0
1 2 3 4 5 6 7 8 9 10
40
DM [% of total DM]
30
20
10
0
1 2 3 4 5 6 7 8 9 10
40
30
Death [% of total]
20
10
0
1 2 3 4 5 6 7 8 9 10
Time of follow-up [years]
of follow-up, there are six times more metastases Early recurrent patients (ugly), which are
than local recurrences. This number decreases to affected by highly aggressive tumour. This group
around 2.5 in the first 2 years and remains con- affects 15–20% of locally advanced tumour pre-
stant afterwards. Figure 6.2 shows that around sentations. They do not seem to get benefit from
80% of the recurrences occur within the first the current treatment intensification and chal-
4 years, while the occurrence of death is more lenge clinicians for better strategies.
frequent from the second to the fourth year Late recurrent patients (bad) probably with
consequently. slightly better pattern of features respect the pre-
Overall, in recurrent patients, two typologies vious one and late onset as for a slow growth, but
of behaviour are identified: that can occur early although aggressive on itself. This presentation
for the most aggressive or late for the less occurs in at least 10–15% of patients, and it
aggressive but still bad prognosis associated benefits from aggressive approach by integrated
tumours. treatment to optimize the curative chance.
52 V. Valentini et al.
On the other hand, two typologies of behav- antigen (PSA) as a surrogate endpoint for sur-
iour are both characterized by chance of cure: the vival in prostate cancer. In colon cancer, 2–3 years
good are patients for whom the cure is achievable of disease-free survival (DFS) correlated better
by the use of the fully integrated treatment, as with 6-year overall survival after adjuvant che-
neoadjuvant chemoradiation or radiation alone motherapy in an analysis of a large pooled data-
followed by surgery ± adjuvant chemotherapy. base from randomized trials [9].
They represent 40–50% of locally advanced rec- For rectal cancer, pathologic complete response
tal cancer patients. (pCR) was argued to identify this more favour-
Finally, there is a group of patients in locally ably in population with less local recurrences
advanced presentations undergoing to the inte- (LR) and distant metastases (DM) and better
grated schedule that shows a high response to overall survival (OS) [10, 11]. Anyway, no ran-
neoadjuvant therapy (the best), suggesting that domized studies showed a significant benefit for
are potentially curable also avoiding surgery. survival for increasing pCR rates [12], which
The random distribution of these four groups questions the role of promoting pCR in preopera-
of patients in the different series could justify the tive approaches.
missing of evidences of clinical benefit for the In a recent analysis of a pooled database of
treatment strategies when they are addressed to five randomized trials, the comparison between
one of them, namely, but applied to the whole the pCR and non-pCR population with respect to
cohort of patients; all single trials of neoadjuvant long-term outcome, all KM curves differed
chemoradiotherapy followed by surgery failed to significantly (Fig. 6.3). After 10 years, the pCR
show a 5-year survival benefit because the ugly population had 11% more local control than the
and bad component hid the benefit of this treat- non-pCR population (96% vs. 85%). For DM and
ment modality in the good and the best ones. The OS, these numbers are 18% (82% vs. 64%) and
main problem is how to distinguish them to tailor 16% (73% vs. 57%).
treatment properly. There are evidences that pCR patients have a
better outcome, but this marker does not have an
impact on the outcome of any single randomized
6.3 Is It Possible to Identify These trial, and the relative small benefit in survival
Different Groups Using (16%) support the value of this surrogate end-
Surrogate Endpoints? point in identifying only a group of patients with
favourable outcome, for whom surgery could be
In a time of limited sources, there is a need to avoided, but not in providing a reliable prediction
have fast validation of new hypotheses to improve for the whole cohort of locally advanced rectal
cancer treatment. One way is to have reliable sur- cancer patients and, namely, about the impact of
rogate endpoints, for example, prostate-specific each treatment in the ugly ones.
OS (-)
LC (-)
Fig. 6.3 Outcome rates local control (LC), distant control (DC) and overall survival (OS) for pCR subpopulation
(green) versus the non-pCR population (blue)
6 Do Different Populations of Rectal Cancer Exist? 53
1.0 1.0
0.6 0.6
OS (–)
Non−pCR
0.4 0.4
0.2 0.2
Fig. 6.4 Comparison between the status of pCR and disease free at 2 years for overall survival (OS)
0.6
OS (–)
0.4
pCR+recurrence
0.2
Non−pCR+recurrence
0.0
In the same study, a further analysis compared recurrence + non-pCR is 0.083, which means that
overall survival of the populations of pCR and being disease free after 2 years can be used as a
disease free after 2 years (Fig. 6.4). Disease free surrogate endpoint for pCR, since knowing the
after 2 years is more beneficial than having just a pCR status does not change overall survival
pCR. A recurrence within 2 years results in 13% significantly when knowing the recurrence state
chance of survival within 10 years, while having after 2 years (Fig. 6.5).
no PCR results in 58% chance of survival after Two-year disease-free survival as an endpoint
10 years. The p value between disease-free + may however be useful to predict survival for the
pCR versus disease-free + non-PCR is 0.396, and subpopulations in the group of more aggressive
the p value between recurrence + pCR versus tumours. This endpoint may promote different
54 V. Valentini et al.
chemotherapy regimens to reduce distant metas- in many forms [13]. Interpretation of the model
tases rates for this subpopulation, but could hide results is very much dependent on model
the overtreatment for the best and the good representation. One highly interpretable way
patients when all are treated by the same approach. to represent a prediction model is the nomogram.
Diversifying the options to personalize treatment A nomogram is nothing more than a visual repre-
is essential with the current increasing complex- sentation of mathematical equations involving
ity of clinical decision making. These hypotheses variables, weights and constants. An example for
require finalized analyses based on large database rectal cancer is given in Fig. 6.6. In the example,
with pooled individual patients, namely, from nomogram six variables were found to be predic-
randomized trials, to identify the different patient tive for the outcome local control. Each of these
population by reliable and validate predictive predictors is represented by a scale with possible
models as early as possible along the multiphase values. When using the nomogram to make a pre-
treatment programmes. diction for a single patient, one may fill in each of
the values for the predictors and read out the score
scale on top by drawing a vertical line between the
6.4 What Could Be a Methodology scales. These scores need to be summed and filled
That Provides Good Prediction in on the scale ‘total score.’ Subsequently, this
of Tumour Behaviour Basing final score corresponds to a probability for the
on Surrogate Endpoints? outcome by reading out the bottom scale. Often,
risk groups are defined or calculated based on this
The presented patient and tumour heterogeneity probability, even if the prediction gives a continu-
allows prediction of primary and surrogate end- ous probability score, because in this way patients
points with the aim of individualizing cancer are assigned to a certain subgroup which could be
treatment. Statistical prediction models able to treated less or more aggressive. Trials could be
find multivariate correlations between patient and designed based on these developed prediction
tumour characteristics and outcome are available models to encourage treatment individualization.
Single score
−2 −1 0 1 2
pT-stage
0 1 2 3 4
pN-stage
0 1 2
Concomitant chemo
Yes No
Adjuvant chemo
Yes No
Radiotherapy dose [Gy]
>45 45 <45
Tumor location
High Mid Low
Total score
−3 −2 −1 0 1 2 3 4 5
Low Medium High
Probability of LR [−]
0.05 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 0.95
Fig. 6.6 Example of a nomogram for locally advanced rectal cancer; prediction of local recurrence (LR) probability
based on clinicopathological data. Three risk groups were defined based on the outcome probabilities
6 Do Different Populations of Rectal Cancer Exist? 55
High prediction accuracy is however a necessity predicts disease-free survival in patients with locally
which can only be achieved with high-quality, advanced rectal cancer receiving neoadjuvant chemo-
radiotherapy. BMC Cancer 11:363
unbiased data from different origins. 7. Lammering G, Buijsen J (2012) What biochemical
and molecular biological factors have greater rele-
Conclusions vance to treatment decisions? In: Multidisciplinary
It is a priority to take in the right account that management of rectal cancer – questions and
answers
a strong component of heterogeneity exists in 8. Valentini V, van Stiphout R, Lammering G et al
rectal cancers: that implies the needing to per- 2-Year Disease Free vs Pathological Complete
sonalize treatments. The correct use of surro- Response as a Surrogate Endpoint by using Pooled
gated endpoints and nomograms can aid to Data of Randomized Trials for Locally Advanced
Rectal Cancer. In Press
tailor the treatments. 9. Sargent D, Shi Q, Yothers G (2011) Two or three year
disease-free survival (DFS) as a primary end-point in
stage III adjuvant colon cancer trials with fluoropy-
rimidines with or without oxaliplatin or irinotecan:
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1. Parkin DM (2001) Global cancer statistics in the year 10. Valentini V, Coco C, Picciocchi A (2002) Does down-
2000. Lancet Oncol 2(9):533–543 staging predict improved outcome after preoperative
2. National Cancer Institute: PDQ® Rectal Cancer chemoradiation for extraperitoneal locally advanced
Treatment. Bethesda, MD: National Cancer Institute. rectal cancer? A long-term analysis of 165 patients.
(2011) http://cancer.gov/cancertopics/pdq/treatment/ Int J Radiat Oncol Biol Phys 53(3):664–674
rectal/HealthProfessional 11. Capirci C, Valentini V, Cionini L (2008) Prognostic
3. Valentini V, van Stiphout RG, Lammering G, value of pathologic complete response after neoadju-
Gambacorta MA, Barba MC et al (2011) Nomograms vant therapy in locally advanced rectal cancer: long-
for predicting local recurrence, distant metastases, term analysis of 566 ypCR patients. Int J Radiat Oncol
and overall survival for patients with locally advanced Biol Phys 72(1):99–107, Epub 2008 Apr 11
rectal cancer on the basis of European randomized 12. Sebag-Montefiore D, Bujko K, Valentini V (2009)
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4. Wang Y, Cummings B, Catton P et al (2005) Primary dences and future landscape. Radiother Oncol
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cinoma: long term outcome of 271 patients. Radiother 13. van Stiphout R, Roelofs E, Dekker A (2012) How to
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Expression of transketolase like gene 1 (TKTL1)
Part III
Q&As on Imaging
How Can We Identify Tumour
Penetration? 7
Manish Chand and Gina Brown
involvement and the importance of tumour spread wall and surrounding mesorectum, and this has
in millimetres beyond the muscularis propria – significant bearing on treatment decisions. The
extramural spread. It has been further noted in only preoperative modality that has been shown
several histopathology studies. As a result, to measure depth of tumour spread with precision
Hermanek proposed a modification of the TNM is high-resolution MRI (Table 7.1).
classification to take into account the survival Accurate preoperative identification of tumour
variation amongst patients with T3 tumours depth is required for:
according to depth of extramural spread. 1. Successful TME surgery
The single-most important factor which has 2. Patient selection for neoadjuvant CRT
led to reduction in local recurrence rates is the 3. Limiting overtreatment of patients with CRT
acceptance of total mesorectal excision (TME) The importance of accurate identification of
as the ‘gold-standard’ surgical technique for T-stage relates to its treatment implications and
rectal cancer surgery. Sharp, precision dissec- prognosis. In essence, tumours which are confined
tion along the mesorectal fascia ensures that to the bowel wall, that is, T1 and T2 tumours, are
the tumour and all local draining lymph nodes referred for immediate surgery and do not need
are excised in a single package. Knowledge of preoperative chemoradiotherapy. In comparison,
the relationship between the tumour edge and tumours which penetrate beyond the bowel wall
the mesorectal fascia is essential to facilitate a into the surrounding mesorectum and beyond,
successful dissection and give a tumour-free e.g. T3 and T4 tumours, are considered for pre-
resection margin. operative chemoradiotherapy to improve overall
As imaging modalities have improved, prog- outcomes. Furthermore, distinguishing early
nostic risk factors in rectal cancer can be demon- T-stage tumours has implications in the type of
strated with much greater accuracy. Tumour surgery. For example, T1 lesions may be suitable
depth or T-stage is one such factor; however, for a less traumatic local excision such as an
there is no single optimal staging classification endoscopic mucosal resection rather than ante-
which can be applied to the entire spectrum of rior resection and total mesorectal excision.
T-stage. Tumour spread can be measured to Clearly, accurate T-staging is essential so not to
within millimetres beyond the layers of the bowel over- or undertreat patients.
7 How Can We Identify Tumour Penetration? 61
fascia. The circumferential resection margin is early T3 tumours may not actually be as clini-
defined by the relationship between the tumour cally relevant as first thought.
edge and the mesorectal fascia. It is known to be an
independent risk factor for local recurrence. In
those patients where the CRM is threatened, neo- 7.4 Extent of Mesorectal Spread
adjuvant aims to downsize the tumour to obtain
tumour-free resection margins following TME sur- The mesorectum is the lymphovascular enve-
gery. Accurate identification and definition of the lope which surrounds the rectum to varying
mesorectal fascia is therefore mandatory in plan- degrees. It completely surrounds the middle
ning optimal treatment. third of the rectum but is virtually absent in the
Brown et al. first demonstrated the accuracy lower third and only covers the posterior aspect
of high-resolution MRI in preoperative predic- of the upper third of the rectum. The extent to
tion of rectal cancer stage [3]. In their study of which tumour penetrates the mesorectal fat is an
28 patients, they not only correlated tumour independent risk factor for recurrence. This is
stage on MRI with histological analysis but not adequately represented in the traditional
showed that MRI can accurately identify extent staging classifications as the level of penetra-
of extramural spread. One of the difficulties in tion into the mesorectum has prognostic
predicting tumour stage on MRI is distinguish- implications.
ing between T2 and T3 tumours. The patho- As described above, total mesorectal exci-
logical difference between T2 and T3 tumours sion (TME) involves excision of the rectum
is invasion of the mesorectal fat. Defining the along with the mesorectum. T3 tumours are
MR characteristics for T3 tumours is therefore those which have traversed the bowel wall and
important so to avoid over-staging. The pres- penetrated into the mesorectum. The majority
ence of spiculation within the extramural fat of patients present with T3 tumours; however,
can lead to misinterpretation and over-staging there is wide variety in survival rates of these
of tumours. Both the tumour itself and the patients. Jass and colleagues were the first to
effects of radiotherapy can produce a host des- describe the importance of the extent of
moplastic reaction resulting in fibrosis. This mesorectal invasion on prognosis [5]. Further
fibrotic reaction can cause spiculation into the work by Cawthorn and Merkel demonstrated an
mesorectal fat and should not be confused with improvement in 5-year survival in patients who
tumour. Through careful correlation with his- had ‘slight’ mesorectal invasion. Cawthorn
topathology whole-mount sections, Brown described ‘slight’ mesorectal invasion as 4 mm
et al. defined T3 tumours by the presence of or less and found 5-year survival to be 55%
tumour signal intensity permeating into the compared to 25% when more than 4 mm [6].
mesorectal fat with a ‘broad-based’ or nodular Another study by Merkel et al. studied patient’s
configuration and in continuity with the intra- survival characteristics with T3 tumours. Those
mural portion of the tumour. Such features patients with extramural spread of more than
could only be appreciated on small field of 5 mm had 5-year survival rate of 54% compared
view high-resolution imaging (3-mm slices, with 85% for those patients whose tumours had
16 cm field of view). Further study of prognos- extramural spread of less than 5 mm [7]. These
tic factors using high-resolution MRI by Brown results were independent of lymph node involve-
and colleagues demonstrated 94% concordance ment. These early studies highlight the impor-
between MRI and histology in terms of T-stage tance of accurate measurement of tumour
in addition to 92% agreement in prediction of penetration into the mesorectum and those
the CRM [4]. tumours with a worse prognosis, namely, T3c
Figure 7.2 shows the difference between and T3d. Therefore, the distinction between T2
fibrotic T2 lesions and actual T3 lesions. However, and T3 tumours with less than 5-mm mesorectal
as we shall see, distinguishing T2 cancers, which spread – T3a and T3b – becomes irrelevant as
would normally not need preoperative CRT, and these patients will have minimal benefit from
7 How Can We Identify Tumour Penetration? 63
Fig. 7.2 (a) This shows the baseline MRI axial image red arrow indicates an example of fibrosis which may be
before chemoradiotherapy and the same patient following mistaken for tumour thus overstaging. (b) MRI axial
chemoradiotherapy. The low signal represents the fibrosis image of a T3 tumour
that has taken place but the actual tumour remains T2. The
circumferential margins. Tumour cells identified at to the mesorectal fascia. Stratifying T3 tumours
the circumferential resection margin is known to con- through the sub-classification described above is
fer poor prognosis in terms of local recurrence and important when deciding preoperative oncological
overall survival. This is related to the depth of inva- therapy. However, identification of those patients in
sion into the mesorectum and proximity of the tumour whom the CRM would be involved is equally impor-
tant in surgical planning. These patients with threat-
ened CRM have been shown to benefit from
Table 7.2 T3 sub-classification
neoadjuvant chemoradiotherapy to downstage the
T-stage Depth of extramural spread tumour and thus allowing for a clear resection
T3a <1.00 mm margin.
T3b 1.01–5.00 mm MRI has been the most useful imaging modal-
T3c 5.01–15.00 mm
ity in identifying the mesorectal fascia. Early
T3d >15.00 mm
studies correlating MRI’s accuracy in identifying
a b
c d
the mesorectal fascia and a subsequent negative nodal status and is independent of known vari-
CRM on histology have led to patients in whom ables such as type of surgery and height of
tumour extends to within 5 mm of the mesorectal tumour. Conversely, patients with more extensive
fascia to be given preoperative CRT [8]. Although tumour spread of 5 mm or more beyond the mus-
detailed staging is important to identify patients cularis propria are at increased risk of local recur-
who would most benefit from preoperative onco- rence and distant failure, and therefore,
logical therapy, it is also important not to offer preoperative identification of such patients will
patients CRT where there is no proven benefit. lead to appropriate intensification of preoperative
The MERCURY Study Group showed that it is therapy aimed at reducing such risks.
possible to predict negative CRM histologically
using a 1 mm cut-off on MRI. Further analysis
using different cut-offs (1, 2 and 5 mm) did not References
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recurrence and may be able to be identified on nostic factors in rectal cancer using high-resolution
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7.6 Summary and involvement of lateral resection margin as prog-
nostic factors after surgery for rectal cancer. Lancet
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the extramural depth of spread and assessment of 7. Merkel S et al (2001) The prognostic inhomogeneity in
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tumour to the potential CRM enables the selec-
298–304
tion of good prognosis rectal cancer patients. In 8. Beets-Tan RG et al (2001) Accuracy of magnetic reso-
clinical practice, this can account for at least one- nance imaging in prediction of tumour-free resection
third of the patients with rectal cancer. With opti- margin in rectal cancer surgery. Lancet 357(9255):
497–504
mal preoperative selection and good quality TME
9. Taylor FG et al (2011) One millimetre is the safe cut-off
surgery, local recurrence rates of 1.7% are achiev- for magnetic resonance imaging prediction of surgical
able in MRI-defined T3a/b. This is regardless of margin status in rectal cancer. Br J Surg 98(6):872–879
How Can We Identify Mesorectal
Fascia Involvement? 8
Regina G.H. Beets-Tan
Contents
8.1 Introduction ..................................................... 67 8.1 Introduction
8.2 What Is the Mesorectal Fascia? ..................... 67
The circumferential resection margin (CRM) is
8.3 Why Do We Need to Evaluate the lateral or radial resection margin created by the
Involvement of the Mesorectal Fascia
surgeon at the total mesorectal excision. A positive
Preoperatively?................................................ 68
CRM is defined as a closest distance of 1 mm or
8.4 Can EUS Visualize the Mesorectal less between tumor and resection margin, as this
Fascia and Its Involvement? ........................... 68
represents the optimal prognostic cutoff point. The
8.5 How Accurately Can CT Identify importance as a prognostic factor and as a param-
Advanced Tumors, Threatening
or Invading the Mesorectal Fascia? ............... 68
eter of surgical quality has been recognized and
confirmed in the past 20 years [1]. Because the
8.6 Is MRI an Accurate Imaging Method to ideal plane of resection in a total mesorectal exci-
Visualize the Mesorectal Fascia and Its
Involvement?.................................................... 69 sion is just outside the mesorectal fascia, a relevant
question in rectal cancer surgery which is addressed
8.7 Can a Restaging MRI After
Preoperative Chemoradiotherapy
in this chapter is “How can we identify mesorectal
Help in Identifying Tumor Regression fascia involvement?”
from the Mesorectal Fascia? .......................... 69
References ................................................................. 71
8.2 What Is the Mesorectal Fascia?
Fig. 8.1 (a, b) Axial CT and T2 weighted MRI of a patient while on the corresponding MRI the tumor is not adjacent
with rectal cancer. On CT a low rectal tumor mass is visual- to the mesorectal fascia but can be delineated at short dis-
ized invading the anterior mesorectal fascia (white arrows) tance from the anterior mesorectal margin (black arrows)
Fig. 8.2 (a, b) Axial and coronal T2 weighted MRI of a patient with rectal cancer. The mesorectal fascia (black arrows)
can be clearly delineated, enveloping the mesorectum
Fig. 8.3 (a) Axial T2 weighted MRI of a patient with 6 weeks after completion of chemoradiotherapy. The tumor
locally advanced rectal cancer, before chemoradiotherapy. (asterisk) has been downsized and has turned fibrotic but the
The tumor (asterisk) is invading the mesorectal fascia ante- fibrosis is still invading the anterior mesorectal fascia (white
riorly (black arrows). Note a suspected node close to the arrow). In this patient one must be reluctant to predict a free
mesorectal fascia (black arrowhead). (b) Axial T2 weighted anterior margin, because the fibrosis may still contain tumor
MRI of the same patient with locally advanced rectal cancer, and the mesorectal fascia may still be involved
8 How Can We Identify Mesorectal Fascia Involvement? 71
reliably identify those tumors that have regressed 5. Taylor A, Slater A, Mapstone N et al (2007) Staging
from the mesorectal fascia. False positivity still rectal cancer: MRI compared to MDCT. Abdom
Imaging 32(3):323–327
occurs in around 50%. These false positives occur 6. Vliegen R, Dresen R, Beets G et al (2008) The accu-
in tumors that show fibrosis after chemoradiation racy of multi-detector row CT for the assessment of
and where the fibrosis has not retracted from the tumor invasion of the mesorectal fascia in primary
mesorectal fascia. In 50%, the fibrosis may still rectal cancer. Abdom Imaging 33(5):604–610
7. Maizlin ZV, Brown JA, So G, Brown C, Phang TP,
contain tumor (Fig. 8.3b). In order not to under- Walker ML, Kirby JM, Vora P, Tiwari P (2010) Can
treat, it is better to err on the safe side and overes- CT replace MRI in preoperative assessment of the cir-
timate an involved margin. cumferential resection margin in rectal cancer? Dis
Colon Rectum 53(3):308–314
8. Beets-Tan RG, Beets GL, Vliegen RF et al (2001)
Conclusion Accuracy of magnetic resonance imaging in predic-
Rectal cancer involvement of the mesorectal tion of tumour-free resection margin in rectal cancer
fascia can be well anticipated by imaging. MRI surgery. Lancet 357(9255):497–504
is the most reliable technique in all rectal can- 9. Blomqvist L, Machado M, Rubio C et al (2000) Rectal
tumour staging: MR imaging using pelvic phased-
cers, while modern multidetector CT could be array and endorectal coils vs endoscopic ultrasonog-
an alternative mainly in mid and high rectal raphy. Eur Radiol 10(4):653–660
tumors. In low tumors, CT cannot replace MRI. 10. Peschaud F, Cuenod CA, Benoist S et al (2005)
Therefore, MRI remains the preferred (re-) Accuracy of magnetic resonance imaging in rectal
cancer depends on location of the tumor. Dis Colon
staging method in rectal cancer. Although EUS Rectum 48(8):1603–1609
is accurate in assessing tumor ingrowth into the 11. Lahaye MJ, Engelen SM, Nelemans PJ et al (2005)
vagina or prostate, it is unable to identify tumor Imaging for predicting the risk factors – the circum-
involvement in the mesorectal fascia. ferential resection margin and nodal disease – of local
recurrence in rectal cancer: a meta-analysis. Semin
Ultrasound CT MR 26(4):259–268
12. MERCURY Study Group (2006) Diagnostic accuracy
of preoperative magnetic resonance imaging in pre-
dicting curative resection of rectal cancer, prospective
References observational study. BMJ 333(7572):779
13. Beets-Tan RG, Lettinga T, Beets GL (2005) Pre-
1. Nagtegaal ID, Quirke P (2008) What is the role for the operative imaging of rectal cancer and its impact on
circumferential margin in the modern treatment of surgical performance and treatment outcome. Eur J
rectal cancer? J Clin Oncol 26(2):303–312 Surg Oncol 31(6):681–688
2. Bissett IP, Fernando CC, Hough DM et al (2001) 14. Burton S, Brown G, Daniels IR et al (2006) MRI
Identification of the fascia propria by magnetic reso- directed multidisciplinary team preoperative treat-
nance imaging and its relevance to preoperative ment strategy: the way to eliminate positive circum-
assessment of rectal cancer. Dis Colon Rectum ferential margins? Br J Cancer 94(3):351–357
44(2):259–265 15. Vliegen RF, Beets GL, Lammering G et al (2008)
3. Peeters KC, Marijnen CA, Nagtegaal ID et al (2007) Mesorectal fascia invasion after neoadjuvant chemo-
The TME trial after a median follow up of 6 years: therapy and radiation therapy for locally advanced
increased local control but no survival benefit in irra- rectal cancer: accuracy of MR imaging for prediction.
diated patients with resectable rectal carcinoma. Ann Radiology 246(2):454–462
Surg 246(5):693–701 16. Kulkarni T, Gollins S, Maw A et al (2008) Magnetic
4. Wolberink SV, Beets-Tan RG, de Haas-Kock DF et al resonance imaging in rectal cancer downstaged
(2009) Multislice CT as a primary screening tool for using neoadjuvant chemoradiation: accuracy of pre-
the prediction of an involved mesorectal fascia and diction of tumour stage and circumferential resec-
distant metastases in primary rectal cancer: a multi- tion margin status. Colorectal Dis 10(5):479–489,
center study. Dis Colon Rectum 52(5):928–934 Epub 2008 Mar 3
How Can We Identify Nodal
Involvement? 9
Regina G.H. Beets-Tan
75% [2]. A comparative meta-analysis of CT, These morphological features are well visu-
EUS, and MRI showed that the receiver operating alized in nodes larger than 6 mm, but a reliable
characteristic (ROC) curves for all three modali- delineation of the nodal feature can be difficult
ties were only moderate [3]. The sensitivity of if not impossible in the smaller nodes. The prac-
EUS, CT, and first-generation MRI for primary tical difficulties in nodal staging with the stan-
nodal staging in rectal cancer varies between 55% dard imaging methods are illustrated by a
and 70% and specificity between 75% and 80%. multicenter report in which T3N0 tumors, staged
with ERUS or MRI, were found to be node posi-
tive at histology in 22%, despite preoperative
9.3 Has Modern Imaging Improved chemoradiation [6].
Its Performance for Detection
of Nodal Metastases?
9.4 Are There New Developments
In the comparative meta-analysis, EUS performed in Imaging Technology That
slightly better than CT or MRI, most likely May Improve Nodal Staging?
because of the use of criteria for nodal metastases
other than size alone: round shape, border irregu- MR techniques and sequences are continuously
larity, and heterogeneous texture. improving, and with modern and more powerful
Recently, modern MRI technology was intro- machines, new sequences, and lymph node–
duced generating very high-resolution images. specific MR contrast agents, the accuracy is likely
Similar morphological criteria as with EUS (shape, to improve. An example of a MR contrast agent
border irregularity, and heterogeneous signal) can proven highly accurate for nodal staging both in
now also be evaluated with MRI and show improved urological and rectal cancer is ultrasmall super-
accuracy over size alone (Fig. 9.1) [4, 5]. paramagnetic particles of iron oxide (USPIO)
[7]. Unfortunately, USPIO is not approved by the
Food and Drug Administration (FDA) and there-
fore not marketed.
A new functional MRI technique, promising
in oncology imaging, is diffusion-weighted MR
imaging. A restricted diffusion of the protons in a
tissue is associated with a tumoral tissue. This
restricted diffusion can be translated into a high
signal on MRI. It can also be quantified as a
coefficient, the apparent diffusion coefficient
(ADC). Visual perception of the MR signal of
nodes cannot discriminate between benign and
malignant nodes, because both show a high sig-
nal. The ADC of malignant nodes is generally
slightly lower than that of benign nodes, but with
an AUC of 0.66, it is very difficult to find the
right cutoff value for malignant nodes [8].
Fig. 9.1 Axial T2-weighted MR image of a rectal cancer Thus, at the time of writing, despite the huge
patient. Two nodes are seen in the mesorectum, large and
variety of new imaging technology, the problem
small. Both nodes show morphological features strongly
indicative for malignant nodes (round, irregular border, of nodal staging in patients with rectal cancer
and heterogenous texture) remains.
9 How Can We Identify Nodal Involvement? 75
9.5 Can Restaging MRI take into account the prevalence of nodal
After Preoperative metastases according to the T-stage. If the
Chemoradiotherapy Identify patient’s MRI only shows small nodes, yet
Patients with Sterilized Nodes these nodes show obvious features strongly
(ypN0)? indicative for malignancy (round, irregular
border, and heterogenous texture), these
For patients treated with neoadjuvant CRT, there patients can be considered N+. In all other
is now a trend toward minimally invasive, organ- circumstances, the nodal status on imaging
saving treatment, when the tumor and nodes have remains uncertain.
responded well to CRT. Organ-saving treatment
is only an option when the true node-negative
patients can be accurately selected.
A restaging MRI, performed 6–8 weeks after References
completion of chemoradiotherapy, has proven
1. Wang C, Zhou Z, Wang Z et al (2005) Patterns of neo-
valuable for evaluation of tumor response and plastic foci and lymph node micrometastasis within the
nodal response. mesorectum. Langenbecks Arch Surg 390(4):312–318
In contrast to primary staging, a restaging 2. Puli SR, Reddy JB, Bechtold ML et al (2009) Accuracy
MRI shows a high NPV of around 95% for the of endoscopic ultrasound to diagnose nodal invasion by
rectal cancers: a meta-analysis and systematic review.
detection of nodal disease. In other words, the Ann Surg Oncol 16(5):1255–1265
ypN0 patients can be identified with post-CRT 3. Lahaye MJ, Engelen SM, Nelemans PJ et al (2005)
MRI [7, 9]. Due to CRT, the number of small Imaging for predicting the risk factors – the circumfer-
nodes decreases and so does the number of inter- ential resection margin and nodal disease – of local
recurrence in rectal cancer: a meta-analysis. Semin
pretation errors. After CRT, the prevalence of Ultrasound CT MR 26(4):259–268
node-positive patients is lower. These may 4. Brown G, Richards CJ, Bourne MW et al (2003)
explain why in a restaging setting size criteria Morphologic predictors of lymph node status in rectal
seem to work. cancer with use of high-spatial-resolution MR imaging
with histopathologic comparison. Radiology 227(2):
371–377
Conclusion and Recommendations 5. Kim JH, Beets GL, Kim MJ et al (2004) High-resolution
So far, clinicians have been reluctant to make MR imaging for nodal staging in rectal cancer: are
decisions based on the nodal staging by there any criteria in addition to the size? Eur J Radiol
52(1):78–83
imaging because of its insufficient accuracy. 6. Guillem JG, Diaz-Gonzalez JA, Minsky BD et al
A reliable preoperative staging of nodes (2008) cT3N0 rectal cancer: potential overtreatment
could however benefit patients with rectal with preoperative chemoradiotherapy is warranted. J
cancer. Clin Oncol 26(3):368–373
7. Lahaye MJ, Beets GL, Engelen SM et al (2009)
The most practical strategy to work with in Locally advanced rectal cancer: MR imaging for
daily practice is the following, while always restaging after neoadjuvant radiation therapy with con-
keeping in mind the limitations of imaging: comitant chemotherapy. Part II. What are the criteria
If on rectal cancer MRI, no nodes are visi- to predict involved lymph nodes? Radiology 252(1):
81–91
ble, the patient is considered N0. 8. Lambregts DM, Maas M, Riedl RG et al (2011) Value
Patients with nodes ³8 mm that show two of ADC measurements for nodal staging after chemo-
or more of the morphological features (round, radiation in locally advanced rectal cancer-a per lesion
irregular border, and heterogenous texture) are validation study. Eur Radiol 21(2):265–273
9. Barbaro B, Fiorucci C, Tebala C et al (2009) Locally
considered N+. advanced rectal cancer: MR imaging in prediction of
For patients who have nodes £7 mm, the response after preoperative chemotherapy and radia-
nodal status is less certain and one should tion therapy. Radiology 250(3):730–739
How Can We Identify Pathologic
Complete Responders After 10
Radiochemotherapy?
a b
c d
Fig. 10.1 Rectal cancer in a pCR 59-year-old woman. tion after CRT. The lesion volumes were displayed
(a, b) HR oblique T2-weighted images of tumor before automatically in three-dimensional format and were cal-
(a) and at the end (b) of treatment show the tumor contour culated by summing each of the cross-sectional volumes
by manual tracing with a cursor. (c) Pre- and (d) posttreat- (multiplying cross-sectional area by section thickness) for
ment 3D reconstructions define 90% tumor volume reduc- the entire lesion. Courtesy of [5]
meet the previous three criteria. Volumetric analysis CRT, yielding a sensitivity of 83% and specificity
provides reliable and more reproducible data than of 86% for prediction of pCR. Kang et al. [3]
conventional measurements which may be reported that more than 75% of the tumor volume
affected by the anatomy of the viscera, including reduction ratios after CRT were significantly
the rectum which is a hollow viscus with irregular associated with a high pCR rate in 84 patients
morphology, and the intrinsic irregularity of tumor with rectal cancer. To date, the correlation between
shape (Fig. 10.1). Tumor volume measurement is rectal tumor histopathologic downstaging after
widely used for antitumor therapy response. CRT and tumor volume reduction remains contro-
Recently, Lambrecht et al. [2] demonstrated in 21 versial, especially concerning the hypothesis that
patients with locally advanced rectal cancer that percentage volume reduction may indicate pCR.
ROC analysis showed an AUC of 86% at an opti- The metric for positive response is based only on
mal cutoff value of 77% volume reduction after anatomical and morphological changes which are
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy? 79
temporally downstream manifestations of under- fibrous tissue present after treatment causes thick-
lying pathophysiological changes which may ening of the rectal wall in most cases; thus, MR
occur earlier. In early 2009, RECIST was updated, imaging cannot readily differentiate yT0 or yT1
as RECIST 1.1, and a major development was the stage tumors from yT2 tumors because it is not
incorporation of fluorodeoxyglucose positron possible to visualize individual rectal wall layers,
emission tomography (FDG-PET) in the guide- and thus, thickened hypointense rectal wall is
lines, albeit in the limited role of assessing pro- classified as yT0–2 lesions at morphologic restag-
gressive disease. This is exciting in the sense that ing (Fig. 10.3). Some treated tumors develop a
this is the first time the working group has incor- “colloid” response with mucin production that
porated a nonanatomical imaging modality in the results in a very high signal intensity on a
assessment of tumor response, a trend that will T2-weighted image, which is potentially confus-
almost certainly continue in the future. ing. When MR imaging is used in posttreatment
More advanced and specific imaging methods restaging, an increase in tumor signal intensity
are needed to characterize the underlying when compared to pretreatment MR findings is
pathophysiological changes induced by specific generally considered indicative of a mucinous
targeting agents. Such methods may be consider- response. This is not to be confused with the highly
ably more likely to offer earlier—and more hyperintense areas seen in pretreatment MR images
specific—information on response to treatment which instead correspond to pretreatment muci-
when compared to changes in longest tumor nous tumors [5]. Irradiated tumors may show a
dimensions. This may be especially true in the mucin component larger than 50% of the whole
case of neoadjuvant treatment of rectal cancer. tumor, reaching 80–90%; thus, it is possible to rec-
pCR is highly predictive of survival in rectal can- ognize in MR images posttreatment mucin differ-
cer and offers an earlier endpoint for preliminary entiation as lake of high increase in the signal
validation of image-based response criteria. intensity (Fig. 10.4). However, MR restaging is
unable to differentiate mucinous response or
fibroinflammatory tissue from residual tumor as
10.2 Magnetic Resonance Imaging persistent intermediate signal intensity. In conclu-
(MRI) sion on standard MRI, a normalized rectal wall
without any detectable wall thickening is consid-
10.2.1 Morphologic Assessment of MRI ered a definite criterion for a CR (Fig. 10.2). A solid
residual mass with intermediate signal intensity on
MR imaging is considered the most accurate tool T2-weighted MRI is considered a definite criterion
for primary staging of the tumor extent; however, it for residual tumor. Hypointense signal intensity
is not accurate in rectal cancer restaging after CRT, that changes indicated fibrosis remains undeter-
especially when there is a fibrotic thickening of the mined; thus, purely anatomic MR imaging is
rectal wall, in distinguishing between ypT0, ypT1, insufficient to reliably assess the true complete
ypT2, or ypT3 tumors [4]. The untreated tumor on responders, and there is considerable enthusiasm
T2-weighted images has intermediate signal inten- for employing functional methods for selection of
sity between the high signal intensity of the fat tis- these patients with high positive predictive values
sue and the low signal intensity of the muscular and consequently to avoid put them at risk for
layer and invades mesorectal fat with nodular pat- undertreatment.
tern growth. After CRT, complete disappearance of
the tumor is classified as CR (Fig. 10.2). Most
tumors develop fibrosis, leading to reduction of T2 10.2.2 Diffusion-Weighted Magnetic
signal and decrease in tumor size. A decrease in Resonance Imaging (DWI)
signal intensity when compared with the pretreat-
ment examination represents response with fibrosis, DW-MR imaging may be an appropriate tool to
that is, replacement of neoplasm by fibrosis. The monitor the effects of treatment in vivo. Advantages
80 B. Barbaro and L. Leccisotti
a b c
d e f
Fig. 10.2 Rectal cancer in a pCR 47-year-old man. (a) intensity at DW image (arrow in b) with b factor 1,000
HR oblique T2-weighted image of tumor before CRT (arrow in d) and as avid tracer FDG uptake in pretreat-
shows a tumor on the right lateral rectal wall protruding ment PET-CT (c). The tumor disappears in posttreatment
into the rectal lumen as moderate hyperintense mass, oblique (arrow in e) HR T2-weighted (arrow in c) MR
invading the rectal wall. It is difficult to determine whether image (d) and in axial DW image (e). No FDG uptake in
the perirectal fat (arrow) is infiltrated or spared; thus, MR the posttreatment PET-CT (f). Note concordance in mor-
pretreatment stage was borderline tumor as stage T2 or phologic MR image (d), DW image (e), and FDG-PET
initial stage T3. The tumor appears as area high in signal CT image (f) in this pCR
Fig. 10.3 A 58-year-old man with pCR low rectal can- mesorectal fat, through the pelvic floor, indicating potential
cer. (a) Axial DW MRIs, with a b value of 1,000 s/mm2 involvement of the left levator ani muscle (white arrow).
showed the tumor as areas of high signal intensity; (b) After treatment, before surgery, the tumor showed
the tumor as low signal intensity areas (opposite to DW shrinkage and the rectal wall was hypointense and thick-
images) was drawn manually in the ADC maps based on ened. The isointense to muscle intensity persisted on the
the corresponding (c) axial T2-weighted MRIs before, left site (white arrow). The patient underwent transanal
during, and after treatment. In the DW-MRIs, the refer- endoscopic microsurgery. In the bottom left corner, pho-
ence signal was the prostate (P), before and during treat- tomicrograph (original magnification, ×20; H&E stain)
ment (black arrows in a); we found no residual after surgery shows marked fibrosis (black arrows) in the
hyperintense area in the corresponding tumor at the end rectal wall. No viable cells were detected in the rectal
of treatment as possible CR (white * in a). In the corre- wall. Final evaluation was ypT0, TRG 1/5. In this patient,
sponding areas on the ADC maps, the ADC value the fibrous tissue represents the site of previous tumor
increased in the tumor from 1 × 10−3 to 1.3 × 10−3 mm2/s and this fibrosis caused thickening of rectal wall; thus,
(30%) during treatment, which indicated a possible early morphologic MR imaging cannot really differentiate T0
response. At the end of treatment, the ADC value of the to T2 stage because visualization of individual rectal
whole tumor was 1.2 × 10−3 mm2/s. (d) Coronal wall layers is not possible, but areas of fibrosis typically
T2-weighted MRIs before and after treatment. Before have a low cellular density, which results in low signal
treatment, the tumor was detected as an intermediate intensity on high b value (b1000); thus, visual diffusion
intensity signal that extended into the surrounding images could hypothesize CR in this patient
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy? 81
d
82 B. Barbaro and L. Leccisotti
a b
c d
Fig. 10.4 62-year-old man with locally advanced lower (g) shows region of interest (ROI) which is drawn manu-
rectal cancer. (a, b) Pretreatment coronal (a) and HR ally using the corresponding oblique HR T2-weighted
oblique (b) T2-weighted MR images show hyperintense image (f) to identify the residual tumor regions. ADC
mass on the lateral low rectal wall with infiltration of the value increases to 1.7 × 10−3 mm2/s reaching
levator ani muscle corresponding to T4 stage (white arrow 1.9 × 10−3 mm2/s in the area of mucin degeneration seen
in a). (c, d) The pretreatment ADC map (c) corresponding as red area in color ADC map (white * in h), as the endolu-
to HR oblique T2-weighted MR image (b) shows a calcu- minal sonography gel (black *). (i) Photomicrograph
lated ADC tumor of 1 × 10−³ mm2/s which appears preva- (original magnification, × 20; [H-E] stain) shows no tumor
lent green in color map (d). (e, f) Coronal (e) and HR in the rectal wall but only inactive mucin lakes (black
oblique (f) T2-weighted MR images obtained 6 weeks arrows) in persistent areas of high signal intensity: ypT0
after the end of CRT show the residual tumor in the rectal TRG 1/5. Note the heterogeneous response in this patient
wall containing heterogeneous high signal intensity in with a substantial posttreatment ADC value increase
keeping with mucin production as possible response related to mucinous response. Courtesy of [5]
(black arrows in e and f). T0–T2 stage at morphologic
presurgical MR imaging. (g, h) Posttreatment ADC map
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy? 83
f
e
g h
of this technique are that it is completely noninva- only a minimal extension of examination time.
sive, does not require exposure to ionizing radia- However, the limited spatial resolution and the
tion or injection of contrast materials, and does not relatively poor signal-to-noise ratio on high-b-value
cause patient discomfort. Another advantage of DW-MR imaging should be considered a limita-
DW-MR imaging is that it can be easily added to tion, and echo-planar imaging sequences, more-
an MR examination protocol because it requires over, have a propensity to yield distorted images.
84 B. Barbaro and L. Leccisotti
DW imaging derives its image contrast from dif- With increasing tumor cellularity and archi-
ferences in the motion of water molecules between tectural distortion, any increase in the tortuosity
tissues. of the extracellular space will additionally con-
tribute to decreased ADC values. It would, there-
10.2.2.1 Qualitative Assessment of DWI fore, be expected that ADC values would correlate
In tissues with normal cellularity, water protons with tumor cellularity and grade. Inverse correla-
can diffuse relatively freely, which results in a tions between MRI-determined ADC values and
loss of signal on DWI. Conversely, in tissues with cellularity and tumor grade have been noted in
increased cellularity (tumor), the diffusion of xenograft and human tumors. The measured
water is restricted, resulting in remaining high ADC is, therefore, inversely related to the cellu-
signal on DWI. Visual assessment of the relative larity of tumors.
tissue signal attenuation at DWI is being applied
for tumor detection, tumor characterization, and 10.2.2.3 Pretreatment ADC Value
the evaluation of treatment response in patients One of the most intriguing findings associated
with cancer. In many reports, DWI has shown with the use of DWI in cancer patients has been
promise for identification of malignant tumors, that ADC measurements appear to be able to pre-
and recent studies on rectal cancer have indicated dict the response of tumor to chemotherapy and
that DWI also may be useful. High-b-value radiation treatment. Many of the clinical studies
DW-MR imaging has shown sufficient diagnostic evaluating DWI for assessing treatment response
ability for detecting colorectal cancer as reflected have been performed in patients with rectal can-
in its high sensitivity and specificity (however, cer that produced provocative results. Dzik-Jurasz
tissues such as the brain, spinal cord, salivary et al. [6] were among the first to find a strong
glands, testes, prostate, endometrium, bowel negative correlation between the mean pretreat-
mucosa, and lymphatic tissues can also be ment tumor ADC and the percentage shrinkage of
visualized). a rectal tumor after CRT. Recently, Sun et al. [7]
reported a similar observation, and Lambrecht
10.2.2.2 Quantitative Assessment of DWI et al. [8] showed that, in 22 patients, the initial
In vivo, intracellular and extracellular compart- ADC was significantly lower in patients with
ments will have their own unique water diffusion pCR compared to those without pCR after CRT.
constants, which are measured in mm2/s. DWI is This negative association is consistent with the
typically performed using at least two b values known relationship between necrosis which
(e.g., b = 0 s/mm2 and other b values from 0 to causes increases in ADC values and poor response
1,000 s/mm2). By performing DWI using differ- to treatment in cancer. Some authors [9], on the
ent b values, quantitative analysis is possible. other hand, found that the pretreatment mean
This analysis is usually performed at a push of a ADCs in patients with rectal cancer did not pre-
button on the scanner or workstation that results dict treatment response. The effects of high-grade
in the calculation of the apparent diffusion tumors on ADC values are potentially problem-
coefficient (ADC). atic when trying to assign predictive significance
By drawing regions of interests on these maps, to pretherapy diffusion MRI values. It is conceiv-
the ADCs of different tissues can be derived. able that low-grade tumors with little necrosis
Areas of restricted diffusion in highly cellular could have similar mean high ADC values to
areas show low ADC values compared with less necrotic high-grade tumors; conversely, low pre-
cellular areas that return higher ADC values. At therapy ADC value could be an indicator of tumor
this point, it is important to mention that although aggressiveness related to the high cellularity in
areas of restricted diffusion will appear to be higher high-grade tumors, particularly for tumors that
in signal intensity on the DW images, these areas are known to do not readily undergo necrosis.
will appear as low signal intensity areas (opposite Nevertheless, caution should be used when
to DW images) on the ADC map (Fig. 10.3). assigning prognostic significance to a mean tumor
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy? 85
pretherapy ADC value. Patterson et al. [10] scored values as prediction of clinical outcome for some
strength of evidence using a five point of scale tumors during treatment. Nevertheless, the body
(1–5: weak–moderate–substantial–firm–definite) of evidence suggests that percentage increase of
based on authors’ perceptions of the literature ADC value measurement is a potentially useful
used for their review and scored as moderate (2/5) tool for personalized treatment management and
the value of pretherapy ADC maps as possible should be more widely investigated in large clin-
indicator of outcome of therapy and concluded ical studies in the future (Figs. 10.3 and 10.5).
that, although acknowledging the potential role of
pre-CRT ADC as a quantitative biomarker to dis- 10.2.2.5 Presurgical Diffusion-Weighted
criminate the T-downstaged group from the non- Magnetic Resonance Imaging
downstaged group in neoadjuvant CRT for locally (DWI)
advanced rectal cancer, the role of pre-CRT ADC In 2009, the first study by Kim et al. [11] in 40
seems to be very limited, particularly when patients investigated the value of visual DWI for
focused on the prediction of pCR. predicting a pCR after CRT. Results for two inde-
pendent readers indicated that the addition of
10.2.2.4 Early Response Evaluation DWI to standard rectal MRI significantly
The sensitivity of DW-MRI to changes in tissue improved the diagnostic performance for selec-
microstructure and organization has led to tion of pCR from an AUC of 0.68 and 0.66,
increasing interest in the potential of ADC mea- respectively for standard MRI to an AUC of 0.88
surements as a biomarker for early evaluation of and 0.82 for standard MRI + DWI. Results of a
response to treatment, and these changes pre- larger, multicenter study [12] confirm these previ-
ceded significant reductions in tumor volume. ous findings and showed that the diagnostic per-
This response occurs within days of initiating formance for predicting a pCR after CRT
therapy and appears to be a consequence of cel- improved for standard MRI + DWI as compared
lular damage leading to necrosis and, thus, a uni- to standard MRI only and resulted in a substantial
versal response to therapy. Viable tumor cells reduction in the number of equivocal scores and
restrict the mobility of water, whereas necrotic an improved interobserver agreement. In this
tumor cells allow increased diffusion of water multicenter study with the addition of DWI, sen-
molecules as a result of treatment-induced tumor sitivity for identification of a pCR improved by
regression such as necrosis, decreased cellular- 16–52% for the three readers, and it resulted in
ity, and compromised cell membrane integrity. less overestimation of residual tumor. This is
In a number of clinical and preclinical studies, mainly because on the restaging MRI without
increases in tumor ADC values were noted early DWI, many interpretation difficulties were
during the course of therapy, allowing early pre- observed when the primary tumor bed had become
diction of treatment response. Although there fibrotic as a result of the radiation treatment. In
have been few clinical studies of the effects of these cases, it is difficult to differentiate small
treatment on tumor ADC in rectal cancer pub- areas of residual tumor from mere fibrosis and
lished to date, the results of the existing studies readers tend to overestimate the presence of tumor
are promising. Some authors showed that, at the (Fig. 10.3). Apparently, this is where the func-
end of the second week of CRT, significant tional information from DWI proves beneficial.
increases in tumor ADCs occurred in the down- Areas of fibrosis typically have a low cellular
staged group. More recently, Lambrecht et al. density, which results in low signal intensity on
[2] showed an optimal cutoff point of 50% for high-b-value (b1000) visual diffusion images.
the percentage of ADC change during therapy Conversely, residual tumor areas have a relatively
for prediction of pCR with a sensitivity, high cellular density and show high signal on
specificity, PPV, and NPV of 100%. Patterson DWI, which stands out within the low signal of
et al. [10] scored (1–5) strength of evidence scale the surrounding tissue/fibrosis. This is the reason
as moderate-firm (2–4/5) the increase in ADC why small areas of residual tumor are better
86 B. Barbaro and L. Leccisotti
Fig. 10.5 70-year-old-woman with T3 middle rectal can- SUVmax). At the end of treatment, the comparison between
cer. Axial DW MRIs (a), with a b value of 1,000 s/mm2 DW image (a) and FDG PET-CT image (b) reveals nei-
before, during, and after treatment compared to FDG- ther area of restricted diffusion nor uptake of FDG as pos-
PET-CT images (b) before, during, and after treatment, sible CR. (c) Pretreatment and presurgical HR oblique
show the tumor as areas of high signal intensity in pre- T2-weighted MR images show tumor shrinkage after
treatment DW image and as avid tracer FDG uptake in CRT, yellow arrows in (c) (in the bottom left corner, the
pretreatment PET-CT. At Axial DW MR image, a tumor tumor was drawn manually in the ADC maps). The stage
signal intensity reduction, yellow arrows in (a), which was ypT2 at histology, TRG 2/5. In this patient, both
corresponds to 30% ADC increase and at FDG-PET-CT DW-MRIs and FDG-PET-CT images cannot reliably dis-
image qualitative and semiquantitative metabolic response criminate residual viable tumor cells from fibrosis
in the second week, are well evident (50% decrease in microscopically
depicted on DWI. Nevertheless, interpretation DWI is >90%, indicating that the residual tumors
errors were still observed with DWI resulting in a are accurately detected and the risk for under-
suboptimal sensitivity of 52–64%. When the sig- treatment will be <10%. Although DWI allows
nal of the normal rectal wall is not fully sup- detection of even small (2–5 mm) tumor volumes,
pressed on DWI, high signal at the location of the the challenge will remain the detection of micro-
initial tumor area may erroneously be interpreted scopically small clusters of residual tumor cells,
as residual tumor, resulting in overstaging errors. which are difficult to detect—even at histology—
In addition, some imaging artifacts may occur on and are currently beyond the detection level of any
DWI, particularly around air-tissue interfaces. In available imaging modality, including DWI
this multicenter study, specificity for MRI and (Fig. 10.5).
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy? 87
In some studies, the diffusion images were not The use of whole-tumor summary statistics
only analyzed visually, but also quantitatively by (mean) has the merit of simplicity but may have
measuring the ADC of the tumors. the potential of overlooking tumor heterogeneity;
Patterson et al. [10] describes the behavior of histogram or voxel-wise analyses are supposed to
tumor after successful therapy and reported that be alternatives for evaluating tumor heterogeneity.
removal of dead and/or dying cells is followed by
tissue compaction, fibrosis, and regeneration of
native tissues. These processes can result in 10.3 Perfusion Computed
decreases in ADC from the elevated levels caused Tomography (pCT) and
by decreased cellularity (Fig. 10.3). In addition, the Dynamic Contrast-Enhanced
presence of residual active disease or repopulation MR Imaging (DCE-MRI)
by resistant cells can also decrease ADC values;
thus, these authors concluded that interpretation of Perfusion computed tomography (pCT) and
changing ADC values must, therefore, be made dynamic contrast-enhanced magnetic resonance
with caution. Preliminary results of many clinical imaging (DCE-MRI) are clinical imaging tech-
studies evaluating quantitative DWI for ADC val- niques that are increasingly applied to noninva-
ues at the end of treatment in relatively small num- sively assess the microvascular status of tumor
bers of patients with rectal cancer reported that a tissue. In clinical cancer research, regression of
reduction in ADC values at the end of CRT which tumor microvasculature is considered an impor-
they ascribed to tumor sloughing (i.e., apoptotic tant early surrogate marker for treatment response,
cell removal) and tissue compaction (i.e., fibrosis) before reductions in tumor volume become appar-
and reductions in blood flow. Conversely, some ent. To date, both pCT and DCE-MRI are increas-
authors more recently reported that the post-CRT ingly used for the prediction and evaluation of
ADCs in the pCR were significantly higher than treatment response, as indicators of tumor angio-
those in the non-pCR. Clinical application of the genesis, and for primary tumor staging. Both
cutoff ADC value of 1.30 × 10−3 mm2/s in the study pCT and DCE-MRI are imaging modalities that
of Kim et al. [9] showed a perfect negative-predictive rely on the dynamic assessment of tracer uptake
value (NPV) useful for proper selection of the non- kinetics, subsequently quantified by means of
CR group but low positive-predictive value (PPV) pharmacokinetic models. These models describe,
of 52%. In these authors’ opinion, the main reason in terms of pharmacokinetic parameters, the
for this poor PPV is the considerable overlap of wash-in and wash-out of contrast agent from the
ADC values between pCR and near-pCR and microvasculature into the surrounding tissues. A
concluded that, although ADC is a promising commonly applied pharmacokinetic two-com-
potential quantitative biomarker, it suffers from the partment model is the extended Kety model,
problem that it cannot reliably discriminate residual which consists of the (transendothelial) volume
viable tumor cells from fibrosis microscopically transfer constant Ktrans, the fractional volume of
(Fig. 10.5). the extravascular–extracellular space (EES), ve,
Careful consideration should be given to the and the fractional blood plasma volume, vp.
role of ADC measurements in the determination Clinically, Ktrans is the most valuable pharmacoki-
of CR in patients with mucinous tumors because netic parameter, which describes the transfer rate
patients in this subset supposedly have higher of the contrast agent from the plasma space to the
ADC values than do patients with ordinary ade- EES and represents a combination of microvas-
nocarcinomas. Furthermore, it is still a challenge cular blood flow, vessel wall permeability, and
to predict disease activity in patients with muci- vessel density (i.e., permeability surface area
nous tumors on conventional MR images, as it is product). The usefulness of DCE-MR and pCT in
difficult to differentiate residual tumors from characterizing rectal tumors and their response to
inactive mucin pools also in mucinous response treatment has been demonstrated in several clini-
in non-mucinous pretreatment tumor. cal and preclinical studies to evaluate tumor
88 B. Barbaro and L. Leccisotti
10.4.1 Pretreatment FDG PET-CT ment response was correlated with the pathologi-
cal response by the evaluation of the TRG and
FDG PET-CT in initial staging of rectal cancer is ypT stage of the resected specimens. Based on
reserved for high-risk patients (locally advanced TRG evaluation, 13 patients were classified as
disease, equivocal findings on morphological pathological responders (TRG1–2), whereas 17
imaging, and high CEA levels). It is well known patients were classified as pathological nonre-
that 95–100% of known primary rectal cancers sponders (TRG3–5). The RI calculated after the
are visible on FDG PET-CT. False-negative first 2 weeks of CRT provided the best predictor
results may be encountered with mucinous tumors of pathological treatment response, reaching
and very small primary tumor. The limited spatial AUCs of 0.87 and 0.84 for the TRG and the ypT
resolution of this technique (4–6 mm) does not stage, respectively. A cutoff value of 43% for the
allow to define the relationship of the primary reduction of SUVmax resulted in a sensitivity of
lesion to the mesorectal fascia or to accurately 77% and a specificity of 93%. Recently, the same
evaluate local nodal disease (sensitivity 30–35%; authors validated their preliminary results on a
specificity ~85%). Pretreatment SUVmax of the larger patient population (n = 51), confirming the
primary tumor does not seem to differentiate pCR potential of PET-based response prediction early
or near-pCR (TRG1–2) from pathological non- during CRT treatment [16]. Applying a cutoff
responders (TRG3–5). However, pretreatment value of 48%, SUVmax reduction to differentiate
FDG PET-CT is essential as baseline scan to pathological responders (TRG1–2) from nonre-
assess metabolic changes of the primary tumor sponders (TRG3–5) resulted in a specificity and
during and after neoadjuvant treatment. sensitivity of, respectively, 93% and 83%, with
only one of the pathological nonresponders being
false-positively predicted as pathological respond-
10.4.2 Early Response Evaluation ing. However, data deriving from tailored therapy
by FDG PET-CT based on metabolic response during neoadjuvant
CRT using alternative dosing, fractionation, or
In locally advanced rectal cancer, there is mount- agents are still lacking.
ing evidence of the value of FDG PET-CT in the
early prediction of the pathological response after
neoadjuvant treatment. SUV reduction as early as 10.4.3 Presurgical FDG PET-CT
12 days after preoperative CRT has been shown
to predict TRG in several published studies. Presurgical PET-CT images usually show a
Cascini et al. [14] correlated the changes in tumor significant lower FDG uptake in the primary
SUVmax 12 days after starting preoperative CRT tumor of patients with pathological confirmed
and 6–8 weeks after the end of preoperative CRT response compared to nonresponders. A mild and
with the pathological results in 33 patients. The diffuse FDG uptake, similar to background activ-
early median decrease of tumor SUV significantly ity, is typical of patients with pCR or near-com-
differed between TRG1–2 (−62%; range: −44% plete pathological response (TRG1–2) (Figs. 10.2
to −100%) and TRG3–5 (−22%; range: −2% to and 10.5). Most of published studies correlated
−48%) (p < 0.0001). Responders were correctly the metabolic tumor response to TRG score and
identified by decreases in the SUVmean (with a more recently to ypT stage. The reported optimal
decrease of ³52% the accuracy was 100%) and cutoff values of the mean reduction in SUV for
SUVmax (with a decrease ³42% the accuracy was identifying a response to preoperative CRT are
94%). Janssen MH et al. [15] studied 30 patients heterogeneous, ranging from 40% to 70%, and
with locally advanced rectal cancer with sequen- mainly rely on post-hoc analysis. Moreover, the
tial FDG PET-CT imaging at four time points: predictive values of FDG PET-CT response
prior to therapy, at days 8 and 15 during CRT, and (NPV) range between 85% and 95%, while pre-
shortly before surgery. Tumor metabolic treat- dictive values of FDG PET-CT nonresponse
90 B. Barbaro and L. Leccisotti
(PPV) range from 75% to 85%. Capirci et al. [17] Moreover, the “stunning” of tumor cells second-
studied 45 patients with locally advanced rectal ary to a therapy-induced reversible decrease in
cancer at baseline and at 5–6 weeks after the glucose metabolism could mimic a response.
completion of neoadjuvant CRT. The baseline Therefore, FDG PET-CT is not accurate in dif-
SUVmax (median 16.7) was not predictive of path- ferentiating TRG1 from TRG2, in completely
ological response. The RI showed a good correla- assessing pCR or predicting tumor clearance from
tion with the TRG. A cutoff value of 66.2% the mesorectal fascia following neoadjuvant CRT
decrease in SUVmax, identified by ROC analysis, treatment. The sensitivity for assessing response
allowed differentiation of responders (8 TRG1 + 15 in regional nodes is also disappointing. Therefore,
TRG2) from nonresponders (9 TRG3 + 13 TRG4– a negative presurgical FDG PET-CT scan cannot
5) with 80% overall accuracy. Melton et al. [18] be considered as surrogate for pCR, because it is
showed that FDG PET-CT parameters are best for not possible to exclude residual microscopic dis-
assessing tumor downstaging and percentage of ease (Fig. 10.5). On the other hand, false-positive
residual tumor after neoadjuvant treatment of rec- presurgical PET images are usually related to the
tal cancer. pCR or microscopic disease (n = 7, inflammation induced by radiotherapy. Activated
33%) was associated with DSUV (AUC = 0.79, macrophages, neutrophils, fibroblasts, and granu-
p = 0.01), while tumor downstaging (n = 14, 67%) lation tissue induced by radiotherapy are known
was associated with greater DPET volume to avidly consume FDG accounting for a consid-
(AUC = 0.82, p < 0.001) and DSUV (AUC = 0.82, erable accumulation of FDG in noncancerous
p < 0.001). Recently, van Stiphout et al. [19] parts of the tumor (Fig. 10.6). Dynamic and dual
developed predictive models based on clinical time point FDG PET-CT imaging as well as dif-
and FDG PET-CT data for pCR based on a pooled ferent PET tracers (i.e., 18F-FLT) might be able to
multicenter database of 953 patients with locally distinguish malignant from inflammatory tissue.
advanced rectal cancer. The authors showed that The emerging need to accurately identify nonin-
tumor dimension in combination with RI and vasively the pCR after preoperative CRT requires
posttreatment SUVmax are the most predictive a reliable test characterized by very PPV to avoid
variable sets for pCR resulting in very good over- undertreatment of patients who still have viable
all performance AUCs of 0.86. It should be keep tumor cells. Although the sensitivity for pCR
in mind that false-negative presurgical PET with FDG PET-CT is quite high with the provided
images may be related to a significant tumor cutoff values, the specificity is actually too low
downsizing after a long course of CRT which can for clinical use. To date, for neither DSUVmax-
result in an underestimation of the FDG uptake mean nor RI, a threshold level rendering a PPV >
within the tumor due to partial volume effect. 90% has yet been determined.
Fig. 10.6 Rectal cancer in a pCR 47-year-old man. (a) (arrow) as possible CR. Note that in the alternative rectal
HR oblique T2-weighted image of tumor before treatment wall layers in posttreatment DW image, the mucosa is
shows a T3 tumor on the anterior rectal wall protruding homogeneously hyperintense, black *, and the submucosa
into the rectal lumen as moderate hyperintense mass is dark, white *, related to edema. ADC value increases to
(arrow). After treatment, before surgery, the tumor showed 1.6 × 10−3 mm2/s in the presurgical image. FDG-PET CT
shrinkage and appears as hypointense area on the anterior scans before and after treatment (c). Focal FDG uptake
site (arrow) (in the bottom left corner, the residual tumor persists in presurgical FDG-PET-CT image (47% decrease
was drawn manually in the corresponding presurgical in SUVmax at presurgical exam). Histology reveals abun-
ADC map). The rectal wall is thickened and alternative dant fibroinflammation tissue without residual viable
rectal wall layers are well evident (yellow * indicates sub- cells. The stage was ypT0, TRG 1/5. Inflammation caused
mucosa which is thickened and hyperintense to muscle errors in FDG PET-CT imaging and is a common source
intensity). Axial DW-MRIs before treatment and before of inaccuracy in tumor restaging. In this patient, the asso-
surgery (b). The tumor appears as area high in signal ciation between DW imaging and FDG PET-CT was use-
intensity in pretreatment DW image (arrow) with b factor ful for predicting response to avoid misinterpretation of
1,000 and disappears in posttreatment axial DW image high residual FDG uptake as residual tumor
10 How Can We Identify Pathologic Complete Responders After Radiochemotherapy? 91
c
92 B. Barbaro and L. Leccisotti
16. Janssen MH, Ollers MC, van Stiphout RG et al (2012) positron emission tomography and computed tomogra-
PET-based treatment response evaluation in rectal phy for assessing primary rectal cancer response to neo-
cancer: prediction and validation. Int J Radiat Oncol adjuvant therapy. J Gastrointest Surg 11:961–969
Biol Phys 82(2):871–876 19. van Stiphout RG, Lammering G, Buijsen J et al (2011)
17. Capirci C, Rampin L, Erba PA et al (2007) Sequential Development and external validation of a predictive
FDG-PET/CT reliably predicts response of locally model for pathological complete response of rectal
advanced rectal cancer to neo-adjuvant chemo-radiation cancer patients including sequential PET-CT imaging.
therapy. Eur J Nucl Med Mol Imaging 34:1583–1593 Radiother Oncol 98:126–133
18. Melton GB, Lavely WC, Jacene HA et al (2007) Efficacy
of preoperative combined 18-fluorodeoxyglucose
How Can We Identify Local Relapse?
11
Doenja M.J. Lambregts
and Regina G.H. Beets-Tan
11.2.3 What Is the Role of CEA During than in patients with colon cancer, a more fre-
Routine Surveillance? quent (3–6 monthly) endoscopic evaluation of
the rectum or rectosigmoid seems to be justified.
Together with clinical symptoms, elevated CEA Especially in patients who have not received pre-
levels have been reported to be the most frequent operative treatment or who have undergone a
first clinical indicator of relapse [1]. The colorec- local or subtotal excision instead of total mesorec-
tal cancer surveillance guideline of the American tal excision (TME), more frequent endoscopic
Society of Clinical Oncology (ASCO) recom- evaluation is indicated.
mends 3-monthly CEA testing in patients with
stage II or III disease for at least 3 years after the
diagnosis [2]. Furthermore, it is advised to initi- 11.2.5 What Is the Role of Imaging
ate the CEA surveillance after adjuvant chemo- During Routine Surveillance?
therapy is finished, as CEA levels may be falsely
elevated in patients who are still receiving There is no solid evidence that routine imaging is
fluorouracil-based treatment. A second issue to beneficial during the surveillance of patients after
take into account is the fact that CEA levels are colorectal cancer surgery. The ASCO guidelines
only elevated in approximately 60% of the state that routine imaging is only justified in
patients with colorectal cancer. Therefore, it may patients with an increased risk for recurrence and
be considered to only perform routine CEA test- should mainly consist of annual CT of the chest
ing in those patients whose CEA levels were ini- and abdomen. Especially regular monitoring of
tially elevated at the time of their primary tumour the liver by imaging (CT or ultrasound) has been
diagnosis. shown to contribute to an improved survival.
Equal results were reported for CT and CEA for
the detection of curable recurrent disease. Pelvic
11.2.4 What Is the Role of Clinical imaging may be considered in patients with rectal
Examination (Endoscopy) cancer, in particular in patients who have not been
During Routine Surveillance? treated with radiotherapy. There is no role for rou-
tine surveillance using positron emission tomog-
Both the ASCO guidelines, the guidelines of the raphy (PET), as the benefits do not outweigh the
European Society of Medical Oncology (ESMO) high costs. Although MRI is known to be the pre-
[4], as well as a recent European consensus paper ferred modality for the primary assessment of rec-
[11], recommend a colonoscopy every 3–5 years tal tumours, pelvic surveillance by MRI as part of
after treatment, with the aim to exclude second- the routine follow-up scheme is not justified as it
ary tumours in the remaining colon and in rectal is known that – compared to follow-up using only
cancer patients to detect a local recurrence. For CEA testing – only little additional curable and
patients with an increased familial or inherited resectable recurrences are detected with MRI and
risk, a more intensive colonoscopic surveillance the yield is less than one percent [9].
is required, depending on their risk category
(which is based on the number of first-, second-
and third-degree relatives with colorectal cancer 11.3 Detection of Local Relapse
and/or genetic carriership for familial adenoma- in Case of an Increased Risk
tous polyposis or hereditary non-polyposis col- for Recurrence
orectal cancer). The yield of colonoscopy in the
detection of locally recurrent tumour in normal 11.3.1 Which Patients Constitute
risk patients is, however, very low. Colonoscopy the ‘Increased Risk’ Group?
seldom provides the first signs of recurrence and
sensitivity for detection of local relapse is less It has been suggested by different authors that a
than 50% [6]. Since the prevalence of a local more intensive follow-up should be preserved for
relapse in rectal cancer patients is much higher patients that have an increased risk to develop
98 D.M.J. Lambregts and R.G.H. Beets-Tan
recurrent disease. This includes patients with mass on consecutive CT examinations (Fig. 11.1).
prognostically unfavourable primary tumours In many patients, however, pelvic CT remains
(high TNM stage, poor histologic grade, blood/ inconclusive and patients need to be referred for
lymphatic vessel and perineural invasion, low additional imaging (PET and/or MRI). A draw-
number of nodes investigated at pathology), back of CT is that its limited soft tissue contrast
patients who have not undergone radiation treat- does not allow for an assessment of tumour resec-
ment, patients with elevated CEA levels or abnor- tability once a recurrent tumour is suspected.
mal liver function tests and patients with clinical
symptoms suspicious for recurrent disease.
Recently, a pooled analysis of the individual 11.3.4 What Is the Role of PET?
patient data from five European trials was per-
formed with the aim to develop a predictive model PET is generally applied as the second-line tech-
(based on clinical, treatment and pathologic nique in patients with a (strong) clinical suspicion
patient variables) to identify patient groups that of a local relapse in whom CT findings are equiv-
have an increased risk for local recurrence and/or ocal (Fig. 11.2). A recent meta-analysis that com-
distant metastases and may benefit from more pared the use of PET, CT and combined PET-CT
close follow-up. Although the use of such ‘nomo- for the detection of recurrent disease after col-
grams’ will need to be validated using external orectal cancer surgery found that PET and PET-CT
patient data, it may prove to be a useful support are superior to CT, especially in the specific sub-
tool to modulate the intensity of follow-up based group of patients who have a strong clinical suspi-
on a patient’s individual risk profile [12]. cion for recurrence (based on elevated CEA levels
or clinical symptoms). Hence, it may be defensi-
ble to immediately go for PET in these particular
11.3.2 What Is the Role of Clinical high-risk patients [7], although this is not the case
Examination? in routine practice, because of the invasiveness of
the technique and its high costs. Like CT, PET is
In patients with an increased risk for recurrence of limited value to determine tumour resectability.
(i.e., rectal cancer patients who have not under- Moreover, false-positive PET findings are fre-
gone radiation treatment and/or who have under- quently observed in areas of inflammation, in dis-
gone local excision instead of total mesorectal placed small bowel loops and in the proximity of
excision), routine endoscopic surveillance is the urinary bladder. Conversely, false-negative
indicated. In addition, endoscopic examination findings are known to occur in recurrent tumours
should be considered in patients in whom an of the mucinous tumour type.
endoluminal recurrence is expected based on
clinical symptoms (e.g., faecal blood loss) or
digital rectal examination. 11.3.5 What Is the Role of MRI?
a b
Fig. 11.1 Two consecutive pelvic CT examinations of a (b) On the CT performed after 14 months, a growing
patient treated with TME for a primary T3N2 rectal pelvic mass (arrows) is identified, suspected for a recur-
tumour. CT examinations were performed 6 (a) and 14 (b) rent tumour. (c) Corresponding PET-CT confirmed the
months after rectal cancer surgery. (a) On the CT per- suspicious finding of a local relapse, which was confirmed
formed after 6 months, there are no signs of a local relapse. to be recurrent adenocarcinoma at biopsy
and PET because of the long acquisition times 11.3.6 What Are the Limitations
required to cover the whole body and because of in the Imaging Detection
its limited use for the evaluation of metastatic lung of Local Relapse?
disease. There are, however, several authors that
have advocated MRI as the technique of first It has been shown that pelvic imaging mainly
choice for the evaluation of local relapse. Due to fails in detecting anastomotic, intraluminal recur-
its excellent soft-tissue contrast, MRI is a valu- rences, which tend to be smaller in size. For the
able tool to assess the extent of a locally recurrent assessment of this type of relapse, endoscopy is
tumour and to evaluate possible tumour growth better suitable. Furthermore, the techniques of
into adjacent organs and tissues. Hence, MRI has first choice (CT and to a lesser extent PET) are
proven most valuable in determining whether a of limited use for the assessment of local tumour
local relapse is still resectable (Fig. 11.3). resectability, whereas MRI – which is more
100 D.M.J. Lambregts and R.G.H. Beets-Tan
a b
Fig. 11.2 CT (a), PET (b) and fused PET-CT (c) images relapse. (b/c) On the corresponding PET examination (b)
of a patient suspected of recurrent tumour. (a) On CT, a and the fused PET-CT images (c), a clear area of increased
mass (arrowheads) is visible, but it is not possible to dif- FDG uptake is identified, which was confirmed to be a
ferentiate between postoperative scar tissue and a local local relapse at biopsy
accurate for the latter purpose – is not helpful for cell proteins and carbohydrates, and other factors
whole-body staging of recurrent disease. So far, such as microvessel density, DNA content and
none of the available imaging techniques thus cell proliferation indices. In the future, such
qualifies as a complete one-stop-shop technique. factors may help to determine prognosis and aid
in establishing a risk-adapted surveillance strat-
egy. However, since multivariate analyses and
11.3.7 Are There Any New Techniques prospective validation studies are not yet avail-
That May Help in the Evaluation able, the use of these markers is currently not
of Local Relapse? recommended. New imaging techniques, com-
bining functional and morphological imaging
Numerous studies are being undertaken investi- information, are also being investigated. The first
gating the clinical value of prognostic and predic- pilot results on techniques such as dynamic con-
tive markers, including molecular markers (e.g. trast-enhanced MRI (DCE-MRI), diffusion-
tumour suppressor genes and growth factors), weighted MRI (DWI) and image fusion techniques
11 How Can We Identify Local Relapse? 101
a b
Fig. 11.3 CT (a), PET (b) and MRI (c) examinations of a feasible to determine the tumour ingrowth into adjacent
patient with a local relapse after rectal cancer surgery. (a) organs or structures. (c) On MRI, it can be appreciated
On CT, a mass is visible, although it is difficult to dis- that the tumour grows into the sacrum (arrowheads), the
criminate between postoperative scar tissue and tumour. iliac vessels on the right side (white arrow) and into the
(b) On PET, a clear uptake of FDG highly suspicious of bladder (black arrow). This example illustrates that MRI
recurrent tumour can be discerned. It is, however, not is the preferred technique to evaluate tumour resectability
combining PET/MRI and DWI/MRI have shown ongoing large trials investigating this issue,
encouraging results, and further large-scale current guidelines are based on common clini-
patient studies are required to establish their cal practice and the evidence provided by pre-
potential clinical value for the evaluation of vious meta-analyses, which used different
recurrent disease. follow-up schedules. These state that routine
follow-up in patients with rectal cancer should
Conclusion at least include regular clinical examination,
To date, there is no strong evidence yet CEA testing and some sort of liver imaging. In
on what should be considered the most opti- patients with an increased risk for local recur-
mal surveillance strategy after colorectal can- rence (based on prognostic factors, elevated
cer surgery. While awaiting the evidence of CEA levels or clinical symptoms), imaging is
102 D.M.J. Lambregts and R.G.H. Beets-Tan
justified and CT is the technique of first choice. 6. Kievit J (2002) Follow-up of patients with colorectal
In case of equivocal CT findings, PET is more cancer: numbers needed to test and treat. Eur J Cancer
38:986–999
beneficial in identifying a local relapse. The 7. Maas M, Rutten IJ, Nelemans PJ, Lambregts DM,
main role of MRI is to establish the resectabil- Cappendijk VC, Beets GL, Beets-Tan RG (2011)
ity of a local tumour recurrence once it has What is the most accurate whole-body imaging
been diagnosed. modality for assessment of local and distant recurrent
disease in colorectal cancer? A meta-analysis: imag-
ing for recurrent colorectal cancer. Eur J Nucl Med
Mol Imaging 38(8):1560–1571
8. Renehan AG, Egger M, Saunders MP, O’Dwyer ST
(2002) Impact on survival of intensive follow up after
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Guidelines Working Group (2010) Rectal cancer: Gambacorta MA, Barba MC, Bebenek M, Bonnetain
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CD002200 3163–3172
Part IV
Q&As on Radiotherapy
When Should Preoperative
Short-Course Radiotherapy 12
or Long-Course Chemoradiotherapy
Be Performed?
In contrast, where the MRI suggests the cir- 12.3 Evidence Supporting the
cumferential resection margin (CRM) or, more Efficacy of Short-Course
accurately, the mesorectal fascia (MRF) is poten- Radiotherapy
tially involved, and a standard conventional total
mesorectal excision (TME) will not offer a cura- Short-course radiotherapy was developed in
tive option, there is almost universal agreement Sweden at a time when surgery was the sole treat-
that the patient requires preoperative chemora- ment modality for rectal cancer and there was no
diotherapy with an interval to allow for downsiz- evidence to support the use of adjuvant preopera-
ing/downstaging. tive radiotherapy. In order to test the role of pre-
This chapter assesses the role of radiation operative radiotherapy, a minimal delay to surgical
therapy in rectal cancer, with emphasis on patient resection was essential, and Swedish investigators
selection for preoperative chemoradiotherapy elected to evaluate the use of a high dose per frac-
(CRT) and short-course preoperative radiother- tion, hypofractionated 1-week regimen.
apy (SCPRT) and the outcomes obtained from
each of these strategies.
12.3.1 Clinical Trials
12.2 Rationale for the Different Following initial development, a sequence of ran-
Approaches domised phase III trials were performed compar-
ing SCPRT followed by surgery with surgery
The rationale for SCPRT is based on the short alone. Although earlier studies used 5 Gy per
overall treatment time (OTT), which allows sur- fraction with total doses of 15–20 Gy, subsequent
gery to take place promptly (ideally within trials evaluated 25 Gy in 5F. Between 1980 and
7 days) before the radiation reaction is expressed. 1993, over 2,000 patients were evaluated in the
The radiotherapy dose (5 × 5 Gy) is high in bio- Stockholm and Swedish Rectal Cancer trials. The
logical terms and avoids the potential for accel- Stockholm I trial used parallel opposed fields
erated repopulation which may occur in the latter treating a large volume. This approach was asso-
part of long-course chemoradiation. Other ciated with increased operative mortality and
advantages include a very short period of deliv- substantial late toxicity.
ery, high compliance and low cost. Adjuvant The Swedish rectal cancer trial [1] (Table 12.1)
chemotherapy with systemically active sched- was performed between 1987 and 1990 and ran-
ules (e.g., FOLFOX) can be started with mini- domised 1,168 patients to receive either SCPRT
mal delay if deemed necessary, within a few followed by surgery or surgery alone. The use of a
weeks of diagnosis. The disadvantage is that 3- or 4-field radiotherapy technique and a reduc-
there is insufficient time for substantial downsiz- tion in the superior limit of the target volume to the
ing/downstaging to occur, although this may in mid-L4 vertebral body prevented any increase in
fact be an advantage because it allows accurate operative mortality. Local recurrence was reduced
pathological staging in terms of the nodal status. from 27% to 11% (p < 0.001), and 5-year survival
However, SCPRT may compensate only partially increased from 48% to 58% with surgery alone
for a positive CRM. and SPCRT and surgery, respectively (p = 0.004).
The rationale for long-course chemoradiation A recent report confirms that the benefits shown
is to achieve additive effects both locally and are sustained after 13 years of follow-up.
systemically with a concurrent fluoropyrimidine, The above trials reported local recurrence
thereby inducing downstaging/downsizing rates of >20% with surgery alone and reflect sur-
reducing metastases and in a small group of gical practice at the time the trials were con-
patients achieving tumour sterilisation. Its role ducted. However, surgical techniques improved
in facilitating sphincter sparing procedures is with the adoption of total mesorectal excision
contentious. (TME) described by Heald, resulting in reported
12
Table 12.1 Key trials of short-course radiotherapy and surgery versus surgery alone/selective post-operative (chemo)radiotherapy
Duration PAT 1° end
Trial of trial NOS Randomisation NOS TME point LR METS OS DFS
Swedish 1987–1997 1,168 25 Gy/5# + surgery 553 11% 23% 58%
Rectal No OS 5 years 5 years 5 years Not stated
Cancer Surgery alone 557 27% 24% 48%
Trial
(1997)
Updated 9% 34% 38%
(2005) 13 years 13 years 13 years Not stated
26% 34% 30%
Dutch Trial 1996–1999 1,861 25 Gy/5# + surgery 897 2% 14.8% 82%
CKVO Yes LR 2 years 2 years 2 years Not stated
95–04 Surgery + highly 908 8% 16.8% 81.8%
(2001) selective RT
Updated 5% 25% 48%
(2011) 10 years 10 years 10 years Not stated
When Should Preoperative Short-Course Radiotherapy or Long-Course
local recurrence rates of 10% or less. A key ques- between 1990 and 2002 that were then divided
tion at this time was whether SCPRT compen- into three time intervals: prior to, during and after
sated for poor surgical technique, and further the Dutch TME trial. The 5-year overall survival
trials were then designed to test the role of SCPRT was 56%, 62% and 65% for the three groups,
combined with TME. respectively. Multivariate analysis demonstrated
The Dutch TME trial [2] and the Medical preoperative radiotherapy had a statistically
Research Council CR07 trial [3] (Table 12.1) significant impact on survival (p < 0.001).
compared a policy of routine SPCRT and imme- A recent publication from Sweden [4] has
diate surgery against initial surgery with a policy evaluated 6,878 patients receiving treatment for
of highly selective post-operative (chemo)radio- rectal cancer between 1995 and 2001 when 41%
therapy restricted to patients with involvement of of patients received SCPRT. Local recurrence at
the circumferential resection margin (the Dutch 5 years was 6% with SPCRT + surgery and 12%
trial used radiotherapy alone and CR07 concur- with surgery alone. The authors elected to com-
rent 5FU chemoradiation). Adjuvant chemother- pare the overall survival of the two groups
apy was not used in the Dutch trial, whereas restricted to patients under the age of 75 and
patients with stage III disease received 5FU che- undergoing anterior resection or APER. The
motherapy in the CR07 trial. Hazard Ratio for overall survival was 0.70 (0.69–
The two trials recruited a combined total of 0.72) in favour of SCPRT. However, the
3,150 patients and have reported very similar justification for this subset analysis of 3,466
results which are summarised in Table 12.1. The patients is limited to the authors stating that the
rate of local recurrence was approximately halved excluded patients have ‘higher comorbidity, their
from 11% with TME to 4–5% with the addition of expected survivals are lower and they are less fre-
SCPRT to TME. There is no evidence of any quently referred for irradiation.’
impact on overall survival for the whole trial pop-
ulation. In the CR07 trial, pathologists assessed
the plane of surgery achieved in the surgical resec- 12.3.3 Meta-analysis
tion specimen (mesorectal, intra-mesorectal and
muscularis propria planes). A higher rate of LR A number of meta-analyses have been performed
was seen in the muscularis propria plane, and a of the phase III clinical trials that tested the addi-
reduction in LR was seen with SCPRT for all three tion of preoperative radiotherapy to surgery
planes. This latter finding confirms that adjuvant alone. The Colorectal Cancer Collaborative
preoperative radiotherapy is of additional benefit Group [5] identified 14 preoperative trials that
even when the surgical technique is optimised. recruited a total of 6,350 patients, with seven tri-
The Dutch group have recently reported 10-year als using a short-course of radiotherapy with
outcome data. Subset analysis of the CRM-ve 5 Gy fractions. A significant reduction was dem-
subset demonstrated a benefit for SCPRT for all onstrated in both local recurrence (p < 0.00001)
rectal subsites. The initial CR07 trial report also and overall recurrence (p < 0.00001). A 2.9%
described this finding. A further subset analysis absolute difference in overall survival was seen
showed a statistically improved overall survival in favour of adjuvant radiotherapy (p = 0.06).
for patients with stage III CRM-ve disease with A significant increase in non-cancer-related
the addition of SCPRT. Long-term follow-up from deaths was also seen for patients who received
the CR07 data is awaited regarding this finding. preoperative radiotherapy. The reasons for this
latter finding remain unclear 10 years after this
finding was reported. Other meta-analyses
12.3.2 Population-Based Data broadly concur with these findings.
There is a strong evidence base supporting
Den Dulk et al. used cancer registry records to the benefit of SCPRT with an approximate
identify 3,179 patients with rectal cancer treated halving in local recurrence both before and
12 When Should Preoperative Short-Course Radiotherapy or Long-Course 109
after the introduction of TME. Its impact on toxicity was also significantly less with the pre-
overall survival is less clear, but the current operative approach.
evidence suggests that if any survival advan- The results of these three trials led to a major
tage is achieved, it is very small and does not shift from selective post-operative CRT-based
exceed 2–3%. Other meta-analyses have reported to imaging-based selection of patients for pre-
similar conclusions. operative CRT. This strategy has been further
supported by the results of the NSABP R03 trial
(Table 12.3) The NSABP R03 used a similar
12.4 Evidence Supporting design to the German trial but only recruited
Long-Course Preoperative 267 of its planned patient target number
Chemoradiotherapy (n = 900), so results should be interpreted with
caution. Five-year loco-regional recurrence was
12.4.1 Clinical Trials 10.7% in each treatment arm (p = 0.693).
A significant improvement of 5-year DFS (65%
This approach was initially developed as post- vs. 53% p = 0.011) and a non-significant
operative adjuvant therapy. In North America, an improvement in 5-year OS (75% vs. 66%
NIH consensus statement in 1990 recommend p = 0.065) were also observed for the preopera-
the use of adjuvant post-operative chemotherapy tive arm.
and concurrent chemoradiotherapy using 5FU for Whilst the trials discussed above selected
all patients with T3/4 or node-positive resected patients with resectable disease, a Scandinavian
rectal cancer. trial of 207 patients with non-resectable rectal
In Europe, two phase III trials were performed cancer conducted between 1996 and 2003 ran-
between 1993 and 2003 that compared long- domised patients to receive CRT with 50 Gy plus
course preoperative radiotherapy (45 Gy in 25 5FU/LV versus long-course radiotherapy alone
fractions) with concurrent 5FU leucovorin added (50 Gy). In this more advanced high-risk group, a
to the same radiotherapy schedule (Table 12.2). statistically significant reduction in local failure,
The FFCD 9203 trial [6] recruited 762 patients time to treatment failure and cancer-specific sur-
and recommended post-operative 5FU/LV for all vival was observed in patients who received pre-
patients, whereas the EORTC 22921 [7] recruited operative CRT.
1,011 patients phase III trials and used a factorial We are not aware of any population-based
design that also compared post-operative CRT analyses of the use of preoperative CRT. This
versus no chemotherapy. approach is however widely used. Concurrent
Both trials demonstrated that the addition of chemotherapy may consist of 5FU either as a
concurrent 5FU/LV was associated with an continuous infusion, in combination with leuco-
acceptable increase in acute toxicity and path- vorin or using an oral fluoropyrimidine such as
ological downstaging. Both trials reported very capecitabine.
similar findings with a significant reduction in
the rate of local recurrence from 15% to
8–10%, but with no difference in disease-free 12.4.2 Meta-analysis
or overall survival. The results are summarised
in Table 12.1. A Cochrane overview identified four trials and
The German rectal cancer group [8] concluded that preoperative CRT enhances path-
(Table 12.3) then directly compared preoperative ological response and improves local control but
versus post-operative 5FU CRT. A total of 823 does not benefit disease-free or overall survival.
patients were randomised between 1995 and A recent pooled analysis of 2,795 patients from
2002. The rate of local recurrence was reduced five European trials showed that preoperative
from 12% with post-operative CRT compared CRT impacted on distant metastases and overall
with 6% with preoperative CRT. Acute and late survival [9].
110
12.5 Direct Comparison of the Two The main concern for many clinicians is the
Approaches use of 5 Gy fractions with the SCPRT regimen
and the risk of substantial late toxicity. This view
Two phase III trials have reported a direct com- is supported by reports from the Stockholm I and
parison of SCPRT with preoperative CRT II trial that reported a significant increase in
(Table 12.4). The Polish trial [10] randomised venous thromboembolism, pelvic and femoral
312 patients with resectable rectal cancer between neck fractures, small bowel obstruction and post-
1999 and 2002. The trial tested the hypothesis operative fistulae. It is possible that the 2-field
that the use of preoperative CRT with a 4–6-week technique and the large field sizes used may
delay to surgery would increase the rate of sphinc- explain some of these findings.
ter preserving resection compared with SPCRT However, the Dutch and CR07 trials have
and immediate surgery. No difference in the pri- reported an increase in faecal incontinence, uri-
mary end point of the sphincter preservation rate nary and sexual dysfunction and second malig-
was seen. The 5-year rate of local recurrence was nancy when SCPRT is combined with TME.
9% and 14% (p = 0.17) for SCPRT and CRT, The data from the MCR CR07 trial demonstrate
respectively, with no significant difference in that a substantial component of late toxicity is
disease-free and overall survival. attributable to surgery with a smaller but
The Trans Tasman Group (TROG) trial also significant additional impact due to the addition
randomised 326 patients with resectable rectal of SPCRT [11].
cancer between 2001 and 2006 to receive either These findings support the concerns regard-
SPCRT or preoperative CRT to compare the rate ing late radiation toxicity with the use of 5 Gy
of local recurrence. The initial report at ASCO in fraction size. However, it is important to recog-
2010 reported no statistical difference in the pri- nise that the key trials of SCPRT have all
mary end point of local recurrence or secondary reported detailed analyses of late toxicity. This
end pointes of failure-free or overall survival. contrasts with very few publications that report
The two trials discussed above are underpow- the incidence of late complications after preop-
ered, either individually or combined, to detect a erative CRT.
clinically relevant but small difference in LR (i.e. A recent publication by Tiv et al. [12] describes
5%) and therefore do not provide sufficient evi- quality of life outcomes in the EORTC 22921
dence to definitively compare efficacy. trial after a median of 4.6 years. Low quality of
life scores for sexual functioning were reported
and were more severe in men than women. The
12.6 Acute and Late Toxicity addition of chemotherapy to radiotherapy was
of SCPRT and CRT associated with increased diarrhoea and lower
global quality of life. There is no data that com-
As SCPRT and CRT appear broadly comparable in pares the late toxicity of surgery versus preopera-
terms of efficacy despite the dangers of cross trial tive CRT.
comparison, a comparison of acute and late toxic- The Polish and the TROG trials are of con-
ity is of considerable importance. Data from the siderable importance when comparing the late
Polish trial demonstrated 18% acute toxicity with toxicity of SCPRT against preoperative CRT
CRT compared with 3% with SCPRT, respectively due to the randomised comparison of the two
(p < 0.001). The provisional report from the TROG treatment approaches. The Polish trial [10]
trial shows a similar pattern. In contrast, SCPRT is reported no significant difference for severe late
associated with a subacute neuropathy in <1–2% toxicity with rates of 10% and 7% for SPCRT
of patients which is usually reversible. This side and CRT, respectively (p = 0.17). A recent pre-
effect has not been reported after CRT. Late toxic- sentation from the TROG trial did not detect any
ity appears also equivalent in the two trials, although significant quality of life differences between
the details and documentation are limited. the treatment arms.
112
12.7 Summary of the Current Data well as the distance from the most lateral extent
of gross tumour to the mesorectal fascia, leva-
There is strong evidence that supports the use of tor or anal sphincter depending on the level
both SPCRT and preoperative CRT. Regarding within the rectum. All imaging modalities have
efficacy, both approaches approximately halve limitations in their accuracy of predicting
the rate of local recurrence with no convincing lymph node involvement. However, enlarged
evidence of an impact in disease-free or overall nodes with an irregular border and mixed signal
survival within the individual clinical trials. This characteristics are more likely to be involved
finding probably reflects the observation that the by tumour.
majority of patients within these trials had early In routine clinical practice, the radiologist can
stage disease. identify the imaging T stage and the presence or
Local recurrence reflects both tumour stage absence of any involved nodes using the above
and surgical technique, but the development of criteria, macroscopic extramural vascular inva-
metastases appears relatively independent of sur- sion, and patients where the lateral resection mar-
gery as the clinical trials demonstrate that 25–40% gin is at risk (<1 mm) or involved by tumour.
of patients with resectable disease develop metas-
tases despite increasingly low rates of local recur-
rence. Hence, the consistent improvement in 12.9 Selection of Patients for
local control resulting from SCPRT and CRT in Preoperative Radiotherapy
rectal cancer in the total mesorectal excision era (SCPRT or CRT)
has not translated into a benefit in overall
survival. The local disease extent demonstrated on pelvic
Both approaches increase the rate of late tox- staging investigations results in a spectrum of
icity when added to TME, and although there are disease ranging from the smallest tumour consid-
more publications describing late toxicity after ered on imaging to be T2 or less without any
SCPRT, it is likely that CRT results in similar lev- adverse radiological features through to very
els of toxicity. This conclusion is supported by large and bulky T3/4 tumours.
the data from the Polish trial. It is therefore essen- Many centres will seek to identify patients
tial that we consider both the risks as well as the with early stage disease where preoperative
benefits when considering the use of either radiotherapy can be avoided at the early end of
SCPRT or CRT. the disease spectrum. The Dutch and CR07 trials
both demonstrate a 3% rate of local recurrence
for patients with T1–2 N0 disease. It is impor-
12.8 Preoperative Staging tant to exclude the presence of any adverse risk
factors (including EMVI and unequivocal lymph
High-quality imaging investigations are of crit- node involvement) to safely omit SPCRT or CRT
ical importance to determine whether there is in patients with a primary tumour staged as T2
any evidence of metastatic disease and the local or less.
disease extent within the pelvis. In early stage At the other end of the spectrum, preoperative
disease, transrectal ultrasound has an important CRT is the treatment of choice when the primary
role, although in the majority of patients, high- tumour is staged radiologically as T4b (involve-
resolution pelvic MRI is considered the investi- ment of another organ) or when macroscopic
gation of choice. The prospective multicentre tumour involved or threatens (<1 mm) the
MERCURY trial established that the measured mesorectal fascia levator or sphincter complex.
extramural spread of primary tumour seen on Current evidence supports the use of concur-
pelvic imaging was equivalent to the same mea- rent 5FU/LV, continuous infusion 5FU or an oral
surement in the resection specimen. The mac- fluoropyrimidine. There is limited comparative
roscopic extramural spread can be measured as data regarding the choice of fluoropyrimidine,
114 D. Sebag-Montefiore and R. Glynne-Jones
although an initial report at ASCO 2011 from the of patients at higher risk of local recurrence or pre-
NSABP R04 trial suggests similar toxicity for dict which patients would benefit most. We there-
concurrent capecitabine compared with continu- fore rely on known histopathological prognostic
ous infusion 5FU. The addition of biological or factors that can also be identified on pelvic MRI
chemotherapy agents should only be evaluated in prior to surgical resection. This included the mea-
the context of clinical trials and is discussed in sured depth of extramural spread of primary T3
Chapters 19 and 18 respectively. disease, the presence of macroscopic vascular
When preoperative CRT is given, an interval invasion and involvement of lymph nodes using
of 4–12 weeks is used to allow tumour regression the criteria described above.
prior to resection with little research evidence to There is clear evidence that supports the
indicate the best time interval to use. choice of either SCPRT or preoperative CRT for
Some patients are considered unsuitable for this group. The current evidence that has com-
preoperative CRT, on the basis of biological age, pared these two approaches is limited but sug-
performance status or major cardiovascular co- gests that the two approaches are broadly similar
morbidity. In this situation, an alternative option in their ability to lower the risk of local recur-
is to use SCPRT with a delay of 6–12 weeks prior rence and so both approaches are acceptable. The
to surgery. The supporting evidence for this authors believe that both SCPRT and CRT are
approach is limited. Individual centre experience acceptable options.
has been reported from Upsalla in Sweden and The National Institute of Health and Clinical
Leeds in the United Kingdom. This is further Excellence has recently released the pre-publica-
supported (albeit in resectable cancers) by an tion of the 2011 colorectal guidelines for the
interim analysis of the Stockholm IV trial which United Kingdom (http://guidance.nice.org.uk/
compares SCPRT with immediate surgery, CG/Wave16/2). This document describes the
SCPRT with delay and 50 Gy in 25 fractions with identification of three differing levels of risk for
delay to surgery. local recurrence and is shown in Table 12.5.
The remaining patients, where the primary Patients are considered low risk when the pelvic
tumour is staged as T3 but does not involve or MRI demonstrated T3a disease or less without
threaten the margins, represent over 50% of adverse features. The authors support the view
patients with rectal cancer, and it is this group that this patient group should avoid radiotherapy
where the role of SPCRT or CRT is frequently altogether and have surgery alone.
debated. The routine use of either SPCRT or CRT Moderate risk is defined as any patient with
represents substantial overtreatment, and in the imaging stage T3b or greater tumour (>5 mm
opinion of the authors, a selective approach is beyond the muscularis propria) or EMVI or
essential, attempting to balance the benefits in the lymph node involvement without any threat to
reduction of local recurrence against the late tox- the margin. The authors support the view that this
icity associated with SCPRT or CRT. patient group should be considered for either
This underlines the need to identify predictive SPCRT or preoperative CRT. Both approaches
factors to assist the decision-making process. Little have supporting evidence, and it is not possible to
progress has been made in the identification of distinguish any clear efficacy or late toxicity dif-
molecular biomarkers to either assist the selection ferences based on the available data.
12 When Should Preoperative Short-Course Radiotherapy or Long-Course 115
Fig. 12.1 Management of Management of local disease - patients with rectal cancer
local disease (From 2011
NICE guidance)
Patient with
rectal cancer
Consider Consider
Chemoradio−
therapy2
SCPRT
Surgery
Patients are considered high risk if tumour local recurrence and entail a high risk of meta-
breaches or threatens (<1 mm) the mesorectal fas- static disease. In contrast to 5FU-based CRT
cia, levator or intersphincteric plane (Fig. 12.1). with an interval to allow downsizing, SCPRT
allows definitive surgery to take place without
Conclusions delay and allows the use of systemically active
Preoperative radiotherapy has a strong sup- chemotherapy (FOLFOX) within weeks.
porting evidence base demonstrating that the In view of the well-documented long-term
rate of local recurrence can be approximately side effects associated with radiation, it is
halved when combined with TME. In contrast important to identify patients at low risk of
to unresectable/borderline resectable cancers, local recurrence who can avoid radiotherapy
there is no evidence for increased efficacy of altogether. Imaging can clearly identify patients
CRT over SCPRT in moderate-risk resectable whose margins are at risk and require preoper-
cancers. The two strategies appear equally ative CRT.
effective, and the main rationale for choosing The main challenge is the majority of patients
between them in this setting relies on high- with T3 disease where the balance between risk
quality MRI-based staging to identify the and benefit must be carefully considered and
extent of local disease and the presence of key where both SPCRT and preoperative CRT are
prognostic factors, which increase the risk of acceptable treatments. Further research is needed
116 D. Sebag-Montefiore and R. Glynne-Jones
in translational molecular biology, pharmacog- 6. Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet
enomics and biological imaging to identify O, Closon-Dejardin MT et al (2006) Preoperative
radiotherapy with or without concurrent fluorouracil
patients either at excess risk of radiation-related and leucovorin in T3–4 rectal cancers: results of
toxicity or whose cancers are more likely to FFCD 9203. J Clin Oncol 24(28):4620–4625
benefit from preoperative radiation and/or 7. Bosset JF, Collette L, Calais G, Mineur L, Maingon P,
fluoropyrimidine chemotherapy. Radosevic-Jelic L et al (2006) Chemotherapy with
preoperative radiotherapy in rectal cancer. N Engl J
Med 355(11):1114–1123
8. Sauer R, Becker H, Hohenberger W, Rodel C,
Wittekind C, Fietkau R et al (2004) Preoperative ver-
sus postoperative chemoradiotherapy for rectal can-
References cer. N Engl J Med 351(17):1731–1740
9. Valentini V, van Stiphout RG, Lammering G,
1. Swedish Rectal Cancer Trial (1997) Improved sur- Gambacorta MA, Barba MC, Bebenek M et al (2011)
vival with preoperative radiotherapy in resectable rec- Nomograms for predicting local recurrence, distant
tal cancer. Swedish Rectal Cancer Trial. N Engl J Med metastases, and overall survival for patients with locally
336(14):980–987 advanced rectal cancer on the basis of European ran-
2. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, domized clinical trials. J Clin Oncol 29(23):3163–3172
Steup WH, Wiggers T et al (2001) Preoperative radio- 10. Bujko K, Nowacki MP, Nasierowska-Guttmejer A,
therapy combined with total mesorectal excision for Michalski W, Bebenek M, Kryj M (2006) Long-term
resectable rectal cancer. N Engl J Med 345(9):638–646 results of a randomized trial comparing preoperative
3. Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, short-course radiotherapy with preoperative conven-
Grieve R, Khanna S et al (2009) Preoperative radio- tionally fractionated chemoradiation for rectal cancer.
therapy versus selective postoperative chemoradiother- Br J Surg 93(10):1215–1223
apy in patients with rectal cancer (MRC CR07 and 11. Stephens RJ, Thompson LC, Quirke P, Steele R,
NCIC-CTG C016): a multicentre, randomised trial. Grieve R, Couture J et al (2010) Impact of short-
Lancet 373(9666):811–820 course preoperative radiotherapy for rectal cancer on
4. Tiefenthal M, Nilsson PJ, Johansson R, Glimelius B, patients’ quality of life: data from the medical research
Pahlman L (2011) The effects of short-course preop- council CR07/National Cancer Institute of Canada
erative irradiation on local recurrence rate and sur- Clinical Trials Group C016 randomized clinical trial.
vival in rectal cancer: a population-based nationwide J Clin Oncol 28(27):4233–4239
study. Dis Colon Rectum 54(6):672–680 12. Tiv M, Puyraveau M, Mineur L, Calais G, Maingon P,
5. Colorectal Cancer Collaborative Group (2001) Bardet E et al (2010) Long-term quality of life in
Adjuvant radiotherapy for rectal cancer: a systematic patients with rectal cancer treated with preoperative
overview of 8,507 patients from 22 randomised trials. (chemo)-radiotherapy within a randomized trial.
Lancet 358(9290):1291–1304 Cancer Radiother 14(6–7):530–534
Should We Tailor the Delineation
of Pelvic Structures According 13
to Tumor Presentation?
with rectal cancer continue to be treated with The presacral space represents the area where
standard pelvic radiotherapy fields irrespective to the majority of local relapses of all rectal cancer
tumor presentation at diagnosis. are concentrated. All studies analyzing rate and
site of local recurrences in rectal cancer described
the majority of them located in the posterior pel-
13.1 Contouring Guidelines vis. Although decreased after the introduction of
TME, the presacral space remains the first area of
After the introduction of conformal radiotherapy, local recurrence in rectal cancer; long-term
recommendations for contouring were published; results from Dutch-TME trial show the presacral
the most followed are essentially two: one from space as the first area of local recurrence in both
Europe and the other from the USA [10, 11]. randomization groups: RT + TME 2% versus
In the European guidelines, provided by Roels TME 3.6% [13]. The mechanism of occurrence
and coworkers, five different pelvic subsites were of presacral recurrence is puzzling: the presacral
identified according to the analysis of the inci- space is the easiest plane of dissection during
dence and site of pelvic relapses in rectal cancer: surgery, is always included in the radiotherapy
• Mesorectal subsite (MS) encompassing the field, is often boosted when long-course radio-
entire mesorectum and the mesorectal fascia therapy is delivered, and develops despite pre-
• Posterior pelvic subsite (PPS) corresponding sacral IORT is delivered. A recent anatomical
to the presacral space analysis did not find lymphatic tissues in the pre-
• Inferior pelvic subsite (IPS) corresponding to sacral space. Different mechanisms for local
the ischio-rectal fossae relapse were supposed other than lymph node
• Lateral pelvic subsite (LPS) encompassing to involvement: tumor cell spillage from positive
the extramesorectal nodes corresponding to margins, although presacral recurrence is com-
the obturator an internal iliac nodes mon even in patients with negative margins, and
• Anterior pelvic subsite (APS) corresponding seedings from tumor cells in the lateral spaces
to all pelvic organs that are located ventrally during surgical manipulation [14].
from the MS The mesorectum with its fascia must always
Anatomical boundaries for CT delineation be included in the CTV delineation.
were defined for each subsite. The mesorectum is the adipose tissue, bound-
The US guidelines, proposed by RTOG, devel- ing the mesorectal fascia, which posteriorly and
oped three elective CTVs for the contouring of rec- laterally surrounds the extraperitoneal rectum. It
tal and anal cancers, based on a consensus process: contains the neural and lymphovascular structures
• CTV A defined as the presacral, perirectal, and and is the first site of lymph node involvement in
internal iliac nodes rectal cancer. Surgical series analyzing mesorec-
• CTV B defined as the external iliac nodes tal lymph node involvement showed at least one
• CTV C defined as the inguinal nodes positive lymph node in this area in 46% of patients
Anatomical boundaries for CT delineation [10]. After the introduction of TME, the inci-
were defined for each CTV. dence of recurrence in this site is very low.
However, the analysis of radiological exams of
patients with local recurrence after TME showed a
13.2 Local Recurrences 50% of presence of perirectal fat below the anasto-
mosis, suggesting a not complete mesorectal exci-
Data reporting the patterns of local recurrence in sion although TME surgery was declared by the
rectal cancer, in the TME era, are scarce and con- surgeon; moreover, the majority of patients having
tradictory, leading to confusion regarding the a local relapse at the anastomosis had residual
definition of radiotherapy treatment volumes. mesorectal fat, suggesting a possible increased
Anyway, the following separated areas at risk rate of anastomotic recurrence due to the residual
could be identified. mesorectal fat left behind after surgery [15].
13 Should We Tailor the Delineation of Pelvic Structures According to Tumor Presentation? 119
This supposition is also supported by the long- laterally to the parietal fascia of the mesorectum
term results of the Dutch-TME trial in which the which is usually not removed with the TME sur-
rate of recurrence was higher in patients with pos- gical procedure [14]. This supports the impor-
itive nodes in the TME arm, when the distal mar- tance of the inclusion of the entire mesorectal
gin was 2 cm or lower; in the RT arm, the rate of fascia (visceral and parietal) in the treatment vol-
local recurrence was low except when the distal umes. Further supporting this is the fact that the
margin was less than 5 mm. Data from pathologi- higher tumor regression achievable with preop-
cal specimens showed a presence of positive erative long-course chemoradiation compared
lymph nodes or tumor deposits in the perirectal fat with short-course radiotherapy could be due to
distal to the tumor between 6.4% and 20.2% and the sterilization of the mesorectal fascia, allow-
usually located within 2–3 cm from the cancer. A ing a TME with clear CRM [18].
higher probability of distal tumor deposits when More controversial is the decision to include
positive mesorectal nodes are present may explain the lymph nodes located in the lateral spaces.
the higher incidence of local relapses in the TME A revision of the sites of local recurrence after
arm of the Dutch trial [13]. For the reasons men- the introduction of TME recommends reducing
tioned above, the mesorectum should always be the volume of treatment due to the higher rate of
included in the CTV of patients with rectal cancer recurrence in the posterior pelvis and the anasto-
treated with preoperative radiotherapy. mosis (overall 68% and as high as 89% when
The involvement of CRM has been demon- excluding cT4 at diagnosis which was significantly
strated to be a highly independent predictor of associated with anterior recurrence) [19]. These
both local control and survival; its positivity is data are consistent with a recently published
well predicted by preoperative MR. The impor- study which demonstrated that radiological evi-
tance of inclusion of the entire mesorectal fascia dence of recurrence in the lateral lymph nodes is
in the CTV, even when negative, is based on a well below 5% [15]. However, these results could
subset of patients from a Japanese surgical study be influenced by classification of the site of local
reported by Moriya et al. [16]. In this trial, relapse on the radiologic images used in that
patients with pathologic positive nodes who study. This finding, together with the observation
underwent lateral lymph node dissection com- that the majority of local recurrences, even after
bined with resection of the autonomic nervous preoperative radiotherapy, are presacral or anas-
system, located along the parietal mesorectal fas- tomotic, supports the idea to limit the radiother-
cia, on the affected site had a significant better apy field to the central areas at higher risk of
DFS compared to patients with positive lateral recurrence, at least in selected cases with both
nodes who underwent lateral dissection with negative mesorectal lymph nodes and CRM [20].
preservation of the autonomic nervous system Conversely, the patterns of local recurrence in the
(53% vs. 27%). These data suggest the presence update from the Dutch-TME trial revealed the
of microscopic residual tumor remaining on presacral space as the first site of relapse in
the parietal fascia following surgery. Recently, both arms, a lower anastomotic recurrence in
Nagtegaal reported increased local recurrence the radiotherapy arm, and lateral recurrences
rates, distant metastases, and a 50% decrease in accounted for about 20% of all local recurrences
survival in patients with close or positive circum- [13]. These data are consistent with those reported
ferential radial margins (CRM) after TME as in surgical series, in which patients with low-
well as the presence of tumor cells in the radial lying tumors have approximately 10–25% [21–
margin far from the macroscopic tumor invasion 25] positive lateral lymph nodes at diagnosis.
[17]. These data are further supported by the Furthermore, as high as 40% of patients with
autopsy data from pelvic dissection in the ten involved extramesorectal nodes developed local
fetuses which confirmed the presence of lym- recurrence. The rate of local recurrence was
phatic tissue around the medial part of the infe- related to the number (³4) and the site (obturator
rior hypogastric plexus, anatomically located area) of positive lateral nodes [21].
120 M.A. Gambacorta and V. Valentini
Table 13.1 Guidelines for pelvic lymph node contouring in rectal cancer
Cranial Caudal Anterior Posterior Medial Lateral
Mesorectum Bifurcation of the Insertion of the levator Superior: Anterior limit Superior: Mesorectal Superior: Mesorectal
inferior mesenteric ani muscle into the rectal of superior rectal vessels fascia in front of sacral fascia/internal and
artery (IMA) in sigmoid wall/disappearing of or a virtual line between concavity external Iliac lymph
and superior rectal artery mesorectal fat tissue the anterior aspect of node area
around the rectum internal iliac vessels of
both sides
Inferior: Bladder, Inferior: Levator ani Inferior: Levator ani
prostate/seminal vesicle muscle muscle
in man, vaginal wall/
uterus in woman
Presacral space Sacral promontory Coccyx Superior: 1 cm in front Sacral concavity Lateral border of the
(posterior pelvic of the bone sacrum
subsite) Mid-inferior: Presacral
fascia/posterior
mesorectal fascia
Internal iliac nodes Bifurcation of common Ending of the mesorec- Superior: Behind the Lateral edge of the Mesorectal Superior: Psoas
(lymph node regions) iliac artery into internal tum /appearance of external iliac vessels sacro-iliac joint fascia, pelvic muscle and ileum
and external iliac arteries ischio-rectal fossae Mid-inferior: Behind Pyriform muscle organs Inferior: Internal
(bony reference L5–S1) obturator nerve obturator muscle
Obturator nodes (lymph Caudal border of The entrance of the Posterior aspect of the Posterior aspect of the Mesorectal Internal obturator
node regions) sacro-iliac joint obturator nerve/artery in external iliac vessels obturator nerve fascia, pelvic muscle and ileum
the obturator canal organs
External iliac nodes Bifurcation of common The start of the femoralSuperior-mid: 0.7 cm Posterior aspect of the Mesorectal Psoas muscle, iliac
(lymph node regions) iliac artery into internal vessels from the vessel external iliac vein fascia, pelvic muscle
and external iliac arteries Inferior: Abdominal wall organs
(bony reference L5–S1) muscles
Sphincter complex 1.5 cm around the internal and external anal sphincters
Inferior pelvic subsite Levator ani muscle Skin Obturator muscle A virtual line between Anal canal Obturator muscle and
(ischio-rectal fossae) the posterior profile of gluteus muscle
the gluteus muscle of
both sides
M.A. Gambacorta and V. Valentini
13 Should We Tailor the Delineation of Pelvic Structures According to Tumor Presentation? 123
MF
a b
MF
ONe GMM
PM
EIV
EIA
IM
c d
MF
GMM
IOM
e f
g h
Fig. 13.3 Anatomic atlas for rectal cancer contouring. muscle (c–d); B: bladder (f); IOM: internal obturator mus-
IPM: ileopsoas muscle (a–b); *: superior rectal artery (b); cle (f); GMM: gluteus major muscle (a–h) PS: yellow
MF: Mesorectal fascia (b–f); ONe: obturator nerve (c–d); (a–e); EIN: green (a–e); IIN: blue (a–f); M: brown (b–g);
EIV: external iliac vein (b-e);, EIA: external iliac artery ON: pink (c–f); IPS: dotted blue (g); SC: dotted yellow
(b–e); PM: pyriform muscle (c–d); U: uterus (e); IM: Iliac (h) (Images by the courtesy of TIGER project)
Guidelines have the advantage to standardize the uterus/vagina, prostate) are present; however, in
target volume delineation; however, some uncer- the superior pelvis, its anterior part has not an ana-
tainties still remain and are hard to be solved [8]. tomical boundary. We suggest to enclose all the
The mesorectum is easy to identify in the mid- superior rectal vessels when visible, since several
low pelvis where the pelvic organs (bladder, times, lymph nodes can be visible in this area
124 M.A. Gambacorta and V. Valentini
GMM
IPM *
IPM
a b
MF
GMM
GMM PM
PM ONe
EIV U
U
IM EIA IM
c d
MF
GMM ONe
GMM
U IOM
B
GMM
e f
GMM GMM
g h
Fig. 13.4 CT Atlas for rectal cancer contouring. IPM: (c–d); B: bladder (f) IOM: internal obturator muscle (f);
ileopsoas muscle (a–b); * superior rectal artery (b); MF: GMM: gluteus major muscle (b–h) PS: yellow (a–f); EIN:
Mesorectal fascia (c–f); ONe: obturator nerve (c–f); EIV: green (a–e); IIN: blue (a–f); M: brown (b–g); ON: pink
external iliac vein (c); EIA: external iliac artery (c); PM: (c–f); IPS: dotted blue (g); SC: dotted yellow (h)
pyriform muscle (c–d); U: uterus (c–d); IM: Iliac muscle
(Figs. 13.3b and 13.4b), which corresponds usu- The internal iliac nodes, in the mid-low pelvis,
ally with the anterior limit of the lateral nodes. have not a corresponding visible vessel on CT.
The presacral space is so tiny that it is often We suggest to contour the triangular lymphovas-
not visible on CT scan or overlaps other areas at cular fat area located between the pelvic wall and
risks. We suggest to enclose it in mesorectum. the mesorectum.
13 Should We Tailor the Delineation of Pelvic Structures According to Tumor Presentation? 125
Table 13.2 Target volume delineation according to tumor stage and location
Presacral Internal Obturator External Sphincter Ischio-rectal
space Mesorectum iliac nodes nodes iliac nodes complex fossae
cT3 high (above + + +
the peritoneal
reflection)
cT3 mid-low + + + + + (when anal + (when direct
(at the peritoneal canal tumor
reflection) invasion) infiltration)
Any cT with + + + + + (when anal + (when direct
massive positive canal tumor
internal iliac invasion) infiltration)
nodes
Any cT with + + + + + + (when anal + (when direct
massive positive canal tumor
obturator nodes invasion) infiltration)
cT4 with for + + + + + + (when anal + (when direct
anterior pelvic canal tumor
organ invasion) infiltration)
The obturator nerve used as posterior limit of rectal cancers located at >1.5 cm from the from
the obturator nodes could seem difficult to iden- the anal-rectal ring, the lower border should be
tify; however, although very tiny, it may be fol- limited at the end of the mesorectum; (2) in
lowed, scrolling CT images, as a straight structure tumors located £1.5 cm from the anal-rectal ring,
located behind the external iliac vessels, through the lower border should extend to encompass
the whole pelvis (Fig. 13.4c–f). 1 cm of the anal canal; (3) in tumors extending
The external iliac nodes are the easiest to through the anal canal, all the anal canal and the
identify, thanks to the external iliac arteries and sphincter complex should be included; although
veins well visible on CT scan (Figs. 13.3c and in the literature the margin around the sphincter
13.4c). We suggest to start from this structure for complex is not indicated, we recommend
the contouring of the lateral lymph nodes. 5–10 mm of fat around it; (4) when the rectal
fossa is directly infiltrated by the tumor, both the
ischio-rectal fossae should be enclosed.
13.4 CTV Definition Inguinal nodes are not the target in rectal can-
cer; however, when most of the anal canal or the
The inclusion of lateral nodes in the pelvic target ischio-rectal fossa is infiltrated in both these cases
volume for preoperative radiotherapy should be also, they should be part of the CTV.
personalized according to tumor stage, tumor The introduction of the IMRT for the treat-
site, and lymph node location as follows ment of rectal cancer requires a proper and shared
(Table 13.2): always include the primary tumor, definition of the volumes of interest on CT
the entire mesorectum, presacral space, and inter- images; moreover, a careful center-based evalua-
nal iliac nodes in all T3 tumors. In addition, the tion of the target motion results is fundamental
obturator nodes should be added for mid-low- for the evaluation of the correct ITV to avoid tar-
located T3 tumors (< at or below the peritoneal get missing [37].
reflection) or in high T3 with massive positive
IIN. In T4 tumors, with anterior organ invasion, Conclusions
or in T3 tumors with massive obturator node Although agreement exists on the areas at risk
involvement, the addition of the external iliac for local recurrence to be included in the CTV,
nodes is recommended [11, 34] (Fig. 13.5). however, this is not the case for the contouring
The lower edge of the CTV may be modulated boundaries. In this chapter, guidelines for the
according to tumor extension and invasion: (1) in contouring of the pelvic subsites in rectal
126 M.A. Gambacorta and V. Valentini
a c
b d
Fig. 13.5 (a) CTV_T3 mid-low; (b) PTV_T3; (c) CTV_T4; (d) PTV_T4
cancer are proposed to increase the confor- tal cancer (MRC CR07 and NCIC-CTG C016): a mul-
mity in volumes definition among different ticentre, randomized trial. Lancet 373:811–820
3. Bosset JF, Collette L, Calais G et al (2007)
radiation oncologists, to decrease uncertain- Chemotherapy with preoperative radiotherapy in rec-
ties when more conformal technique of irra- tal cancer. N Engl J Med 355:1114–1123
diation such as IMRT are used, to modulate 4. Gerard JP, Conroy T, Bonnetain F et al (2006)
volume definition according to tumor presen- Radiotherapy with or without concurrent fluorouracil
and leucovorin in T3–4 rectal cancers: results of
tation (stage and location), and to facilitate FFCD 9203. J Clin Oncol 24:4620–4625
training of radiation oncologists in training. 5. Gunderson LL, Russell AH, Llewellyn HJ et al (1985)
Treatment planning for colorectal cancer: radiation
and surgical techniques and value of small-bowel
films. Int J Radiat Oncol Biol Phys 11:1379–1393
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What Is the Role of IMRT and IGRT
in Rectal Cancer? 14
Jasper Nijkamp, Karin Haustermans,
and Corrie A.M. Marijnen
The ‘good’ rectal cancers are T1 or T2, node- ‘Ugly’ tumours have features such as a T4 stage,
negative rectal cancers that show no bad prognos- extensive lymph node involvement and are cor-
tic factors on their MRI image. After TME related to a high risk of local recurrence and dis-
surgery, local recurrence rates in these patients tant metastases. Improvement in treatment can be
are very low and cure rates are high [9, 10]. More achieved by early prediction of response, allow-
experimental treatment options such as transanal ing quick adaptation of treatment such as
endoscopic microsurgery (TEM) with or without intensification of chemotherapy, dose escalation
preoperative chemoradiotherapy (CRT) or or the addition of targeted therapies.
chemoradiotherapy followed by a wait-and-see The above-mentioned approaches call for
policy are becoming more popular [11–15]. The improvement of the current possibilities. First of
major aim of these strategies is rectum preserva- all, we need appropriate imaging to select the
tion with the subsequent improved quality of life patients, to allow for preoperative risk indication.
[16]. The question is whether these approaches Second, we need strategies to select patients well
are safe and feasible with local recurrence rates responding to preoperative treatment, either to
varying between 5% and 28% for T1 patients and have them qualified for organ-saving strategies or
11–45% for T2 patients in the context without to adapt the chemotherapy in non-responding
preoperative treatment [11, 12]. Treatment with patients. We may need a higher dose to the gross
TEM surgery alone should only be considered in tumour volume to improve the complete response
those patients with the lowest risk of local recur- rates of patients selected for organ-saving proce-
rence. Since lymph nodes are not removed with dures. An integrated boost may be a way to
TEM surgery, a negative lymph node status is by accomplish this.
far the most important prognostic factor for the
local recurrence risk in patients treated with TEM
only. At present, a chance of lymph node involve-
ment of 6% is considered acceptable to proceed 14.2 Evolution of Radiotherapy
with local excision only. Treatment Technique in Rectal
Cancer
Fig. 14.1 Example of a three-field conformal plan (left) outlined in dark blue, the PTV in aqua and small bowel in
and a seven-field IMRT plan (right) on the same patient in yellow
transversal (top) and sagittal (bottom) view. The CTV is
PTV. An improvement in conforming the dose to Besides having a limited number of beam angles
the PTV was made with the introduction of three- (step and shoot), the IMRT can also be delivered
and four-field box techniques, although the lack in a continuous fashion during which the collima-
of visualization of the actual target volume tor, rotation speed and intensity can be modulated
resulted in field borders defined by bony anatomy (intensity-modulated arc therapy (IMAT)) [21].
on fluoroscopic images. Each beam was rectangle Each of the above-described improvements in
shaped, and the size was defined by the outer bor- radiotherapy delivery resulted in more confor-
ders of the PTV. With the introduction of com- mality to the PTV and, subsequently, lower dose
puted tomography (CT), delineation of the CTV, to the surrounding healthy tissues. Several options
3D treatment planning and the multi-leaf colli- are available to further improve radiotherapy.
mator, each beam could be adapted to the actual The required PTV margin is based on geometri-
shape of the PTV, resulting in conformal RT. cal uncertainties, which describe the differences
Nowadays, we have the ability to deliver the RT between how the radiation was planned and
dose using intensity-modulated radiotherapy the actual treatment situation [18]. With the
(IMRT), where typically seven beams from dif- introduction of image-guided radiotherapy
ferent angles are subdivided into segments, for (IGRT), geometrical uncertainties can be mea-
which the intensity is modulated. With IMRT, the sured and corrected during treatment, allowing
conformality and homogeneity of the dose to the for a reduction of the PTV margin. The acquired
PTV are further improved [19, 20] (Fig. 14.1). IGRT images also enable visualization of the
132 J. Nijkamp et al.
target volume during treatment, for example, 25] and the volume receiving more than 45
with cone beam CT scans, enabling better under- (V45) and 50 Gy (V50) [26, 27], are significantly
standing of the treatment situation. With the reduced using IMRT [6–9]. Recently, Samuelian
introduction of more sophisticated response et al. [28] compared 92 consecutive patients of
monitoring, such as with PET and diffusion- which 61 were treated with conformal RT (CRT)
weighted MRI [22], during treatment, the possi- and 31 were treated with IMRT. In the IMRT
bility of adapting treatment according to group, significantly less patients experienced
radiotherapy response has become possible. acute grade 2 or higher GI toxicity with 32% vs.
These techniques allow for tailoring of the treat- 62% in the CRT group, with differences espe-
ment for each patient, improving the efficacy. cially in diarrhoea (23% vs. 48%) and enteritis
In this chapter, we will address the implications (6% vs. 30%). Although these findings were not
of IMRT and IGRT for rectal cancer treatment as based on randomized phase III evidence, they
well as the possible pitfalls that one may encoun- do indicate that the theoretical dosimetric benefit
ter during introduction of those techniques. of IMRT does translate into a clinical benefit.
IMRT has also shown to be an excellent tech-
nique to deliver a boost to the GTV, simultane-
14.3 Benefits of IMRT ously delivering the standard dose to the CTV [19,
29, 30] without compromising the organ at risk
As mentioned before, CTV for radiotherapy of dose. The boost dose can be used to increase
rectal cancer generally consists of the tumour and down-staging, improve the ability to have an R0
involved lymph nodes (GTV), the mesorectum, resection and increase the percentage of patho-
the internal iliac lymph node regions and the pre- logic complete responders [31]. With 3D confor-
sacral lymph node region [23]. This definition of mal RT, it is almost impossible to deliver a
the CTV results in a horseshoe-shaped target vol- simultaneously integrated boost (SIB) without
ume when visualized in the transversal plane increasing the dose to the organs at risk. More
(Fig. 14.1). The challenge in radiotherapy is to often, the boost dose is delivered in a number of
deliver the dose to the target volume while mini- fractions after the standard dose is delivered, unfa-
mizing the dose to the surrounding organs at risk, vourably increasing the overall treatment time.
such as the small bowel and the bladder. The general advantage of IMRT is a more accu-
In current clinical practice, 3D conformal rate delivery of the dose to the target volume, espe-
three- or four-field dose delivery techniques are cially when the shape of the target differs from a
used most often. For each field, the shape of the sphere-like shape. Different tumour presentations
beam is adapted to the shape of the target volume will generally not result in different shape complex-
using a multi-leaf collimator, while using a uni- ities, and as a consequence, advantages of IMRT
form intensity for the field. With this type of treat- will be applicable to all tumour presentations. IMRT
ment, it is impossible to fully conform to the should therefore ideally be implemented for all rec-
horseshoe shape of the CTV, resulting in delivery tal cancer RT treatments. However, IMRT cannot
of dose to the organs at risk anterior of the CTV, be safely implemented without attention for a num-
especially the small bowel (Fig. 14.1). With IMRT, ber of difficulties that need to be solved.
it is possible to deliver more concave dose distri-
butions, which also have a more uniform dose dis-
tribution. During IMRT, typically seven or nine 14.4 Prerequisites for IMRT
fields from different gantry angles are used with
each field subdivided into different segments with 14.4.1 Target Volume Definition
each of their own intensity (Fig. 14.1).
Important parameters for prediction of acute As more conformality to the target volume is
and late bowel toxicity, such as the volume of reached with IMRT, knowledge and application
small bowel receiving 15 Gy or more (V15) [24, of geometrical uncertainties in the construction
14 What Is the Role of IMRT and IGRT in Rectal Cancer? 133
of a PTV is important to prevent underdosage of CTV and OAR delineation nationwide and estab-
the target volume. lish a learning curve by giving feedback [35].
The first step that needs to be taken for every Multi-modality imaging has been proven to
patient is defining the CTV. In general, the reduce target volume delineation variation in
tumour, involved lymph nodes, the mesorectum other tumour sites [36, 37]. For rectal cancer
and the perirectal, presacral and internal iliac target volume delineation, there is only one study
lymph node regions are advised to be included. In available evaluating the influence of FDG-PET/
rectal cancer RT, several guidelines are available CT imaging [38] (Fig. 14.3). The use of FDG-
as how to interpret these CTV definitions [23, 32, PET resulted in reduced variation for delineation
33]. Roels et al. [23] developed an atlas by first of the GTV. However, tumour cells might also be
selecting required subregions based on literature present outside this GTV and should therefore be
about patterns of local recurrences and subse- included in the CTV. So far, no reliable imaging
quently defining the anatomical borders of these of microscopic tumour cells is available, and
subregions of the CTV. The atlas of Myerson from this perspective, the FDG-PET has no addi-
et al. [32] was developed by an RTOG consensus tional value.
panel. The atlas of Nijkamp et al. [33] was based The value of the MRI in visualizing the
on the guidelines of Roels et al. [23] and was pro- tumour, mesorectal fat and mesorectal fascia is
vided digitally, such that users could approach undisputable. Despite this common knowl-
the atlas similar to approaching a CT scan at edge, delineation on MRI is not routinely done,
delineation. and studies demonstrating its superiority are
not available, except for delineation of the
GTV in low-seated tumours [39] (Fig. 14.4).
14.4.2 Target Volume Delineation Challenges in CTV delineation on MR for
treatment planning are in the image fusion with
Delineation variation of the CTV in rectal can- the planning CT. Problems may occur when
cer is known to be larger than set-up errors [33, large anatomic differences exist between both
34]. Interpretation differences of the CTV scans (Fig. 14.4).
between radiation oncologists can result in
CTV differences up to centimetres, resulting in 14.4.2.1 Small Bowel Toxicity
large systematic errors (up to a standard devia- One of the critical organs in treatment for rectal
tion (SD) of 1 cm) (Fig. 14.2). Delineation vari- cancer is the small bowel. Due to its mobility,
ation is not the same for all regions of the CTV. there is no easily defined maximum tolerated
Close to bony anatomy and muscles, variation dose. However, from literature it can be concluded
is in the order of 0.2–0.4 cm SD, while for the that the occurrence of toxicity is primarily depen-
upper anterior part, close to the bladder and dent on the amount of dose to the small bowel.
small bowel, variation up to 1 cm SD is mea- Baglan et al. [24] showed that a cut-off at
sured [33, 34]. 150 cc of small bowel receiving more than
Measures to reduce delineation variation are 15 Gy divided a group of 40 patients into 0%
the use of guidelines and delineation atlases, the and 50% chance of developing acute grade 3
use of central reviewing experts and addition of diarrhoea. This was later confirmed in a larger
other modality scans such as MR and PET to study by Robertson et al. [25], who showed that
increase the anatomic and functional information. a cut-off point of 120 cc and 15 Gy divided the
Guidelines and a delineation atlas can reduce group into 9% vs. 38% risk of developing grade
the delineation variation significantly down to 3 diarrhoea.
approximately 0.7 cm SD [33]. For late toxicity, Gallagher et al. [26] found
In the ongoing Belgium PROCARE radio- already in 1986 a critical level of 45 Gy to 78 cc
therapy reviewing project, CTV delineations are and 50 Gy to 17 cc of the small bowel predictive
reviewed in a central expert institution to monitor in post-operative RT. Letschert et al. [27] showed
134 J. Nijkamp et al.
afterwards, at a dose range of 40–50 Gy, that a 14.5 Measures to Reduce Irradiated
small bowel volume increase by a factor of 2 Small Bowel Volume
demands for a total dose reduction of 17% for the
same complication rate. 14.5.1 Full Bladder Protocol
Besides the earlier-described effect of using
IMRT instead of conformal RT, several additional Due to the definition of the CTV up to the bifurca-
measures can be taken to further reduce the irra- tion of the common iliac artery into the internal and
diated small bowel volume. In the section below, external iliac artery, there is a high probability that
an overview of all measures and their possible small bowel will be located anterior of the CTV. In
advantages is given. order to reduce the dose to the small bowel, it is
14 What Is the Role of IMRT and IGRT in Rectal Cancer? 135
a b
Fig. 14.3 Example images acquired using a PET-CT and also in the rectum. In (b), the same patient is shown in
scanner. In (a), a sagittal view of a total body FDG-PET a transversal view, with the CT image on the left and on
image is shown, with clear uptake in the brain, the bladder the right the PET overlaid on the CT image
necessary to push the small bowel out of the high- between increasing bladder volume and decreasing
dose region. Kim et al. [40] showed in a study bowel dose was shown in the context of IMRT.
comparing the small bowel dose using conformal A disadvantage of full bladder instructions is
radiotherapy on full and empty bladder scans of the the large day-to-day variation of the bladder vol-
same individuals a significant reduction in bowel ume [42]. This can potentially lead to large sys-
exposure with increasing bladder volumes. In a tematic differences between planned and delivered
recent study by Nijkamp et al. [41], the relation dose to the small bowel.
136 J. Nijkamp et al.
Fig. 14.4 Sagittal view of a male rectal cancer patient sue contrast, especially useful in the caudal region at the
both on CT (left) and MR (right) after bony anatomy reg- level of the prostate
istration. The MR image has clear superiority in soft tis-
14.5.2 Patient Orientation and Belly combined measures resulted in the least bowel expo-
Board Use sure. When combining a full bladder and a belly
board, patients do however indicate discomfort due
The position of the small bowel can also be to the pressure that is put on the full bladder. In the
influenced by the orientation of the patient dur- study of Nijkamp et al. [41], the clinical relevance of
ing treatment. Supine set-up is generally associ- the significant reduction in bowel exposure using the
ated with more stability during irradiation, easier belly board was questioned. With IMRT and a full
set-up and more patient comfort, while prone bladder protocol, the bowel exposure was on average
treatment, especially on a belly board, is associ- already lower than the cut-off values, predicting
ated with reduced dose to the small bowel [40, acute and late toxicity, independent of patient
41, 43, 44]. orientation.
In many radiotherapy institutes, patients are
treated in prone positioning on a flat table to
reduce small bowel toxicity. However, several 14.5.3 Reduction of CTV
studies failed to show significant differences in
bowel exposure between prone and supine posi- Besides putting effort in changing the patient’s
tioning on a flat table [41, 45]. anatomy or improving the conformality of the
Instead of using a flat table, patients can also be treatment plan, it might also be possible to revise
positioned prone on a belly board, compressing the the currently accepted definition of the clinical
lower abdomen and pushing small bowel away from target volume (CTV) in certain cases. The inter-
the high-dose region. With the belly board, the bowel nationally recognized CTV definition [23] is
exposure is significantly reduced compared to prone based on all available literature about patterns of
or supine positioning on a flat table [40, 41]. This local recurrences to come to a general definition
effect is present both when using conformal RT [40] of the CTV and is irrespective of known risk fac-
and when using IMRT [41]. The study of Kim et al. tors, such as T or N stage. In certain subgroups,
[40] showed relatively more benefit from having a however, a smaller CTV might also be sufficient
full bladder than from the belly board, where the [46–49]. Using a 3D-computed model of all
14 What Is the Role of IMRT and IGRT in Rectal Cancer? 137
Fig. 14.5 Representation of the locations of the local locations are coloured for original tumour distance from
recurrences in the Dutch TME study, with patients treated the anal verge, with 0–5 cm (aqua), 5–10 cm (yellow) and
with a TME only on the left and patients treated with >10 cm (red). The top plane indicates the cranial border
5 × 5 Gy followed by a TME on the right. Recurrence of the used RT treatment fields
Fig. 14.6 Selection of the local recurrences in the Dutch plane indicates the cranial border of the used RT treat-
TME study for patients with node-negative disease, a ment fields. The lower plane indicates the S2-S3 inter-
negative CRM and the tumour <10 cm from the anal verge space, to which the cranial border of the CTV could be
(red dots). Patients in the left image were treated with lowered for these patients
TME only; on the right, RT + TME was given. The top
recurrences in the Dutch TME study, Nijkamp patients received radiotherapy (Fig. 14.5). For
et al. [49] demonstrated that most cranial recur- patients without primary nodal and MRF involve-
rences were located a few centimetres caudal of ment, the most cranial recurrences were all located
the promontory, irrespective of whether the below the level of the S2–S3 interspace (Fig. 14.6).
138 J. Nijkamp et al.
Lowering the cranial CTV border in early rectal conventional fractionated RT, the gain in set-up
cancers may therefore be a very effective way of accuracy should be balanced with the increase in
reducing the irradiated small bowel volume. imaging dose and treatment time, but also with the
other uncertainties.
Set-up errors also occur during treatment frac-
14.6 IGRT tions. These intra-fraction set-up errors are gen-
erally not corrected but need to be quantified to
Apart from the above-mentioned CTV and delinea- be taken into account in the PTV margin. The
tion uncertainties, geometrical uncertainties as magnitude of these errors is dependent on the ori-
inter- and intra-fraction set-up errors and inter- and entation of the patient and the immobilization
intra-fraction target volume variation need to be devices that are used for patient set-up. Prone
compensated for to ensure safe application of IMRT positioning on a flat table is associated with errors
in rectal cancer. All these factors together will up to 0.24 cm systematic and 0.22 cm random in
finally result in a CTV-PTV margin that ensures left-right direction [51], while supine positioning
sufficient coverage of the clinical target volume. is associated with errors £0.1 cm systematic and
The introduction of the cone beam CT has made a random [52].
reliable estimate of these uncertainties possible.
Fig. 14.7 Male patient in a repeat CT study treated with (brown) and CTV (red) are delineated. On the last picture, all
CRT. Sagittal view of a planning CT scan (top left) and nine CTVs of the repeat CT scans are projected on the planning
repeat CT scans. On each scan, the bladder (yellow), rectum CT scan (with the planning CTV in white for visibility)
followed by weekly scans (Fig. 14.7). On a total 14.7.3 Planning Target Volume
of 482 CT scans, the CTV, bladder and rectum Margins to Account for
were delineated and the CTV shape variation was Geometric Uncertainties
determined. In this preoperative study, the het-
erogeneous shape variation as shown by Nuyttens PTV margins are designed to take geometric
et al. [56] was confirmed (Fig. 14.8). In the uncertainties into account and assure a certain
patients treated with CRT, a negative time trend minimum dose to the CTV for a certain percent-
in rectal volume was present, which translated in age of the patient population [18, 58]. Known
a group mean error of approximately 0.5 cm at margin recipes for calculation of PTV margins
the upper anterior border of the mesorectum are defined for rigid translational geometric
(Fig. 14.8). The maximum systematic error was uncertainties, such as patient set-up and CTV
slightly larger in the SCRT patients compared to position variation. However, as described above,
CRT. Based on these results, it is clear that the one of the major geometric uncertainties in
CTV shape variation is one of the major geomet- rectal cancer RT is shape variation of the CTV,
ric uncertainties in radiotherapy of rectal cancer. which cannot be incorporated in the currently
The shape variation is also complex due to its available PTV margin recipes [18, 58]. In the
heterogeneous presentation in different areas of design of a margin recipe for shape variation of
the CTV. the CTV, the first step is to take the correlation
140 J. Nijkamp et al.
−0.4
−0.5
(cm)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
(cm)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
14 What Is the Role of IMRT and IGRT in Rectal Cancer? 141
between the different regions of the CTV into It is important to note that these margins only
account for the systematic error [59, 60]. In the account for shape variation. Other uncertainties,
rigid setting, all movements are correlated, such as set-up and delineated errors, should also be
which is taken into account in the van Herk mar- incorporated in the PTV margin. With online set-
gin recipe by multiplying the systematic error up correction, only intra-fraction stability is impor-
with a factor a = 2.5 [18]. In the deformable set- tant for patient set-up errors. With intra-fraction
ting, it is unclear how, for example, the shape set-up errors being small compared to shape varia-
variation around the sphincter is correlated to tion, influence on CTV coverage is small.
shape variation of the anterior part of the Incorporation of delineation uncertainties is much
mesorectum. To overcome the step of determin- more complex since generally the golden standard
ing the correlation between regions, Nijkamp CTV is not known. Observers who delineate always
et al. [57] used the repeat CT data to estimate too small or always too large will have a different
factor a for shape variation. By varying a effect on cure and toxicity of a patient. Just adding
between 2 and 4 in steps of 0.1, 21 different the derived standard deviations for delineation
PTVs were calculated using: variation to the shape and set-up variation in the
margin concept will probably not solve the prob-
mPTV = α ´ å +0.7 ´ σ + GM lem. This would imply addition of several centime-
tres to PTV margin for delineation variation, while
with the group mean, systematic and random clinical evidence on local control is generally good
errors shown in Fig. 14.8. For each PTV, a dose and not suggesting underdosage. As suggested by
distribution was calculated, and the dose was Weiss and Hess [61], it would be more beneficial to
accumulated over the repeat CT data. With focus on strict delineation guidelines, multi-modal-
a = 3.2, a minimum dose of 95% of the pre- ity information and multidisciplinary discussions
scribed dose could be assured for 90% of the with radiologists to reduce delineation variation.
patients. The subsequent required margins are
shown in Fig. 14.9 for SCRT and CRT sepa-
rately. The provided margin recipe was devel- 14.7.4 Correcting Shape Variation
oped and tested within one data set. To fully
validate the proposed margins, a confirmation Correcting for shape variation errors using IGRT
study is needed. is not as easy as dealing with set-up errors. Due to
142 J. Nijkamp et al.
the changes in the shape of the CTV, a simple local control rates and disease-free survival
adaptation of the table position is not sufficient. regardless of their initial clinical staging [67, 68].
Online shape variation correction would involve Up to now, the gold standard to accurately
on-site treatment planning or choosing the most assess tumour response to preoperative CRT
appropriate plan out of a library of plans for the remains pathological examination of the resec-
shape of that day. Although these strategies seem tion specimen. Standard imaging modalities
promising, they have not been investigated in using morphologic and size-related criteria lack
clinical practice yet. Offline shape variation cor- sufficient accuracy for the differentiation of
rection can be done by means of adaptive radio- responders from non-responders [69]. Functional
therapy (ART). By averaging the shape of the imaging modalities allow to assess treatment-
CTV during the first fractions, a better estimate of induced changes before volumetric changes
the ‘real’ CTV shape can be obtained. This ART become apparent [70, 71].
CTV can be used for replanning, in which smaller In rectal cancer, two imaging techniques show
PTV margins can be used because the shape vari- great promise for response prediction during and
ation error is reduced compared to using the plan- after preoperative treatment, namely, 18fluoro-
ning CTV alone. ART has previously been deoxy glucose positron emission tomography-CT
investigated for prostate cancer patients [62] but (18F-FDG PET-CT, Fig. 14.3) and diffusion-
never for rectal cancer. Like offline set-up correc- weighted MRI (DW-MRI). Changes in 18FDG
tion, ART also focuses on minimizing the sys- uptake, quantified by the standardized uptake
tematic part of the shape variation. Due to the value (SUV), appear to be a valid predictive fac-
large systematic errors in shape variation, up to tor for treatment response. This has been investi-
1.0 cm SD at the upper anterior part of the CTV gated in various studies [22, 64, 72–80]. All these
(Fig. 14.8), ART seems to be promising for rectal studies show that the metabolic response to CRT
cancer RT. The downside of ART is that CTV in rectal cancer with 18FDG-PET-CT, both early
needs to be delineated on the scans made in the and pre-surgical, is correlated to the histo-
beginning of the treatment as well as replanning pathological response in rectal cancer, and this
on the average CTV, which is labour intensive. is despite the differences in study set-up, scan
In summary, the dominant uncertainties that type, pathological and metabolic evaluation.
need to be taken into account in the PTV margin Based on both clinical tumour data and
are shape and delineation variation of the CTV sequential 18FDG-PET information, van Stiphout
and with smaller magnitude the set-up errors. et al. developed a predictive model for pathologi-
Current image-guided RT is very effective in cal complete remission (pCR) based on a pooled
minimization of the set-up errors, but not for the multicentre database of 953 patients [81].
other uncertainties. Extensive research in offline Although further prospective validation is neces-
or online adaptive replanning or plan selection sary, this model could prove to be a valuable
needs to be performed to really utilize IGRT for decision support tool towards a more patient-
rectal cancer. In the meantime, proper training, tailored approach.
guidelines and delineation atlases need to be pro- However, 18FDG-PET has some inherent
vided to minimize the delineation variation shortcomings, such as spatial resolution and
between radiation oncologists. difficulty in differentiation between tumour and
inflammation.
As a stand-alone modality in rectal cancer,
14.8 Response Evaluation DW-MRI can be a powerful tool in response
assessment both before and during preoperative
With the current standard treatment of rectal can- treatment as it allows with a high specificity to
cer, about 10–30% of all patients achieve a com- differentiate persistent tumour from therapy-
plete pathological response [63–66]. They have a related inflammation or necrosis [82–87]. Patients
favourable long-term outcome with excellent with a good response to treatment generally show
14 What Is the Role of IMRT and IGRT in Rectal Cancer? 143
a lower apparent diffusion coefficient (ADC) the response of the patient to radiotherapy [94]. If
prior to treatment, with a higher change in ADC dose escalation is considered, accurate knowl-
during and after CRT. The hypothesis is that a edge of the exact tumour volume is required to
low initial ADC value represents a more restric- maintain an acceptable small bowel and bladder
tive environment with less interstitial oedema, toxicity.
necrosis and a higher cellularity. Necrosis is gen- In rectal cancer, the data on the role of func-
erally associated with an acidic environment and tional imaging in dose painting are rather limited
a low oxygen concentration which influences the [95]. Roels et al. investigated the different bio-
response to radiotherapy and chemotherapy [88]. logical characteristics of rectal cancer by repeated
The combination of 18FDG-PET/CT and imaging with three different PET tracers (18F-
DW-MRI increases the accuracy of the predic- FDG, 18F-FLT and 18F-FMISO), aiming at refining
tion. The combination of the thresholds for the the definition of target volume and at testing the
initial ADC value and the change in SUVmax after possibility of radiation dose boosting. They found
ten fractions of chemo-radiation increases the that the mean 18F-FDG, 18F-FLT and 18F-FMISO-
sensitivity to 100% and the specificity to 94% for PET tumour volumes showed a tendency to
prediction of a pathological complete remission shrink during preoperative CRT. At each time
[22]. However, before these complex imaging point, the mean FDG-PET GTV was significantly
techniques and consequent analyses can be imple- larger than the FMISO-PET GTV, but not
mented in daily practice, considerable effort significantly larger than the mean FLT-PET GTV.
towards standardization of protocols and analysis Mismatch analysis confirmed that FDG, FLT and
is necessary to ensure reproducibility of the results FMISO-PET reflect different biological charac-
and enable widespread implementation [89]. teristics and can be used as a target for dose-esca-
lation RT in rectal cancer. In general, FDG and
FLT GTVs corresponded better than FDG and
14.9 Possibility of Dose Escalation FMISO GTVs, probably due to the non-specific
FMISO uptake in normoxic bowel wall and diffu-
Several studies have shown a dose-effect relation sion of FMISO through the rectal wall. Moreover,
in rectal cancer [90–93], implying that dose esca- the spatial distribution of FMISO varied consid-
lation might be an interesting option. Dose escala- erably during RT, while FDG and FLT uptake
tion generally consists of a boost dose given to the was less variable over time. These findings favour
GTV while maintaining a standardized dose to the the use of FDG and FLT as potential tracers for
CTV, for which IMRT seems a suitable option. TV definition in dose escalation and proof that
With use of IMRT, it is possible to deliver a simul- reimaging is important if these GTVs are used as
taneously integrated boost (SIB) to the GTV, a target for dose escalation.
while giving the standard dose to the CTV [19, 29, A second study by Roels et al. investigated
30]. The advantage of SIB over more local thera- FDG-PET/CT and MRI before the start of treat-
pies like contact therapy or brachytherapy is that ment, after ten fractions of radiation and before
treatment time is not prolonged and treatment surgery [96]. The FDG-PET GTV was automati-
burden is not increased, although dose to the cally delineated with two different segmentation
organs at risk might potentially be larger using algorithms: a modified threshold-based method
the SIB technique. and a gradient-based method. The mean FDG-
The concept of GTV as presently used is an derived GTVs were significantly smaller when the
oversimplification of the reality as it does not gradient-based method was used, and the FDG-
approach the complexity of the tumour biology. PET GTVs obtained in this way correlated best
A more elaborate delineation taking into account with the GTV measured on the pathological speci-
the biological components of tumours should men. Ciernik et al. found that the automated seg-
allow a more tailored and refined dose prescrip- mentation of the FDG signal strongly correlated
tion and dose distribution, which might enhance with the CT-derived GTV and the volume as
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89. Padhani AR, Liu G, Koh DM et al (2009) Diffusion- (2011) FDG-PET provides the best correlation with
weighted magnetic resonance imaging as a cancer the tumor specimen compared to MRI and CT in rec-
biomarker: consensus and recommendations. tal cancer. Radiother Oncol 98:270–276
Neoplasia 11:102–125 103. Vorwerk H, Liersch T, Rothe H et al (2009) Gold
90. Viani GA, Stefano EJ, Soares FV, Afonso SL (2011) markers for tumor localization and target volume
Evaluation of biologic effective dose and schedule of delineation in radiotherapy for rectal cancer.
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Radiat Oncol Biol Phys 80:985–991 tion for rectal cancer? Clin Oncol 19:730–737
What Are the Dose-Volume
Constraints to Reduce Late Toxicity? 15
Krzysztof Bujko
the local recurrence rate after TME is higher non-cancer deaths after preoperative radiation
than observed in the specialized centres and was also due to an increase in deaths attributed
amounts 20% of pathologically staged T3 dis- to vascular and infective causes [5]. This meta-
ease [6]. In addition, with radiotherapy technique analysis also showed that the favourable effect of
modifications, the risk of late toxicity might be radiation still dominated, as at 5 years, there
reduced. Taking both of the above arguments into were 3.3% more of non-cancer deaths and 8.3%
account, a risk/benefit ratio analysis may favour fewer rectal cancer deaths in the irradiated
the use of preoperative radiation for all cT3 can- patients compared to those treated with surgery
cers. Thus, a reduction of the risk of late postra- alone. The above results suggest that preopera-
diation toxicity is a key issue in the current debate tive radiation has a potential for improving over-
on the indications for preoperative radiotherapy. all survival which is counterbalanced by the
In rectal cancer preoperative radiotherapy, two excess of non-cancer deaths.
guidelines showing anatomical borders of clini- Small bowel late toxicity has been reduced
cal target volume (CTV) are available [15, 22]. after replacing postoperative radiation with pre-
The objective of the current article is to provide operative radiation [8, 23]. This is because small
readers with a proposal of modifying these guide- bowel fills up the dead space left behind in a pos-
lines in order to diminish the risk of postradiation terior pelvis after removal of mesorectum and
late side effects. It should be stressed that this rectum. Thus, in order to provide large dose to
proposal is not accepted as a routine procedure the tumour bed, irradiation of large volume of
by all investigators and is still a matter of debate. small bowel cannot be avoided in the postopera-
tive setting. In contrast, in the preoperative set-
ting, when the mesorectum and rectum are still in
15.2 Cranial Border of the CTV situ, the amount of irradiated small bowel is much
smaller. Despite this, in the Swedish randomized
The recent update of the Dutch TME trial, which trial, severe late small bowel side effect, namely,
compared preoperative radiation and TME with small bowel obstruction, has occurred more often
TME alone, demonstrated no difference in over- after preoperative radiation and surgery than sur-
all survival [28]. However, when patients were gery alone – 13.9% versus 5.5% at 14 years [2].
operated with negative circumferential margin, It might be reasonable to assume that a reduc-
higher cancer-specific survival and 10% gain in tion of irradiated volume may result both in a
overall survival at 10 years in stage III cancer decreased risk of postradiation, second malig-
were reported in the preoperative radiation nancy and in the reduction of early and late small
group. Of note, slightly more non-cancer deaths, bowel toxicity. Traditionally, the sacral promon-
mostly due to secondary malignancy, were tory has been the anatomical landmark for cranial
reported in the radiotherapy group. Similar border of CTV [15, 22]. The appropriateness of
observations were recorded in Sweden. The data this rule has been questioned by two recent arti-
from two trials demonstrated that, after a long cles on location of in-pelvic recurrences after
follow-up, 7% of patients had second cancers TME. Syk et al. [26] identified a total of 155
[1]. More patients treated with radiotherapy and patients with local recurrence from a population-
surgery developed a second cancer as compared based cohort of 2,315 patients. The site of recur-
to those treated with surgery alone; the relative rence was observed in the lower half of the pelvis
risk was 1.85 with 95% confidence interval in more than two-thirds of all patients. All recur-
between 1.23 and 2.78. However, the favourable rences were situated below S1–S2 interspace.
effect of radiation still dominated, as 20.3% of Nijkamp et al. [18] analysed the site of recurrence
the irradiated patients got either local recurrence in 94 patients treated within the frame of the
or a secondary cancer, compared with 30.7% of Dutch TME trial. Only 3% of recurrences were
the patients treated with surgery alone (relative situated above the S2–S3 interspace and addi-
risk, 0.55; 95% confidence interval 0.44–0.70). tional 2% at the level of S2–S3 interspace.
The meta-analysis showed that the excess of However, if patients with negative circumferential
15 What Are the Dose-Volume Constraints to Reduce Late Toxicity? 151
resection margin were considered, only in 2% of tinence in the irradiated patients was observed
these patients, recurrence was observed above or only at low level of severity; severe incontinence
at S2–S3 interspace. The corresponding figure for rate was similar in both treatment-assigned groups.
the patients with positive circumferential resec- In the Dutch TME trial, at 24 months post treat-
tion margin was 12%. Interestingly, in the patents ment, 67% of male patients receiving preoperative
with positive circumferential resection margin, irradiation and who were previously sexually
the recurrence did not always appear at the same active, were still active after treatment compared
level as the primary tumour. With a cranially to 76% of patients from the surgery alone group,
reduced CTV to the S2–S3 interspace, over 60% p = 0.06 [14]. For female patients, these figures
of reduction of absolute small bowel exposure at were 72% and 90%, respectively, p = 0.01. It should
dose levels of 15–35 Gy could be achieved with be stressed that the main cause of faecal inconti-
three-field conventional radiotherapy, increasing nence and male sexual dysfunction is surgery,
to 80% when IMRT was used [18]. Both of the rather than radiotherapy [24].
above reports suggested that the cranial border of Excluding the anal canal, or part of it, from the
CTV can be lowered to the S2–S3 interspace in CTV is a strategy that prevents radiation-induced
patients in whom pelvic MRI predicts negative faecal incontinence [12, 29]. Lange et al. [12]
circumferential resection margin (Fig. 15.1). It reported incontinence in 93% of patients in whom
should be stressed that this guideline should be sphincter was included in the preoperative radia-
used selectively. For patients with the primary- tion fields compared to 65% of patients in whom
tumour extension in the presacral region above sphincter was not irradiated, p = 0.059. In addi-
the S2–S3 interspace or with enlarged lymph tion, one can assume that the exclusion of inferior
nodes abutting mesorectal fascia at this level, part of the vagina may prevent vaginal dryness
CTV should be extended cranially. Nijkamp and pain during intercourse. It is also worth to
et al. [18] recommended CTV reduction to the note that scattered cumulative radiation dose at
S2–S3 interspace only in patients without the testicles was reported between 0.7 and 8.4 Gy,
expected nodal or circumferential resection mar- with a mean of 3.56 Gy [10]. Such doses may
gin involvement. result in a permanent infertility and in a risk of
Apart from lowering of caudal border of the hypogonadism in substantial proportion of pati-
CTV, belly-board and distended urinary bladder ents [10, 30]. The increase of the distance between
result in a reduction of small bowel radiation lower field margin and testicles exponentially
exposure [11, 19] (Fig. 15.1). decreased the amount of this dose [10]. Another
way of reducing sexual function impairment is
to avoid irradiation of the penile bulb. Several
15.3 Caudal Border of the CTV studies reported that penile bulb dose-volume
parameters correlated with the risk of erectile dys-
Anorectal and sexual function impairments caused function [21]. For example, erectile dysfunction
by surgery and radiation are the most important was observed in 0%, 80% or 100% of patients
adverse side effects as they affect large proportion with a D70 (i.e. minimum dose received by 70%
of patients and are permanent as well as they inter- volume of the penile bulb) of 0–40, 40–70 and
fere with patients’ daily activity. These adverse >70 Gy, respectively [7]. In addition, excluding
side effects have been reported in details on large the perineal skin and distal part of ischiorectal
number of patients treated within the frame of the fossa is a strategy that prevents wound healing
Dutch TME trial and the MRC CR07 trial [14, 20, delay after abdomino-perineal resection and pain-
24]. Faecal incontinence was reported in 62% of ful acute perineal skin reaction. Marijnen et al.
patients having preoperative radiation compared to [13] reported that 31% of 174 patients irradiated
38% of those treated with surgery alone, p < 0.001 preoperatively with perineum included into the
in the Dutch TME trial [20] and 53.2% versus fields had perineal wound complications in com-
37.3% in the MRC CR07 trial, p = 0.007, respec- parison with 18% of 40 patients in whom the
tively [24]. In the latter trial, the increase of incon- perineum was not irradiated.
152 K. Bujko
gross cancer [9]. For this reason, it is recommended 4. Bujko K, Bujko M, Pietrzak L (2007) Clinical target
that mesorectum with mesorectal visceral fascia volume for rectal cancer: in regard to Roels et al. (Int
J Radiat Oncol Biol Phys 2006;65:1129–1142). Int J
should be resected at least 4 cm caudally from the Radiat Oncol Biol Phys 68:313 (letter)
tumour. This confers that for tumours in the upper 5. Colorectal Cancer Collaborative Group (2001)
rectum, 4 cm of mesorectal clearance distal to the Adjuvant radiotherapy for rectal cancer: a systematic
tumour is sufficient, and for tumours located in the overview of 8,507 patients from 22 randomised trials.
Lancet 358(9290):1291–1304
lower rectum, total mesorectum is removed down 6. Eriksen MT, Wibe A, Haffner J et al (2007) Prognostic
to the pelvic floor. Intramural subclinical spread groups in 1,676 patients with T3 rectal cancer treated
within a bowel wall may occur caudally from gross without preoperative radiotherapy. Dis Colon Rectum
primary cancer. This spread has been found rarely 50:156–167
7. Fisch BM, Pickett B, Weinberg V et al (2001) Dose of
beyond 1–1.5 cm from gross tumour. If distal radiation received by the bulb of the penis correlates
spread occurs beyond 1–1.5 cm, the prognosis is with risk of impotence after three-dimensional
poor due to a high risk of occult distant metastases. conformal radiotherapy for prostate cancer. Urology
For this reason, 1 cm of distal bowel surgical clear- 57:955–959
8. Frykholm GJ, Glimelius B, Pahlman L (1993)
ance is regarded as sufficient in patients undergo- Preoperative or postoperative irradiation in adenocar-
ing anterior resection for low tumours [17]. It cinoma of the rectum: final treatment results of a ran-
should be pointed out that even in low-lying domized trial and evaluation of late secondary effects.
tumours, if levators and external sphincter are not Dis Colon Rectum 36:564–572
9. Heald RJ, Husband EM, Ryall RD (1982) The
invaded, anterior resection is still possible as the mesorectum in rectal cancer surgery – the clue to pel-
ischiorectal fossa is not at risk of tumour recur- vic recurrence? Br J Surg 69:613–616
rence. It seems that levators constitute an effective 10. Hermann RM, Henkel K, Christiansen H et al (2005)
barrier against downwards cancer spread. There Testicular dose and hormonal changes after radiother-
apy of rectal cancer. Radiother Oncol 75:83–88
are no regional lymph nodes in the ischiorectal 11. Kim TH, Kim DY, Cho YH et al (2005) Comparative
fossa. In the literature, recurrences in the ischi- analysis of the effect of belly board and bladder dis-
orectal fossa or in the perineum were reported only tention in preoperative radiotherapy in rectal cancer.
in the patients who have undergone abdomino- Strahlenther Onkol 181:601–605
12. Lange MM, den Dulk M, Bossema ER et al (2007)
perineal resection. It can be assumed that these Cooperative Clinical Investigators of the Dutch Total
recurrences likely originate from contamination of Mesorectal Excision Trial. Risk factors for faecal
cancer cells during surgery because no such cases incontinence after rectal cancer treatment. Br J Surg
were reported after anterior resection. 94:1278–1284
13. Marijnen CA, Kapiteijn E, van de Velde CJ (2002)
The above surgical rules can be applied in the Acute side effects and complications after short-term
CTV construction. The examples are depicted in preoperative radiotherapy combined with total mesorec-
the figure. It should be noted that the rules for tal excision in primary rectal cancer: report of a multi-
CTV lower border location presented in this center randomized trial. J Clin Oncol 20:817–825
14. Marijnen CAM, van de Velde CJ (2005) Impact of
figure are different to those recommended by short-term preoperative radiotherapy on health-related
other investigators [22]. quality of life and sexual functioning in primary rectal
cancer: report of multicenter randomized trial. J Clin
Oncol 23:1847–1858
15. Myerson RJ, Garofalo MC, El Naqa I et al (2009)
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22. Roels S, Duthoy W, Haustermans K et al (2006) Preoperative radiotherapy combined with total
Definition and delineation of the clinical target vol- mesorectal excision for resectable rectal cancer:
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65:1129–1142 controlled TME trial. Lancet Oncol 12:575–582
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Preoperative versus postoperative chemoradiotherapy (2003) Association of anorectal dose-volume histo-
for rectal cancer. N Engl J Med 351:1731–1740 grams and impaired fecal continence after 3D confor-
24. Stephens RJ, Thompson LC, Quirke P et al (2010) mal radiotherapy for carcinoma of the prostate.
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What Is the Contribution of
Intraoperative Radiotherapy 16
(IORT) in Tailoring Local Therapy
in Primary or Recurrent Rectal
Cancer?
Felipe A. Calvo
margin involvement (20% yes, 6.2% no). This recurrences at 43 sites: 28 (65%) were in-field, 7
general pattern of local relapse can be further (16%) marginal, and 8 (19%) out-field radiother-
analyzed in terms of topographic distribution apy recurrences. The total rate of presacral
within the pelvic anatomy. After total mesorectal in-field recurrences was 41%, and the low pelvic
excision (TME), the presacral subsite is the domi- region was dominant for both pre- (60%) or post-
nant involved pelvic area with an incidence of operative (43%) irradiation. Pathologic N1–2 sta-
3.6% of all recurrences and 35% of the local tus was predictive of in-field locoregional
recurrences observed. Other sites of recurrences recurrence in multivariate analysis, while T4,
identified are lateral (18%), anterior (18%), anas- downstaging and pN status were significant in
tomosis (24%), and perineum (5%). univariant evaluation.
Fig. 16.1 Three-dimensional virtual treatment planning of an IORT procedure with an electron beam positioned over
a limited area of the presacral space
paradigm. The large and mature nature of this 16.4 Recurrent Rectal Cancer:
cohort of patients allowed the authors to generate Isolated Pelvic Relapse
a prognostic model based on the calculation of an
individualized prognostic index formula. Overall 16.4.1 Mayo Clinic 25 Years Experience
survival of rectal cancer patients was able to be
grouped in four different prognostic categories Haddock and coworkers [11] have reported
using the following formula: results in 607 patients with recurrent colorectal
cancer that received an IOeRT (electrons) com-
Age over 70 years Yes:0.60;no:0 ponent of the treatment (70% rectal cancer, 46%
Male gender Yes:0.36;no:0 previous radiotherapy, 41% in-field relapses).
Any downstaging Yes:0;no:0.30 Survival at 5 and 10 years were 30% and 16%,
Lymph node positivity Yes:0.86;no:0 respectively. Local relapse at 5 years was observed
Margin positivity Yes:0.70;no:0
in 28% of patients. Survival was influenced by
Adjuvant Yes:0;no:0.64
chemotherapy
resection status, period of IORT (before or after
1997), and prior chemotherapy. Disease relapse
Survival ranged from 90% for category with in the central IORT boosted region at 10 years
prognostic index 0–0.5 or 20% for values over was 18% versus 12% regarding the fact of previ-
2.5 (Fig. 16.2). ous radiotherapy or not and 12% versus 16%
16 What Is the Contribution of Intraoperative Radiotherapy (IORT) 159
Overall survival
0.6
0.4
Prognostic index
0.2 0−0.5
0.5−2
2−2.5
2.5>
0.0
regarding margin involvement. Neuropathy was resection had a significantly worse prognosis in
observed in 94 patients and was more common posterolateral recurrent subsite. Authors suggest a
with IORT doses exceeding 12.5 Gy. classification of subsite of pelvic recurrence as a
predictor for radical resection and consequently
promotion of improved survival.
16.4.2 Catharina Hospital and Leiden
University Medical Center Conclusions
1994–2008 Experience 1. IORT is a feasible, tolerable, and efficient
radiation-boosting technique that can be
Kusters, Rutten, and colleagues [12] described explored in tailored treatment for rectal
that radicality of resection and survival is influenced cancer patients (Table 16.1).
by subsite of locally recurrent rectal cancer after 2. Recommendations available to guide tai-
multimodality treatment including a component of loring IORT in primary disease in terms of
IORT. In 170 patients (30% not receiving IORT), local tumor control promotion are:
22% had a presacral recurrence, 34% lateralized • The unfavorable nature of nodal and
disease, 22% anastomotic, 23% anterior, and 2.6% margin positivity together with no
perineal. Local re-recurrence occurred in 54 downstaging effects. IORT is an alter-
patients (46%) after 5 years: 52% in the presacral native for further dose-escalation and
subsite, 20% posterolaterally, 17% anterolaterally, target volume redesign to improve local
and 11% other sites. Anastomotic recurrences had control under these conditions.
the highest cancer-specific survival (58%) • The tendency of T4 stage to recur in
(significantly better than the combined group anterior pelvic structures, although
34%). Presacral recurrences resulted in 19% IORT has also been reported to promote
cancer-specific survival, significantly worse than high local control rates in this disease
other recurrences in group (48%, p = 0.03). Radical category [14].
160 F.A. Calvo
Table 16.1 IOeRT 5-year results in primary and recurrent rectal cancer: local control, in-field recurrence, and factors
associated with local relapse
In-field IORT Adverse factors for local
Author/year (reference) Pts Local control recurrence relapse
Dubois 2011a [6]; 72 91% na na
Primary
Roeder 2007 [7]; 243 93% 2.8% presacral Postoperative
Primary chemoradiation (10/17)
Node positive
(4/7 presacral)
Kusters 2009 [8]; 290 86% 5.9% Margin positive
Primary 64% (lateral/ventral)
Calvo 2011 [8, 10]; 241 92% 3% presacral Node positive
Primary
Kusters 2010 [13]; 605 88% na No downstaging
Primary Nodal metastasis
Margin involvement
No adjuvant
chemotherapy
Haddock 2011 [11]; 607 77% (3 year) 12% R1/R2 26% vs. RO 15%
Recurrent Previous RT 31% vs.
17%
Kusters 2009 [12]; 170 54% 14.9% R1/R2 54% vs. R0 9%
Recurrent (57% presacral)
na not available, pts patients
a
Randomized trial
colorectal cancer: a systematic review. Cancer Lett presacral radiation boost for rectal cancer. Radiother
306:121–133 Oncol 99(suppl 1):S18
6. Dubois JB, Bussieres E, Richaud P et al (2011) Intra- 11. Haddock MG, Miller RC, Nelson H et al (2011)
operative radiotherapy of rectal cancer: results of the Combined modality therapy including intraoperative
French multi-institutional randomized study. Radiother electron irradiation for locally recurrent colorectal
Oncol 98:298–303 cancer. Int J Radiat Oncol Biol Phys 79:143–150
7. Roeder F, Treiber M, Oertel S et al (2007) Patterns of 12. Kusters M, Dresen RC, Martin H et al (2009)
failure and local control after intraoperative electron Radicality of resection and survival after multimodal-
boost radiotherapy to the presacral space in combina- ity treatment is influenced by subsite of locally
tion with total mesorectal excision in patients with recurrent rectal cancer. Int J Radiat Oncol Biol Phys
locally advanced rectal cancer. Int J Radiat Oncol Biol 75:1444–1449
Phys 67:1381 13. Kusters M, Valentini V, Calvo FA et al (2010) Results
8. Kusters M, Holman FA, Martijn H et al (2009) Patterns of European pooled analysis of IORT-containing mul-
of local recurrence in locally advanced rectal cancer timodality treatment for locally advanced rectal cancer:
after intra-operative radiotherapy containing multimo- adjuvant chemotherapy prevents local recurrence rather
dality treatment. Radiother Oncol 92:221–225 than distant metastases. Ann Oncol 21:1279–1284
9. Díaz-Gonzalez JA, Calvo FA et al (2006) Prognostic 14. Valentini V, Coco C, Rizzo G et al (2009) Outcomes
factors for disease-free survival in patients with T3–4 of clinical T4M0 extra-peritoneal rectal cancer treated
or N + rectal cancer treated with preoperative chemo- with preoperative radiochemotherapy and surgery: a
radiation therapy, surgery, and intraoperative irradia- prospective evaluation of a single institutional experi-
tion. Int J Radiat Oncol Biol Phys 64:1122–1128 ence. Surgery 145:486–494
10. Calvo F, Serrano J, Lozano MA et al (2011) Presacral
evolutive events after post-neoadjuvant intraoperative
What Is the Contribution
of Brachytherapy in Tailoring 17
Local Therapy?
20 mm
5 mm
Fig. 17.1 Endoluminal HDR 192 iridium brachytherapy. the positioning of the applicator through the anus, and the
This figure is showing the rectal brachytherapy applicator, dose distribution in a sagittal plane
the loading of five channels in front of the rectal tumor,
50.0
40.0
30.0
20.0
10.0
0
0 2.00 4.00 6.00 8.00 10.0
Dose [Gy]
Fig. 17.2 HDR 192 iridium implant for distal supra-anal implant through a transverse axial plane, the 3D recon-
rectal cancer. This figure is showing the perineal template struction of the implant, and the dose-volume histogram
fixed to the patient perineum and connected to the remote for the tumor volume
iridium unit, the CT scan slices showing the needle
Fig. 17.3 Contact X-ray 50 kV. Male patient of 74 years Xeloda 1,600 mg/m2 on radiation day). Treatment deliv-
referred by a surgeon for a distal rectal adenocarcinoma ered with the Papillon 50 machine which allows direct
staged T2N0. Patient treated in October 2010 with CXRT viewing of the tumor during irradiation. It is possible to
(110 Gy in 4 fractions) and chemoradiotherapy CAP50 record the progressive shrinkage of the tumor until clinical
regimen (EBRT 50 Gy/25 F/5 weeks and concurrent complete response. Patient alive and well in May 2011
was good in 95% of cases. Surgery was performed 17.3.3.2 CXRT Alone (or with EBRT) After
4–6 weeks after (anterior resection: 60%). The rate Local Excision for Malignant
of sterilized operative specimen (ypCR) was 27%. Polyp (T1N0)
At 5 years, the rate of local relapse was 5% [12]. In this adjuvant situation, a local control was
In Vejle, the endoluminal brachytherapy was achieved in 90% of cases in different institutions
used after preoperative EBRT radiochemotherapy treating between 20 and 60 patients [2].
(RT-CT). Out of 58 patients operated, the rate of
ypCR was 27%. Toxicity was low [6]. In 17.3.3.3 CXRT and EBRT for T2 Early T3N0
Clatterbridge, out of 29 patients treated with pre- in Elderly Unfit Patients
operative chemotherapy and a boost of 10 Gy These patients usually inoperable or elderly were
with HDR brachytherapy, 9 (31%) achieved a treated with curative intent. According to institu-
ypCR [11]. tion, the association was initiated with CXRT fol-
lowed by EBRT (± chemotherapy) or with EBRT
17.3.1.2 Combined with EBRT Without followed by CXRT. In T2 tumors, a 5-year local
Surgery in Unfit Patients control was achieved in 70–80% of patients and
Between 2005 and 2010, 41 patients were treated in 45–55% for T3 lesions [1,10].
in Montreal, McGill University (median age
82 years) without surgery. EBRT delivered 17.3.3.4 The Lyon R96.02 Randomized
40–45 Gy/4–5 weeks followed by HDR endolu- Trial
minal brachytherapy (30 Gy/3 F). With a follow- Between 1996 and 2001, 88 patients (T2: 19 pts
up of 14 months, a local control was achieved in – early T3: 69 pts) with a distal rectal cancer were
76% (31/41). Tolerance was good with G3 rectal randomized between preoperative EBRT
bleeding in seven patients and rectal stenosis in (39 Gy/13 F/3 weeks) or the same EBRT with a
three patients [12]. CXRT boost of 90 Gy/3 Fr. The main end point
was sphincter-saving treatment.
The clinical complete response (cCR) was 2%
17.3.2 Interstitial Iridium Implant in the EBRT alone group and 29% in the CXRT
group. After 10 years of follow-up, the colos-
In very low rectal cancer close to the anal canal, tomy-free rate is 40% with EBRT alone and 84%
iridium implant either with low- or high-dose rate in the CXRT group. Out of 45 pts in the CXRT
combined with EBRT (± chemotherapy) and group, 9 were able to preserve their whole rectum
CXRT is able to achieve 50% of long-term local (and anus) either with RT alone (seven patients)
control inoperable patients presenting with early or after transanal local excision (TLE) in two
T3N0 tumors [3]. patients [4].
A quality assurance program of all these different 5. Goes RN, Beart RW Jr, Simons AJ et al (1997) Use of
brachytherapy techniques is needed. A regular brachytherapy in management of locally recurrent
rectal cancer. Dis Colon Rectum 40:1177–1179
cooperation with the other specialists is manda- 6. Jakobsen A, Mortensen JP, Bisgaard C et al (2006)
tory. Finally, informed patients should agree to Preoperative chemoradiation of locally advanced T3
participate in these clinical trials or observational rectal cancer combined with an endorectal boost. Int J
studies. Radiat Oncol Biol Phys 64(2):461–465
7. Lindegaard J, Gerard JP, Sun Myint A et al (2007)
Whither papillon? Future directions for contact radio-
Disclosure Jean-Pierre GERARD is the medical advisor therapy in rectal cancer. Clin Oncol (R Coll Radiol)
of the Ariane Medical systems company (UK). 19(9):738–741
8. Papillon J (1975) Intracavitary irradiation of early
rectal cancer for cure. A series of 186 cases. Cancer
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9. Papillon J, Montbarbon JF, Gerard JP et al (1989)
Interstitial curietherapy in the conservative treatment
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2. Gérard JP, Chapet O, Romestaing P et al (2000) Local 19(9):674–681
excision and adjuvant radiotherapy for rectal adeno- 11. Sun Myint A, Mukhopadhyay T, Ramani VS et al
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24(4):430–435 brachytherapy boost following preoperative chemora-
3. Gerard JP, Romestaing P, Chapet O (2003) Radio- diotherapy for advanced rectal cancer improve surgi-
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Part V
Q&As on Chemotherapy
Should Oxaliplatin Be Added
to Preoperative Chemoradiation? 18
Carlo Aschele
225 mg/m2/day) is 60 mg/m2 given weekly ×6 Of note, all of these studies have used a
[4]. The feasibility of this regimen and the rec- weekly schedule for oxaliplatin administration
ommended dose of weekly oxaliplatin previously building on the chemoradiation regimen origi-
established in our study (60 mg/m2/week) were nally generated by our group. Only our study
confirmed in CALGB 89901 [16]. (the Italian STAR-01 trial), however, maintained
At the recommended dose, this regimen allows the six oxaliplatin courses as in the original regi-
therefore to deliver a total dose of oxaliplatin men. Both the NASBP and the French study had
(360 mg/m2 of over a 6-week time concomitant in fact five oxaliplatin administrations while
to radiation) substantially higher compared to oxaliplatin was administered on days 1, 8, 22,
other oxaliplatin-based chemoradiation programs and 29 in the German study that prescribed a
[9,10,17]. In addition, this oxaliplatin dose is poten- chemotherapy break during the third week of
tially active also systemically with a dose intensity radiation.
approximately 50% higher compared to the regi- As to control arms, the STAR-01, NSABP,
mens commonly used in the treatment of metastatic and French trials used exactly the same FP dose
colorectal cancer [8]. This schedule has therefore and schedule as in the experimental arm, while a
an added advantage over a traditional week 1 and 5 shorter infusion with higher 5-fluorouracil daily
chemotherapy program in that it incorporates a doses (mimicking the chemoradiation regimens
dose and schedule of both oxaliplatin and used in the treatment of anal cancer) was used in
5-fluorouracil known to be systemically active. the control arm of the German study.
This may be particularly important to optimize Radiotherapy intensification was pursued
both local control, with an enhanced chemoradia- in the experimental arm in the French study
tion regimen, and the control of (micro)metastases (45 Gy in the control arm vs. 50 Gy in the experi-
at distant sites with the concomitant administration mental arm) while the planned radiotherapy dose
of systemically active combination chemotherapy. was 50.4 Gy for both arms in the other three
studies.
Data on safety, surgery, and response to preop-
18.4 Phase III Studies erative chemoradiation have been reported for all
of these studies [5,11,14,15]. These results
There are four completed phase III randomized confirm that weekly oxaliplatin can be added to
clinical trials assessing the value of oxaliplatin FP-based preoperative chemoradiation even
combined with fluoropyrimidines (FPs) and pre- though toxicity is increased. Unexpected adverse
operative external-beam pelvic radiation in locally events were not reported, and there was no excess
advanced rectal cancer (Table 18.2). Infused treatment mortality in the oxaliplatin arms; over
5-fluorouracil was the FP backbone in the STAR- 95% of patients were operated as planned within
01 and CAO/ARO/AIO studies, while weekly 6–8 weeks from the end of chemoradiation inde-
oxaliplatin was combined with capecitabine in pendent of the preoperative treatment they had
the French ACCORD trial and either capecitabine received, and surgical mortality was also low and
or infused 5-fluorouracil in the NSABP study that similar with or without oxaliplatin. Treatment
entailed a 2 × 2 factorial design. compliance was reduced with an apparent
176 C. Aschele
Table 18.2 Phase III randomized studies of FP-based preoperative chemoradiation ± oxaliplatin
Primary Postoperative
Study n endpoint Status Control arm Experimental arm treatment
ACCORD 598 pCR Reported Cape 1,600 mg/m2/
Cape 1,600 mg/m2/ Center choice
0405 (primary day d1–5 weekly day d1–5 weekly ×5;
endpoint) ×5; RT 45 Gy OXA 50 mg/m2 d1
weekly ×5; RT 50 Gy
STAR-01 747 OS Reported CI FU 225 mg/m2/ CI FU 225 mg/m2/ FU/LV
(secondary day d1–35; RT day d1–35; OXA (both arms)
endpoint) 50.4 Gy 60 mg/m2 d1 weekly
×6; RT 50.4 Gy
NSABP R-04 1,608 LR Reported CI FU 225 mg/m2/ CI FU 225 mg/m2/ Center choice
(secondary day or Cape day or Cape
endpoint) 1,650 mg/m2/d d1–5 1,650 mg/m2/d d1–5
weekly ×5; RT weekly ×5; OXA
46 Gy 50 mg/m2 d1 weekly
(+5.4–10.8 Gy) ×5; RT 46 Gy
(+5.4–10.8 Gy)
CAO/ARO/ 1,265 DFS Reported CI FU 1,000 mg/ CI FU 250 mg/m2 FU 500 mg/m2
AIO-04 (secondary m2/day d1–5, d1–14, 22–35; OXA day ×5 q 4 week
endpoint) 29–33; RT 50.4 Gy 50 mg/m2 d1, 8, 22, (4 cycles) vs.
29; RT 50.4 Gy mFOLFOX-6
(8 cycles)
PETACC-6 634 (1,090) DFS Accruing Cape 1,650 mg/m2/ Cape 1,650 mg/m2/ Cape 2,000 mg/
day d1–33; RT day d1–33; OXA m2/day d1–14 q
45 Gy (±5.4 Gy) 50 mg/m2 d1 weekly 3 week ± OXA
×5; RT 45 Gy 130 mg mg/m2
(±5.4 Gy) d1 q 3 week
(6 cycles)
Abbreviations: pCR pathologic complete response, OS overall survival, LR local relapse, DFS disease-free survival,
Cape capecitabine, RT pelvic radiotherapy, OXA oxaliplatin, CI continuous infusion, FU fluorouracil, mFOLFOX-6
modified FOLFOX-6
relationship between the oxaliplatin dose deliv- be less pronounced in the German study, possibly
ered concomitant to radiation and the proportion because of the lower cumulative dose of oxalipla-
of patients receiving a reduced radiotherapy dose tin administered along with radiation. The higher
(6% in the German study where 200 mg/m2 of rate of severe toxicity in the control arm of this
oxaliplatin were delivered concomitant to radia- study (22% compared to less than 10% in the
tion, 13% in the French study with 250 mg/m2, Italian and French studies) provides an alterna-
and 16% in the STAR-01 study with 360 mg/m2 tive explanation for the less evident increment
of oxaliplatin added to 5-fluorouracil and radia- observed with the addition of oxaliplatin.
tion). However, even in the STAR study that Despite the promising phase II data (Table 18.1),
entailed the highest added oxaliplatin dose, more these randomized studies indicate that adding
than 90% of the patients in the oxaliplatin arm oxaliplatin to preoperative 5-fluorouracil and
received at least 45 Gy and more than 80% had at pelvic radiation does not improve primary tumor
least 5 weekly administrations of oxaliplatin response. pCR rates were identical, or nearly
(Tables 18.3 and 18.4). identical, in the experimental compared to the
The addition of oxaliplatin resulted in more control arms in the STAR-01 and NSABP-R04
toxicity with grade III–IV events reported in studies and numerically, but not significantly,
more than 20% of patients and rates of grade increased in the French study (that also entailed
III–IV diarrhea between 12% and 15% in all the intensified radiotherapy in the oxaliplatin-
four studies. This increase in toxicity appears to containing arm). A 3.7% absolute difference in
18 Should Oxaliplatin Be Added to Preoperative Chemoradiation? 177
Table 18.3 Treatment compliance and safety of preoperative chemoradiation ± oxaliplatin in randomized
phase III studies
STAR-01 ACCORD 0405 NSABP R-04 CAO/ARO/AIO-04
Study arm, n Study arm, n Study arm, n Study arm, n
Ctr OXA Ctr OXA Ctr OXA Ctr OXA
379 352 293 291 622 631 624 613
RT full dose, % 92 84 100 87 nr nr 95 94
OXA full dose, % – 66a – nr – nr – 85c
Grade III–IV toxicity, %
Overall 8 24b 11 25b nr nr 22 23
Diarrhea 4 15b 3 13b 7 15b 8 12
Neuropathy (³G2) 0 8b 0.4 6b b
nr nr <1 2c
Abbreviations: ctr control arm, OXA oxaliplatin-containing arm, RT radiotherapy, CT chemotherapy
a
83% received at least 5 weekly courses
b
Statistically significant
c
Chemoradiation full dose
Table 18.4 Response to preoperative chemoradiation ± oxaliplatin in randomized phase III studies
STAR-01 ACCORD NSABP R-04 CAO/ARO/AIO-04
Study arm, n Study arm, n Study arm, n Study arm, n
Ctr OXA Ctr OXA Ctr OXA Ctr OXA
379 352 293 291 622 631 624 613
ypCR, % 16 16 14 19 19 21 13 17*
ypT0, % 18 19 14 20 nr nr 13 18
ypN+, % 26 29 30 28 nr nr 30 28
R0 resection, % 94 97 nr nr nr nr 92 90
CRM + (£1 mm), % 7 4 13 8 nr nr 6 5
SSS, % 78 79 75 75 64 60 71 69
Abbreviations: ctr control arm, OXA oxaliplatin-containing arm, ypCR pathological complete response, CRM circum-
ferential resection margin, SSS sphincter-saving surgery
*p = 0.045 (unplanned exploratory analysis)
favor of the oxaliplatin arm that reached statis- not have TME surgery, and at least 90% had an
tical significance in an exploratory unplanned R0 resection. This may have contributed to lower
analysis was reported in the German study. Other the pCR rate compared to initial phase II studies.
measures of response to preoperative chemoradi- The quality of surgery and pathology indeed
ation (including tumor regression grade, the pro- affect the ability to detect residual tumor after
portion of patients with residual tumor confined preoperative chemoradiation and is therefore
to the muscular layer of the rectal wall, the rates inversely correlated with the pCR rate.
of node-positive disease found at surgery, and The lower pCR rate observed with OXA in
the incidence of circumferential resection margin these randomized studies probably reflects also
positivity) were also similarly distributed among the better control for the multiple factors affect-
patients treated with or without oxaliplatin in ing response to preoperative chemoradiation
the four studies ruling out any clinically relevant and the larger sample size compared to phase II
effect on primary tumor response. assessment. This underlines the crucial impor-
Although surgery details are not available for tance of properly designed, adequately powered
NSABP-R04, in the three European trials, the randomized multidisciplinary studies with stan-
median number of examined lymph nodes was dardized and optimized radiological staging,
between 12 and 15, less than 10% of patients did radiotherapy, TME surgery, and pathologic
178 C. Aschele
evaluation to assess the effect of new treatment long-term outcome in a phase III trial are pre-
strategies in rectal cancer. dicted comparing pCR rates between treatment
This lack of improvement in tumor response arms. The mechanisms of cytotoxicity and radio-
does not appear to be explained by a lower adher- sensitization may in fact not be the same, and
ence to the treatment program due to the increased local tumor regression does not necessarily pre-
toxicity in the oxaliplatin arms. In the STAR-01 dict responsiveness of disseminated tumor cells
study, where all measures of compliance were toward the chemotherapy component of combined
significantly reduced in the group randomized to modality treatment programs.
receive oxaliplatin compared to the control group, Of interest, in these studies, extrapelvic metas-
pCR rates were similar between the two arms also tases were found at surgery less frequently in
in exploratory analyses restricted to patients that patients treated with oxaliplatin compared to those
completed all the planned radiation and chemo- receiving single-agent FP and radiation, although
therapy as assigned [5]. In addition, even in the statistical significance was reached only in the
study that had the highest treatment compliance in STAR-01 trial.
the oxaliplatin arm, with 85% of patients receiving Further follow-up is thus required to establish
full-dose chemoradiation [14], a marginal, clini- if the early introduction of oxaliplatin in the man-
cally not relevant, although statistically significant, agement of locally advanced rectal cancer can
4% increase in the pCR rate was observed. improve longer-term outcomes such as disease-
These results indicate therefore that oxalipla- free and overall survival. At the present time,
tin is not a clinically effective radiation sensitizer however, oxaliplatin has no role in the neoadju-
in rectal cancer (or at least that oxaliplatin does vant radiochemotherapy of this disease and should
not increase radiosensitization achieved with not be added to preoperative chemoradiation.
5-fluorouracil or capecitabine administration Single-agent FPs thus remain the standard che-
concomitant to radiation). motherapy in this setting. Given this lack of effect
Of note, the pCR rates in the control arms of on primary tumor response, even future favorable
these four studies appear to be higher than those results in long-term efficacy should be weighed
reported in less recent studies, probably thanks to against the increased toxicity observed when
optimized radiotherapy techniques and higher oxaliplatin has been added to preoperative chemo-
radiation doses. In particular, pCR rates in the radiation. The control of metastases at distant
control arm were above 15% in the ACCORD- sites could in fact be improved, also adding oxali-
PRODIGE, STAR-01, and NSABP R-04 trials all platin in the postoperative setting at a lower toxic-
involving continuous administration of the FP ity cost as successfully done in colon cancer.
(protracted 5-fluorouracil infusion or oral capecit- Alternative strategies are thus required to
abine) for all the duration of radiotherapy. It is improve primary tumor response to preoperative
thus conceivable that optimal radiotherapy with treatment in patients with locally advanced rectal
optimal radiosensitization by FPs already maxi- cancer. Induction chemotherapy and image-
mizes primary tumor response with little or no guided radiotherapy techniques are actively
room for further improvement with additional investigated at this end. Preclinical data also sug-
radiation sensitizers. gest that the synergism between oxaliplatin,
Primary tumor response was the main endpoint 5-fluorouracil, and radiation is restricted to cell
only for the French study, while the other studies lines with specific gene expression profiles [12].
were designed to test the impact of oxaliplatin on Future studies of novel therapies in rectal cancer
long-term efficacy endpoints (overall survival for should thus include molecular profiling to indi-
the STAR-01 study, local relapse in NSABP R04, vidualize therapy protocols and identify patients
and disease-free survival for the German trial). that may achieve a good response even with
The lack of effect on primary tumor response does standard treatment and those demonstrating
not contradict this hypothesis. In rectal cancer, aggressive biology that could benefit from a more
there is in fact no evidence that differences in intensified approach.
18 Should Oxaliplatin Be Added to Preoperative Chemoradiation? 179
19.3 VEGF Inhibitors in Rectal Again, substantial differences were noted between
Cancer studies concerning the inclusion criteria and the
applied drug regimen, dose, treatment duration,
Neoangiogenesis is crucial for tumor growth and sequence. The rate of a pathological com-
and malignant progression. In the majority of plete response, although difficult to compare,
cancers, tumor vessels appear to be abnormal tends to be somewhat higher with bevacizumab-
in structure and function, leading to a hostile based regimens than seen with EGFR inhibitor
microenvironment characterized by hypoxia, low containing regimens, ranging from 13% to 36%
pH, and high interstitial fluid pressure [32]. On of patients.
the one hand, the escape of tumor cells through The reported incidence of grade 3–4 diarrhea
leaky vessels is facilitated, and on the other hand, ranged between 20% and 40% in most trials.
transport and distribution of cytotoxics and oxy- Other more typical bevacizumab-related adverse
gen seem to be impaired. Blockade of VEGF sig- events, such as hypertension, proteinuria, mucosal
naling by pharmacological agents can transiently bleeding, and arterial thrombosis, were reported
repair these vascular abnormalities, thus improv- at rates similar to those seen in phase III trials of
ing oxygenation and lowering interstitial fluid bevacizumab in metastatic colorectal cancer.
pressure. This process is referred to as “vascular Postoperative complication rates, including pel-
normalization” [32]. Improving oxygenation can vic infection, delayed wound healing, anasto-
sensitize tumors to the cytotoxic effects of irra- motic leak, and fistulae, were relatively high in a
diation, while a decrease in interstitial fluid pres- number of trials, ranging between 36% and 63%
sure improves cytotoxic drug delivery. Extensive of cases [37, 39, 43–45]. On the other hand, a
preclinical studies in human tumor xenograft recent report of Liang et al. investigated the tech-
models have demonstrated tumor suppression nical feasibility of laparoscopic TME for low rec-
ability of VEGF blockade [2] as well as its radio- tal cancer after preoperative treatment with the
sensitizing ability [33]. Willett and colleagues combination bevacizumab-oxaliplatin-5FU and
have assessed the effect of a single administration fractionated radiotherapy [46]. Although the
of bevacizumab (Avastin; Roche/Genentech), a interval to surgery after the last dose of bevaci-
recombinant humanized monoclonal antibody to zumab was only 2–4 weeks, a R0 resection was
VEGF, on vascular biology in human rectal can- achieved in all 28 treated patients at a postopera-
cer [34]. This study indicates that, even at low tive complication rate of “only” 21.4%. Long-term
doses, bevacizumab alone can decrease perfu- results after bevacizumab-containing chemora-
sion, microvascular density, and interstitial fluid diation were only available for the study by
pressure in a solid tumor. Addition of bevaci- Willett et al. providing a 5-year actuarial overall
zumab to conventional chemotherapy in meta- survival rate of 95.0%, a disease-free survival of
static colorectal cancer has resulted in significant 68.9%, and a local control rate of 91.7% [47].
and clinically meaningful survival benefit in a In summary, results of these phase I/II trials
number of phase III trials [1]. indicate that integration of VEGF inhibition, in
The potential benefit of VEGF blockade was this case bevacizumab, into preoperative chemo-
further explored in a number of phase I and II radiation regimens is feasible at a manageable
studies, summarized in Table 19.2. The reported toxicity rate but does not appear to dramatically
trials have integrated bevacizumab into preopera- enhance pathological downstaging rates when
tive 5FU- or capecitabine-based chemoradiation compared to more conventional preoperative reg-
regimens for locally advanced rectal cancer [35– imens. There are however no data available from
46]. Five of them also used oxaliplatin as a sec- larger studies whether the addition of bevaci-
ond cytotoxic agent during treatment [35, 39, zumab decreases the rate of metastases in rectal
44–46]. Surgical intervention was usually delayed cancer, and some concerns may of course be
until at least 4–6 weeks after the last dose of bev- raised in view of the lack of benefit of bevaci-
acizumab to prevent postoperative complications. zumab in improving the outcome of stage III
19
Table 19.2 Published papers and abstracts reporting use of VEGF inhibitors in preoperative chemoradiation in rectal cancer
Authors Chemoradiotherapy (CRT) Interval
[Ref.] Phase N Pre-CRT Target FU cap oxa iri RT (Gy) Post-CRT (weeks) pCR (%)
Czito et al. I 11 bev × × 50.4 6–8 18
[35]
Blaszkowski I/II 21 bev/erl × 50.4 6–9 47
et al. [36]
Willett et al. I/II 32 bev bev × 50.4 7–10 16
[37]
Crane et al. II 25 bev × 50.4 6–10 32
[38]
Kennecke II 42 bev bev × × 50.4 7–9 18
et al. [39]
Nogué et al. II 47 cap/oxa/bev bev × 50.4 6–8 36
[40]
Resch et al. II 8 bev × 45 6–8 25
[41]
Spigel et al. II 35 bev × 50.4 2–8 29
[42]
Velenik et al. II 61 bev bev × 50.4 6–8 13
[43]
Dipetrillo II 26 FU/oxa/bev bev × × 50.4 4–8 20
et al. [44]
Hoehler et al. II 70 bev × × 50.4 NR 17
[45]
Liang et al. II 28 bev × × 45 FU/oxa/bev 2–4 25
[46]
N number of patients entering study, pre-CRT agents given before start of radiotherapy, target targeted agent used, FU 5-fluorouracil, cap capecitabine, oxa oxaliplatin, iri irino-
tecan, RT(Gy) radiotherapy dose, post-CRT agents given after completion of radiotherapy, interval therapy-free interval between the end of preoperative therapy and surgery,
pCR pathological complete response, bev bevacizumab, erl erlotinib, NR not reported
Should Biologic Targeted Agents Be Combined with Preoperative Chemoradiation in Rectal Cancer?
187
188 P.-J. Cuyle and E. Van Cutsem
colon cancer [48]. Moreover, the high incidence combination in treatment of metastatic colorectal
of postoperative complications has raised some cancer demonstrated an inferior median progres-
concerns about the safety of this approach. sion-free survival at the cost of an unfavorable
So far, no molecular biomarkers reliably pre- toxicity profile [2]. A small phase I/II study by
dicting response to VEGF inhibition therapy are Blaszkowski et al. investigated the combination of
available in clinical practice. Pretreatment VEGF bevacizumab and erlotinib in combination with
concentrations in tumoral tissue and circulation infusional 5FU and pelvic radiation in patients
failed to correlate with outcome to therapy with with LARC [36]. This combination appeared to
VEGF blocking agents [49], although some be well tolerated, and a pCR of 47% was achieved
recent studies suggested a potential predictive in 15 patients undergoing surgery so far.
role of serum VEGF-A, as determined with
newer assays, in some cancers including pancre- Conclusions
atic and gastric cancer [50, 51]. Willett and col- Improving survival in locally advanced rectal
leagues have put considerable effort in identifying cancer, while minimizing treatment-related
the kinetic changes in tumor cell proliferation comorbidity, remains challenging. Integration
and apoptosis indices in response to anti-VEGF of targeted therapy in preoperative chemora-
treatment. They found that bevacizumab admin- diation regimens is supported by a strong the-
istration increases levels of plasma VEGF and oretical background, promising preclinical
placental-derived growth factor (PlGF) and data, and encouraging experiences with these
decreases levels of circulating endothelial cells agents in metastatic colorectal cancer and
(CECs) and progenitor cells (CPCs) [37, 52]. locally advanced head and neck cancer. Phase
This group also looked at soluble VEGF recep- I results have demonstrated that this approach
tor 1 (sVEGFR-1), which is an antiangiogenic is feasible with an acceptable toxicity.
factor released by endothelial cells, playing an However, results from phase II studies, incor-
important role in the process of vascular normal- porating EGFR and VEGF targeting therapy,
ization [49]. They noticed a striking association have been unimpressive, showing no clear
of pretreatment plasma sVEGFR-1 concentra- response benefit by adding these agents to
tions and both primary tumor response and tox- standard therapy. No randomized phase III
icity after bevacizumab-based chemoradiation. studies are currently available. Consequently,
However, further evaluation of these markers is the use of these agents in the preoperative
needed in larger studies to confirm their predic- treatment for rectal cancer remains experi-
tive and/or prognostic value. We are coordinat- mental. The use of the pathological complete
ing at the moment in our center a multicenter response as an endpoint remains controversial
randomized phase 2 study evaluating the combi- since it is largely influenced by the initial size
nations of bevacizumab/capecitabine or bevaci- of the tumor, the interval between radiother-
zumab/capecitabine/oxaliplatin plus radiotherapy apy and surgery, and the quality of histopatho-
in locally advanced rectal cancer, with a focus on logical examination. The correlation between
marker analysis and translational research (AXE- pathological complete response and long-term
BEAM study). outcome has been variable in previous trials.
A better understanding of the mechanisms
responsible for the disappointing results in
19.4 Combined EGFR and VEGF these phase II trials is necessary before pro-
Inhibition in Rectal Cancer ceeding to phase III. Future strategies should
focus on accurate identification of biomarker-
Despite evidence from preclinical data for a syn- defined subpopulations with high-risk rectal
ergistic effect of EGFR and VEGF blockade, tumors that will benefit most from a certain
results from phase III trials implementing this treatment approach.
19 Should Biologic Targeted Agents Be Combined with Preoperative Chemoradiation in Rectal Cancer? 189
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study of bevacizumab (bev) with gemcitabine-Erlotinib 23(31):8136–8139
Should Upfront Chemotherapy
Precede Preoperative 20
Chemoradiation and Surgery?
90
84.7% 83.7%
81.9%
79.9%
80 5FU/LV FOLFOX
5FU/LV
Control
70 68%
66.4% 65%
Postop
58.9% FOLFOX Preop FU/RT 59.4%
60 FU/RT FU 58.2%
Postop 55.5% Preop
5F/LV FU/RT Preop
FU 52.2% FU/RT
Preop Postop
RT Or RT
50 Postop
FU
Preop NO
FU FU/RT PostopFU
Or RT
NO
40 PostopFU
30
20
10
0
QUASAR MOSAIC MOSAIC CAO/ARO/AIO FFCD 9203 EORTC 22921
Stage II Stage II Stage III 94 Stage II/III Stage II/III Stage II/III
Fig. 20.1 5-year disease-free survival for landmark clini- EORTC 22921 [5] (Adapted from Ther Adv Med Oncol
cal trials in colon. Quasar [24]; MOSAIC [1] and rectal [3]. © Sage Publications, INC. London:SAGE)
cancer trials; CAO/ARO/AIO [40]; FFCD 9203 [20];
may be genetically different. Different levels of was statistically significantly increased in the
microsatellite instability and mutations in BRAF subset of patients with positive regional lymph
and NRAS have been described [19, 28, 39] and nodes but not in patients with N0 disease when
can be of importance for the efficacy in the adju- compared to patients not receiving chemotherapy
vant setting in these two different anatomic sites. [21]. Although results of a subset analysis of data
from the MOSAIC trial did not show a significant
DFS benefit of FOLFOX over 5FU/LV for patients
20.2 Adjuvant Chemotherapy with stage II disease at a follow-up of 6 years, a
in Colon Versus Rectal Cancer trend was observed for improved DFS in high-risk
stage II patients (i.e. disease characterized by at
In colon cancer, adjuvant chemotherapy is rec- least one of the following: T4 tumour, tumour per-
ommended in stage III because, as demonstrated foration, bowel obstruction, poorly differentiated
in the MOSAIC trial, DFS at 5 years was tumour, venous invasion, £ lymph nodes exam-
significantly better in the FOLFOX arm (66.4%) ined) receiving FOLFOX compared to infusional
when compared with those receiving 5FU/leu- 5FU/LV, suggesting that this patient population
covorin (58.9%) P = 0.005. Overall survival at may benefit from treatment with FOLFOX. No
6-year follow-up was also significantly increased benefit, however, of FOLFOX over 5FU/LV was
(72.9% vs. 68.7%; HR = 0.80; P = 0.023) [1]. seen for patients with low-risk stage II disease in
The impact of adjuvant chemotherapy for the MOSAIC trial.
patients with stage II disease is much less clear. Although, to date, there has been no definitive
An analysis of pooled data from seven random- randomized study to identify the optimal post-
ized trials indicated that overall survival of operative adjuvant treatment and the optimal
patients with resected early stage colon cancer duration of therapy in rectal cancer [43], the
treated with 5FU-based adjuvant chemotherapy general recommendation is to give adjuvant
20 Should Upfront Chemotherapy Precede Preoperative Chemoradiation and Surgery? 195
chemotherapy to patients with stage II and III By contrast, the adherence to the planned treatment
[22, 35]. is higher in colon cancer trials. In the MOSAIC
European Organization for Research and trial, 98.6% of patients received at least one cycle
Treatment of Cancer (EORTC) 22921 was a ran- of fluorouracil/leucovorin and oxaliplatin and
domized trial to evaluate the role of concurrent 98.9% received at least one cycle of fluorouracil/
chemoradiation in the neoadjuvant setting, along leucovorin and 74.7% of patients in the group given
with the role of adjuvant chemotherapy in patients fluorouracil plus oxaliplatin and 86.5% in the FL
with resectable stage T3/T4 rectal cancer [5]. group received the planned 12 cycles [2]. This fact
Patients (n = 1,011) were randomized to one of could explain, at least in part, the lack of a clear
four treatment arms: benefit to DFS or OS in the EORTC trial.
1. Preoperative radiation (45 Gy over 5 weeks) Second, this trial included clinically staged
alone T3/T4 patients [6], 35% of whom were recruited
2. Preoperative radiation plus two 5-day courses after a clinical examination that included some
of chemotherapy (5FU at 350 mg/m2/day and subjective criteria (i.e. clinical T3 had to have
leucovorin at 20 mg/m2/day in week 1 and 5 of one of the following at digital rectal examination:
radiation therapy) a circular extension, a lateral or posterior fixity
3. Preoperative radiotherapy plus four postoper- and an anterior adhesion to the prostate or inva-
ative courses of chemotherapy sion of the rectovaginal wall), and 60% were
4. Preoperative radiotherapy and chemotherapy ultrasound-staged T3, and as the German study
plus postoperative chemotherapy demonstrated, about 20% could be stage I [40].
The adjuvant chemotherapy used in this study Therefore, in this study, the methods used for
was 5FU (350 mg/m2/day) and leucovorin (20 mg/ staging could have determined that the true popu-
m2/day) given on days 1–5, and this regimen was lation would be made up of stages I, II and III.
given every 3 weeks for a total of four courses. Third, the survival curves for patients who
At the time of the initial analysis, which was received postoperative adjuvant chemotherapy
reported after a median follow-up of 5.4 years, begin to diverge after 2 years for DFS and after
adjuvant chemotherapy did not appear to confer 4 years for OS when compared to those who did
benefit in terms of DFS or OS. There are, how- not receive adjuvant chemotherapy, suggesting
ever, three important points to note. The first is that further follow-up is required to determine
that 26.9% of patients randomized to receive whether these differences will continue.
adjuvant chemotherapy actually never started the An updated analysis was subsequently per-
treatment and only 43% received 95% of the formed to determine the long-term results of the
planned dose of chemotherapy. Data from other EORTC 22921 study [14]. The goal of this
modern phase II and phase III [18, 37, 40, 41] exploratory multivariate analysis was to investi-
trials are similar, showing that applying chemo- gate whether it was possible to identify a sub-
therapy (5FU or capecitabine/oxaliplatin) after group of patients who would benefit most from
preoperative chemoradiation and surgery is prob- adjuvant chemotherapy in the long term. Adjuvant
lematic and often not feasible with adequate dos- chemotherapy did not improve DFS or OS for all
ing. More recently, a National Comprehensive patients with resectable T3/T4 rectal cancer.
Cancer Network (NCCN) analysis carried out on A subset analysis, however, revealed that patients
810 stage II and III patients from eight specialty whose disease responded to neoadjuvant therapy,
cancer centres shows that 20% of patients treated specifically those patients whose tumours were
with neoadjuvant chemoradiation did not receive downstaged to ypT0–T2 compared with stages
any adjuvant CTX [30]. The most frequent ypT3–T4 with preoperative therapy, experienced
causes are the patient’s decision to abandon a survival benefit from adjuvant chemotherapy.
treatment because of the fatigue following the Exploring the same issue, more recently a
aggressive therapy schedule, toxicity, and physi- large retrospective analysis has been reported.
cian’s recommendation due to comorbid illness. Two thousand seven hundred twenty-four
196 C. Fernandez-Martos and X.G. de Albeniz
patients were included. Forty-one percent under- clear (R0) resections despite nearly a third having
went adjuvant chemotherapy, which consisted had tumours that were initially threatening or
mostly of 5FU-based chemotherapy. The aim of involving the circumferential resection margin
that analysis was to determine whether patients (CRM). However, only one pathological com-
with pathological complete response, ypT1–T2 plete response was achieved.
or ypT3–T4 tumour after CRT have different More recently, investigators from the same
benefits of adjuvant chemotherapy for DFS. The group have published the largest phase II trial
HR with 95% CI for DFS for adjuvant chemo- (first published in 2006 with 77 patients and
therapy was 0.94 (0.50–1.78) for patients with updated 2010 with 105 patients and median fol-
pCR, 0.61 (0.40–0.92) for patients with ypT1–T2 low-up of 55 months) which examined the use of
tumours and 0.97 (0.75–1.25) for patients with four cycles of induction, this time with capecit-
ypT3–T4 tumours. ypT1–T2N0 benefit most abine plus oxaliplatin (CAPOX) followed by
from adjuvant CT, and for ypT3-T4 patients, pN- CRT with capecitabine [11, 13]. This trial
stage did not alter benefit of adjuvant chemo [4]. included poor-risk rectal cancer patients as
defined by magnetic resonance imaging (MRI).
Eligible patients must have tumours within 1 mm
20.3 Induction Chemotherapy of mesorectal fascia (i.e. circumferential resec-
Followed by Concomitant tion margin threatened), T3 tumours at or below
Chemoradiotherapy levators, tumours extending 5 mm into perirectal
and Surgery fat, T4 tumours and T1–4N2 tumours. There was
a clinically significant occurrence of cardiac/
Treatment of high-risk patients with fluoro- thromboembolic (CTE) toxicity during neoadju-
pyrimidines and concurrent radiotherapy without vant oxaliplatin/capecitabine, which led to three
the addition of adequate doses and cycles of CT mortalities. This fact prompted a protocol amend-
appears to be less than optimal. Strategies to ment, and more stringent criteria were added to
improve adherence to the systemic component of exclude entry of patients with a previous history
the treatment are necessary. of stable angina, arrhythmia, acute coronary syn-
One approach to address this issue is to deliver drome (even if controlled by drugs) or myocar-
induction CT before preoperative CRT. Induction dial infarction within the past 12 months. After
CT may be associated with better treatment com- amendment of the protocol, only one further fatal
pliance and may enable full systemic doses of CT pulmonary embolism occurred.
to be delivered. Other theoretical advantages of High radiological response rates to preopera-
induction CT include the possibility of shrinking tive treatment were recorded (96% of assessable
or downstaging a locally advanced tumour, thereby patients), 20% pCR and no disease progression
facilitating more effective local treatment and early during preoperative treatment. Three- and 5-year
treatment of micrometastasis. Disadvantages failure-free survival (ITT population) was 68%
include the delay in surgery and the reduced and 64%, respectively; 3- and 5-year overall sur-
efficacy of subsequent radiotherapy with selection vival was 83% and 75%, respectively. Clinical
of radiotherapy-resistant clones [23]. results of these and other phase II trials are given
The first study published with this strategy in Table 20.1.
was from the UK, in which 36T3/T4 and N×/+ On the basis of these encouraging results, we
rectal cancer patients were treated with 12 weeks designed a phase II, randomized trial to compare
of induction protracted venous infusion of this approach with conventional preoperative CRT
fluorouracil and mitomycin C before standard followed by surgery and postoperative adjuvant
chemoradiation and surgery [12]. A high rate of CT [17] (Fig. 20.2). A total of 108 patients with
tumour downstaging was recorded without any locally advanced rectal (LAR) cancer as defined
progressors during neoadjuvant chemotherapy, by magnetic resonance imaging (MRI) of the pel-
and 82% of patients achieved microscopically vis were randomly assigned to preoperative CRT
Table 20.1 Phase II studies with induction chemotherapy followed by chemoradiotherapy (CRT) with or without adjuvant chemotherapy in rectal cancer patients
20
5-FU 5-Fluorouracil, MMC Mitomycin C, pCR pathological complete response, CT chemotherapy, RT radiotherapy, MRI Magnetical Resonance Image, DRE Digital Rectal Examination,
US Ultrasonography, FOLFOX 5FU Leucovorin and Oxaliplatin, CAPOX Capecitabine and Oxaliplatin, N.R. Not reported
198 C. Fernandez-Martos and X.G. de Albeniz
Stratification: center
Randomization
Cape: 825 mg/m2 × 2 Cape : 2,000 mg/m2 14 days. 1 week rest
5 days/ week-5 weeks Oxa: 130 mg/m2 day 1
Concomitant with RT 4 cycles
+
Oxa: 50 mg/m2 weekly × 5 Cape: 825 mg/m2 x2
Concomitant with RT 5 days/ week-5 weeks
+ Concomitant with RT
Pelvic RT : 5,040 cGys +
5 − 6 weeks Oxa: 50 mg/m2 weekly x 5
Surgery Concomitant with RT
+
Pelvic RT : 5,040 cGys
Cape : 2,000 mg/m2 14 days. 1 week rest 5 − 6 weeks
Oxa 130 mg/m2 day 1
Surgery
4 cycles
Fig. 20.2 Schema for randomized, Grupo Cáncer de Recto (GCR) 3, phase II study. Cape capecitabine, RT radiation
therapy, Oxa oxaliplatin
with capecitabine, oxaliplatin and concurrent Furthermore, 25% of patients in the adjuvant arm
radiation followed by surgery and four cycles of A did not begin treatment, and 51% received all
postoperative adjuvant capecitabine and oxalipla- four cycles, whereas 100% of patients in the
tin (CAPOX) or induction CAPOX followed by induction arm began treatment, and 92% received
CRT and surgery. MRI criteria for LAR cancer all four cycles. These differences reached statisti-
were as follows: tumours extending to within cal significance.
2 mm of, or beyond, the mesorectal fascia (i.e. an The updated results with a median follow-up
involved or threatened circumferential resection time of 39.3 months and 36 months DFS rates
margin); lower third (£6 cm from the anal verge) were 68% (95% CI, 53–80%) for adjuvant arm
cT3 tumours; resectable cT4 tumours and any and 70% (95% CI, 55–80%) in the induction arm
cT3N+. The primary endpoint was pathologic (P = 0.97) (Fig. 20.3). Analyzing the subset of
complete response rate (pCR). On an intention- patients at higher risk (i.e. patients with cT4, cT3
to-treat basis, the pCR for the standard strategy distal third or CRM + tumours), the 36 months
(adjuvant CT) was 13.5% (95% CI, 5.6–25.8%) DFS was 62% for the adjuvant arm versus 70%
and for the induction strategy 14.3% (95% CI, for the induction arm. Although the numbers are
6.4–26.2%) respectively. There were no statisti- small, this insignificant difference may indicate a
cally significant differences in other endpoints, trend towards some benefit of the induction strat-
including downstaging, tumour regression and egy in the higher-risk population [16]. Further
R0 resection. evidence that induction chemotherapy can con-
The most compelling results of this study tribute to better control of distant relapse comes
concern the secondary endpoints. In the course from the recently published NSABP R-03 phase
of CRT, there were no differences between the III trial [38]. This is the first trial to document a
arms in the number of patients with grades 3–4 significant improvement in disease-free survival
toxicity. However, during adjuvant/induction in patients undergoing neoadjuvant chemoradio-
CT, significantly more patients in adjuvant arm therapy therapy. Patients enrolled in R-03 received
than in the induction arm had grades 3–4 toxic- 6 weeks of fluorouracil (500 mg/m2) and leuco-
ity (54% vs. 19%; P = 0.0004, respectively). vorin (500 mg/m2) before the start of radiotherapy
20 Should Upfront Chemotherapy Precede Preoperative Chemoradiation and Surgery? 199
1.00
0.75 69%
Survival probability
68%
0.50
Adjuvant arm
0.25 Induction arm
Subjects Event Censored Median (CL 95%)
Brazo A 52 29% (15) 71% (37) NA (NA, NA)
Brazo B 56 29% (16) 71% (40) NA (NA, NA)
Log−Rank 0.9704
0.00
0 6 12 18 24 30 36 42 48 54
Time from consent date (months)
Number of patients at risk
Brazo A 52 47 44 41 40 36 27 18 2 0
Brazo B 56 54 46 41 38 28 16 5 0
Fig. 20.3 3-year failure-free survival for all eligible patients in GCR 3 trial
(cycle 1). Two courses of chemotherapy (cycles 2 5FU and radiation increases the pathological
and 3) were administered during the first and fifth complete response (pCR) rate over radiother-
week of radiotherapy and four courses (cycles apy alone and improve locoregional control
4–7) postoperatively. Perhaps a 6-week course of but to date have not demonstrated an improve-
induction chemotherapy and a greater total cumu- ment in survival outcomes. The phase III stud-
lative dose of FU are more effective in control- ies published in the last decade include a
ling micrometastatic disease and improving clinically staged population of heterogeneous
disease-free survival. risk. Added to this, a frequently occurring fact
is that there is a poor adherence to the adjuvant
Conclusion treatment with chemotherapy after surgery. In
Several conclusions can be drawn based on the this scenario, no randomized study has shown
studies discussed above. In colon cancer, the that delivery of adjuvant chemotherapy in
recommended adjuvant treatment is based on patients undergoing preoperative radio(chemo)
trials with an appropriate selection of patients therapy improves outcome as compared with
with pathological stages II and III, and one observation. Emerging evidence from several
important observation is that the benefit in phase II trials and, recently, randomized phase
terms of DFS is more evident in high-risk II trials indicates that induction chemotherapy
groups. Moreover, the patients are included in for rectal cancer patients is feasible, does not
clinical trials following surgery, including only compromise pCR, or R0 resection rates, is
patients who are well recovered after surgery less toxic and enables chemotherapy to be
and with a good performance status to receive delivered in adequate dose and intensity.
complementary treatment, allowing in this way Nonetheless, while these data are statistically
a high compliance with the planned treatment. and potentially clinically meaningful, these
On the other hand, in cancer of the rectum, pre- remarkable findings are regarded as hypothesis
operative combined modality treatment with generating. Given the fact that the predominant
200 C. Fernandez-Martos and X.G. de Albeniz
20.4.3 Biomarkers
20.4.2 Study Design
A recent publication [10] showed that a 13-gene
20.4.2.1 Primary Endpoint signature could predict, with 86% accuracy, rec-
Superiority in disease-free survival (DFS), tal cancer patients that will respond to CRT. This
defined as the time from date of randomization study was retrospective and validation in a differ-
until disease progression, relapse or death from ent population and prospectively is mandatory to
any cause. establish the clinical utility to such a signature.
20 Should Upfront Chemotherapy Precede Preoperative Chemoradiation and Surgery? 201
Therefore, we considered our study an ideal sce- is 62%. The hazard ratio comparing the DFS in
nario for such a validation. the induction arm to the control arm is 0.78. This
is equivalent, based on design assumptions, to a
3-year DFS rate in the control arm of 62% versus
20.4.4 Randomization 70% in the induction arm. Under these assump-
tions, a total of 1,028 patients would be needed.
A blocked randomization with blocks of size 4
and 6 is proposed with the following stratification
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20 Should Upfront Chemotherapy Precede Preoperative Chemoradiation and Surgery? 203
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37. Rödel C, Liersch T, Hermann R et al (2007) Multicenter Oxaliplatin, Radiotherapy, and Excision) study after
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40. Sauer R, Becker H, Hohenberger W et al (2004)
Preoperative versus postoperative chemoradiotherapy
for rectal cancer. N Engl J Med 351:1731–1740
How to Achieve Long-Term
Survival in Patients 21
with Metastatic Rectal Cancer?
<T3 NO ≥ T3 or N+
or
3 months Preop RT (5x5) 3 months
preop FOLFOX or CRT preop FOLFOX
6months postop
3 months postop FOLFOX
FOLFOX
Fig. 21.1 Treatment algorithm for resectable synchronous metastatic rectal cancer
more than one line and six cycles (3 months) of disease. Although number (more than 4) and size
preoperative treatment, incomplete macroscopic (more than 5 cm) have an impact on prognosis
resection (R2), concomitant extrahepatic metasta- [69], patients could still be deemed resectable
ses and progression during preoperative chemo- with these characteristics. The ‘European Expert
therapy were associated with poor prognosis [1]. Panel’ recently stated that the resection should
Whereas scoring for survival is broadly have the potential to be complete and macroscopi-
accepted, criteria for resectability of CLM are cally curative [49].
difficult to define. Although several approaches
were published, no consensus could be reached
yet [43, 49, 52, 62, 69]. In the EORTC 40983 trial, 21.4 Management of Patients with
patients with up to four potentially resectable liver Initially R0 Resectable
metastases and no evidence of extrahepatic dis- Liver+/−Lung Metastases
ease were included [48]. Current clinical trials
include patients depending on resectability deter- The role of perioperative treatment in resectable
mined by a surgeon with hepatic surgery exper- liver+/−lung metastases, especially the point
tise. Limitations for liver surgery are remnant in time (pre- vs. postoperative), mode (systemic
liver of less than 30%, unfavourable location, co- vs. local) and intensity (monotherapy vs. combi-
morbidities excluding major surgery, aggressive nation), is still a matter of debate. Although
tumour biology and/or presence of extrahepatic postoperative therapy after resection of liver
208 A. Stein and H.-J. Schmoll
Upfront chemotherapy
Yes No
Continue/change chemotherapy
< T3 N0 ≥ T3 or N+
Yes No
Resection of primary
+ resection of metastases
Avoid radical and mutilating surgery
RCTx or short course RT for locally
advanced tumors
Resume initial treatment for a total
of 6 months
Fig. 21.2 Treatment algorithm for unresectable synchronous metastatic rectal cancer
Metachronous liver/lung
metastases
Resection No resection
Table 21.1 EORTC trial 40983 of perioperative chemotherapy versus observation in patients with resectable colorec-
tal liver metastases: results by group of analysis
Perioperative Surgery Absolute difference for 3-year
Patients chemotherapy alone progression-free survival rate HR p-value
All 182 182 +7.3% (28.1–35.4%) 0.79 (0.62–1.02) 0.058
Eligible 171 171 +8.1% (28.1–36.2%) 0.77 (0.60–1.00) 0.041
Resected 151 152 +9.2% (33.2–42.4%) 0.73 (0.55–0.97) 0.025
HR hazard ratio, p-value significance level
metastases of colorectal origin CLM has become toxicities occurred in the chemotherapy arm.
an accepted standard of care in many parts of Nearly 80% of patients completed the preopera-
the world, data on the benefit are limited. There tive part. After resection, 76% of patients were
are only a few randomized trials comparing pre- receiving postoperative treatment, with 52% of
and/or postoperative intravenous chemotherapy patients (n = 80) completing six cycles.
or hepatic artery infusion with or without intra- During preoperative chemotherapy, main
venous chemotherapy to surgery alone. grade 3/4 toxicities were nausea and vomiting
Moreover, in adjuvant systemic chemotherapy, 4%, diarrhoea 8%, stomatitis 7%, sensory neu-
none of the conducted clinical trials achieved ropathy 2% and neutropenia 18% (febrile 2%).
the recruitment goal, leading to solely prema- Postoperative reversible complications were
ture data. significantly higher (25% vs. 16%, p = 0.04) in
the chemotherapy group. Particularly intra-
abdominal infections, biliary fistulas with an out-
21.4.1 Perioperative Treatment of put of more than 100 ml/day for more than
Patients with R0 Resectable 10 days and hepatic failure with a bilirubin eleva-
Liver Metastases tion grade 3/4 for more than 3 days occurred
more often in the perioperative group. There was
The EORTC 40983 trial accrued 364 patients to no impact on postoperative death rate (1% in both
be randomized between surgery alone and che- arms). During postoperative chemotherapy, tox-
motherapy with 5-fluorouracil, leucovorin and icities were similar, with a higher rate of grade 3
oxaliplatin (FOLFOX4 regimen), administered sensory neuropathy (10%) and other neurological
3 months pre- and postoperatively [48]. Patients toxicities (12%) due to the higher cumulative
had to be technically resectable (as stated by CT dose of oxaliplatin.
scan) with a maximum of 4 CLM and no prior According to those data, this approach is
treatment with chemotherapy. Despite favourable widely considered as a standard for patients with
patients`characteristics, with 50 % bearing only resectable CLM.
one CLM and surgery at “high-quality” institu-
tions the 3-year progression-free survival rate
was relatively poor. A significant increase in pro- 21.4.2 Postoperative Treatment of
gression-free survival rate at 3 years from 33.2% Patients with R0 Resectable
to 42.4% was shown in the group of patients Liver+/−Lung Metastases
(n = 171) receiving chemotherapy and resection
of CLM (HR 0.73, 95% CI 0.55–0.97). In the Despite being the standard of care in patients
randomized population (‘intent-to-treat analy- with stage III disease, data for adjuvant treatment
ses’), the difference was not statistically after resection of stage IV disease are still limited.
significant due to ineligibility of 6% of patients Two randomized phase III trials have compared
(HR 0.79, 95% CI 0.62–1.02) but still favouring adjuvant systemic chemotherapy with 5FU/FA
the chemotherapy arm (Table 21.1). No unusual after resection of liver or lung metastases to
210 A. Stein and H.-J. Schmoll
surgery alone, but both closed prematurely due to However, the lack of a clear benefit might also be
slow accrual. A small but significant improve- related to the relatively poor efficacy, as shown in
ment in disease-free survival rate (DFSR) was the adjuvant treatment of stage III colorectal dis-
demonstrated in the FFCD trial at the time of clo- ease with FOLFIRI [57, 61, 71]. Recently, results
sure, with a 5-year DFSR of 26.7% vs. 33.5% of the prematurely closed Dutch HEPATICA trial
(p = 0.028), favouring the group with adjuvant were presented, demonstrating a DFS benefit
treatment after resection of CLM [51]. Although after 2 years of 18% (70% vs. 52%) in favour of
the 5-year overall survival rate (OSR) increased 12 months bevacizumab with 6 months chemo-
from 41.1% to 51.1%, this difference was not therapy with capecitabine and oxaliplatin com-
significant (p = 0.13). The ENG (EORTC/NCI- pared to the same chemotherapy alone after R0
CTG/GIVIO) trial, still not fully published, dis- resection of CLM in 79 patients [64]. Further
played a non-significant trend towards a prolonged follow-up might reveal whether this benefit is
DFS with a median of 39 vs. 20 months (p = 0.35) only transient, as recently seen with bevacizumab
and an increased overall survival (OS) with a after resection of stage II or III colon cancer
median of 53 vs. 43 months (p = 0.39) in patients [2, 13]. However, it is questionable whether fur-
with liver (n = 90) or lung (n = 13) metastases ther results regarding adjuvant chemotherapy will
[36]. However, a combined analysis of both trials be available, as most current postoperative trials
(n = 278) showed a non-significant prolongation (ADHOC, NSABP C-09 and HEPATICA) were
of the median disease-free survival (DFS) from closed due to insufficient accrual (Table 21.2).
18.8 to 27.9 months (p = 0.058) and the OS from
47.3 to 62.2 months (p = 0.095) [41]. Both trials
were using a non-contemporary 5FU bolus regi- 21.4.3 Peri- Versus Postoperative
men, which is more toxic and possibly not active Treatment of Patients with R0
enough to reveal a significant increase in this lim- Resectable Liver+/−Lung
ited number of patients. Postoperative treatment Metastases
with 5FU plus irinotecan in a prematurely
stopped, randomized phase III trial revealed no Currently, available data seem to favour peri-
additional benefit over 5FU alone in terms of OS operative chemotherapy in clearly R0 resect-
(3-year survival rate of 73% vs. 72%) [70]. able liver metastases, although OS data for the
Regarding median disease-free survival (DFS), perioperative approach are still lacking. In case
there was a non-significant increase of 3 months final analyses of the EORTC 40983 trial cannot
(21.6 vs. 24.7 months, HR 0.90, 95% CI 0.67– demonstrate a significant OS benefit, both
1.2, p = 0.47). The gain in DFS is possibly smaller approaches (peri- and postoperative) would be
as to be detected with 150 patients per group. of similar evidence. However, preoperative
21 How to Achieve Long-Term Survival in Patients with Metastatic Rectal Cancer? 211
treatment offers the option of individual assess- (HR 1.0, 95% CI 0.84–1.21; p = 0.96) [46, 67].
ment of tumour biology and response to chemo- Recently, a small phase II trial, evaluating the
therapy and does therefore help to better select addition of bevacizumab to HAI and systemic
patients for surgery and postoperative treatment; chemotherapy with 5FU/FA and either oxalipla-
e.g., patients with progressive disease during tin or irinotecan, demonstrated increased biliary
preoperative chemotherapy will have no benefit toxicity (p = 0.02) without any difference in RFS
from liver surgery in case of extrahepatic spread or OS [31]. Regarding these results, application
of disease, and even if still resectable, continua- of HAI may not be recommended as a standard
tion of same chemotherapy postoperatively of care.
would not be meaningful. Furthermore, the peri-
operative approach enables administration of
chemotherapy to a higher rate of patients, as 21.5 Management of Patients
postoperative treatment will not be feasible in with Initially Unresectable
up to 20% as demonstrated in the EORTC 40983 Metastases
trial, with 115 of 151 resected patients starting
postoperative FOLFOX and only 80 completing The group of patients with potentially resectable
6 cycles [48]. metastases warrants a highly active, neoadjuvant
treatment aiming on conversion into resectabil-
ity, with tumour shrinkage as an important goal.
21.4.4 Local Treatment/Hepatic Artery Regarding the reported RECIST overall response
Infusion (HAI) After Resection rates (ORR) displayed in clinical trials in the
of CLM first-line treatment for metastatic colorectal can-
cer, either a chemo-doublet in combination with
Several trials were comparing postoperative a monoclonal antibody (e.g., cetuximab, panitu-
hepatic artery infusion combined with or without mumab or bevacizumab) or a three-drug chemo-
systemic treatment to surgery alone after resec- therapy (e.g., FOLFOXIRI) are possible options
tion of CLM with diverging results [37, 55, 65]. [8, 15, 19, 27, 39, 56, 60]. However, the avail-
The systematic review by Nelson et al. of 592 able large trials have included all patients with
patients revealed a non-significant survival metastatic CRC, and the bene fi t con fi ned to
advantage in favour of the control (non-HAI) CLM and ‘conversion rates’ cannot be assessed
group of 8.9% (HR 1.089, 95% CI 0.887–1.334), (Table 21.3).
which is in contrast to a current meta-analysis The CELIM included ‘potentially resectable’
demonstrating a RFS benefit (HR 0.78, 95% CI CLM only. With RECIST response rates of
0.65–0.95; p = 0.01), although OS did not differ 70% resulting from treatment with oxaliplatin- or
Table 21.3 Efficacy of first-line chemotherapy in unselected patients with metastatic colorectal cancer
R0 rate
Trial Treatment Pat. (n) RR (%) RR (‘liver only’) R0 rate all ‘liver only’
Van Cutsem et al. [60] FOLFIRI + cet 316* 57.3* 70.6* (n = 68) 5.1 13.2
Bokemeyer et al. [8] FOLFOX + cet 82* 57* 76* (n = 25) 7.3 16
Maughan et al. [39] 5FU/cape + oxali + cet 362* 64* nr nr nr
Douillard and Siena [15] FOLFOX + pan 593 57* nr nr 28
Hurwitz and IFL + beva 402 45 nr <2% nr
Fehrenbacher [27]
Saltz et al. [56] 5FU/cape + oxali + beva 699 47 nr 6.3 12.3
Falcone et al. [19] FOLFOXIRI 122 66 nr 15 36
*KRAS wildtype, (n) number of patients, R0 (n) number of R0-resections, 5FU 5-fluorouracil, cape capecitabine, oxali
oxaliplatin, irino irinotecan, beva bevacizumab, cet cetuximab, pan panitumumab, nr not reported
212 A. Stein and H.-J. Schmoll
Increased risk of perioperative bleeding, postop- tumour dissemination (peritoneal cancer index,
erative complication rate and poorer functional PCI < 20), limited small bowel disease and no
reserve was found to be associated with vascular extra-abdominal metastasis. Furthermore localiza-
lesions. Although influence on morbidity is still tion, histology and lymph node status of the pri-
controversial, mortality was not affected [44, 63]. mary tumour as well as response to systemic
In the EORTC 40983 trial, the perioperative treat- chemotherapy should be considered.
ment resulted in a similar postoperative death rate
as compared to surgery alone, with a significantly Conclusion and Recommendations
higher rate of reversible postoperative complica- Multidisciplinary management of patients
tions (p = 0.04). Higher risk of complications and with metastatic rectal cancer is crucial in order
an increased 90-day mortality (1.6% vs. 14.7%, to select patients amenable for a curative
odds ratio (OR) 10.5) was reported for irinotecan- approach. In regard to long-term survival
associated steatohepatitis [34, 63]. The addition achievable in liver+/−lung metastases or even
of bevacizumab to neoadjuvant oxaliplatin-based in localized peritoneal carcinomatosis, patients
treatment is feasible and does not limit the ability eligible for a curative intent approach should
of liver regeneration [25, 53]. Duration of preop- be transferred to specialized centres for hepatic
erative treatment seems to have major impact on or peritoneal surgery.
perioperative morbidity and prognosis and should Patients with synchronous metastatic rec-
therefore be as short as possible in case of tal cancer should be treated with primary
initially unresectable disease [1, 3, 30, 32]. chemotherapy, followed by secondary local
Duration of perioperative chemotherapy in case treatment including surgical resection if fea-
of initially R0 resectable CLM should be either sible according to extent of disease, response
6 months postoperatively or 3 months pre- and to chemotherapy and co-morbidity with the
postoperatively. aim of long-term survival. Achievement of
resectability of metastatic disease is the main
treatment aim; therefore, the primary tumour
21.7 Management of Limited is less relevant. Only in case of symptomatic
Peritoneal Disease rectal primary tumour local measures (e.g.,
with Cytoreductive insertion of a stent or stoma) and in specific
Surgery (CRS) and circumstances palliative surgical resection
Hyperthermic Intraperitoneal should be performed.
Chemotherapy (HIPEC) For synchronous R0 resectable liver+/−lung
metastases, treatment approaches are as follows:
Peritoneal carcinomatosis as single lesion in • For clearly R0 resectable metastatic dis-
advanced colorectal cancer represents a special ease, irrespective of primary tumour, peri-
biologic entity with poor prognosis under systemic operative chemotherapy (3 months pre- and
chemotherapy alone. Current data including one postoperative FOLFOX) should be applied
randomized controlled trial and numerous pro- analogue to the EORTC 40983 trial [48].
spective and retrospective studies suggest a role of • In locally advanced primary tumours (³T3
CRS and HIPEC within the multimodal treatment or N+): upfront chemotherapy with
regimen and may improve PFS as well as OS for FOLFOX for 3 months and local treatment
selected patients with peritoneal carcinomatosis according to stage (or reverse sequence)
[16, 17, 24]. The procedure can be performed with followed by resection of the primary (staged
acceptable morbidity and low mortality in special- or synchronous) followed by postoperative
ized centres. Nevertheless, preoperative patient FOLFOX for 3 months should be applied.
selection is crucial for the success of the combined • In early primary tumours (<T3 N0): resec-
treatment concept. Main selection criteria are good tion of primary and metastases followed by
general health status, limited intraperitoneal postoperative treatment with FOLFOX for a
214 A. Stein and H.-J. Schmoll
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necessary (e.g., CRM+ or N+) postoperative FOLFIRINOX (ERBIRINOX) as first-line treatment
for unresectable metastatic colorectal cancer: a phase
local treatment according to stage. II trial. Oncologist 16(11):1557–1564
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nous, potentially resectable metastatic disease response of colorectal liver metastases after chemo-
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tases become resectable, local treatment accord- tive chemotherapy in patients with resectable colorectal
ing to stage for primary followed by resection liver metastases. Ann Surg Oncol 16(9):2385–2390
of primary and metastases should be performed, 7. Blazer DG 3rd, Kishi Y et al (2008) Pathologic
response to preoperative chemotherapy: a new out-
followed by postoperative continuation of the come end point after resection of hepatic colorectal
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able, treatment should be continued or switched, according to biomarker status of cetuximab plus
FOLFOX-4 as first-line treatment for metastatic col-
depending on quality of response. orectal cancer: the OPUS study. Ann Oncol 22(7):
In case of metachronous disease, similar 1535–1546
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• Cleary, R0 resectable liver+/−lung metasta- vival after resection of liver and lung colorectal metas-
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Acknowledgments The manuscript was prepared with- with bevacizumab for colorectal liver metastases.
out any funding or contribution of persons not mentioned JAMA 302(21):2338–2344
in the authors’ section. 13. De Gramont A, Van Cutsem E (2011) AVANT: Results
from a randomized, three-arm multinational phase III
Conflict of Interest AS honoraria: Roche, Merck study to investigate bevacizumab with either XELOX
Serono. HJS: consultant or advisory role: Roche hono- or FOLFOX4 versus FOLFOX4 alone as adjuvant
raria: Roche; research support: Roche and Merck Serono. treatment for colon cancer. J Clin Oncol 29(suppl 4):
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Will Adjuvant Chemotherapy
Improve Outcome After 22
Preoperative Chemoradiation?
comparatively few patients with rectal cancer or 22.3 Summary of Published Data
have focused on colon cancer alone. Most patients
with rectal cancer receive loco-regional treatment The published data on the role of adjuvant chemo-
with RT or CRT, either after or, currently more therapy in rectal cancer derive from several
common, before surgery, whereas this is rarely decades during which the loco-regional treatment
done in colon cancer. This more complex treat- has undergone considerable changes. The data are
ment scenario has made the effect of systemic divided based on whether surgery was the only
adjuvant chemotherapy in rectal cancer more treatment or was accompanied by RT or CRT and
difficult to study, and the evolvement over time of whether such treatment was given before or after
the local treatment strategies has added further to the surgery. Very few studies about the value of
this complexity. adjuvant chemotherapy for rectal cancer have
The low level of scientific evidence for a been performed after preoperative CRT followed
benefit from adjuvant chemotherapy in rectal by TME, i.e. the focus of this review.
cancer is acknowledged in authoritative treatment
guidelines and by expert groups that still often
conclude that such treatment should be consid- 22.3.1 Adjuvant Chemotherapy
ered based on the principles used for colon can- Following Surgery Alone
cer [25, 40, 51]. In a recent systematic review, it
was concluded that adjuvant chemotherapy after This treatment setting, in most cases not rele-
surgery for rectal cancer following RT or CRT is vant today to the treatment of rectal cancer in
not ‘evidence-based’ [7]. In this review, where the Western world, except for the early stages,
the key findings from the pivotal clinical trials has mostly been studied in Japan, and the
performed in this field are summarized, we dis- fluoropyrimidine used was mostly uracil/tegafur
cuss how to interpret the current state of knowl- administered for 1–2 years, sometimes also
edge to be able to answer the question posed in together with mitomycin C. Several Japanese tri-
the title and related questions. als, including more than 5,000 patients, showed
statistically significant benefit from adjuvant che-
motherapy in DFS and/or OS with risk reductions
22.2 Retrieval of Published Data in the 15–40% range [31, 32, 45, 46]. Similar
observations were also observed in two western
Although the recent systematic review by Bujko world trials, including the QUASAR trial which
et al. concentrated on its role following CRT, the explored the value of adjuvant folinic-acid-
literature search covered all treatment settings modulated 5-FU in patients with colon cancer or
and was performed through August 2009 [7]. rectal cancer where the benefit of adjuvant chemo-
The current review is based on the literature therapy was considered uncertain [43].
retrieved by Bujko et al., updated with the addi- Of 3,239 patients in the QUASAR trial, 984
tional relevant data published from August 2009 had rectal cancer. In this group, a survival benefit
through May 2011. The PubMed and Cochrane from adjuvant chemotherapy was shown with a
databases were searched using the keywords 5-year OS of 78% compared with 74% in the
‘rectal cancer and adjuvant chemotherapy’. In control group (HR 0.77; p = 0.05). Subgroup
addition, abstracts and conference reports from analysis with patients divided into those with sur-
the scientific meetings of the American Society gery alone (n = 549) or pre- (n = 198) or postop-
of Clinical Oncology and the European Society erative (n = 201) RT was presented separately
of Medical Oncology and smaller focused meet- [27]. This analysis showed no significant hetero-
ings 2009–2011 relevant to the field were geneity between the groups, which separately
retrieved. We limited our report to data from tri- were too small to show statistically significant
als in which treatment allocation was randomized differences, but all showed point estimates indi-
and to patients operated on with curative intent. cating benefit from adjuvant chemotherapy.
22 Will Adjuvant Chemotherapy Improve Outcome After Preoperative Chemoradiation? 219
A joint analysis of Nordic trials showed no for DFS 0.87 (0.72–1.04). However, in patients
statistically significant benefit in OS at 5 years in given adjuvant chemotherapy, the local recur-
stage II/III rectal cancer (n = 691) from 4 to rence rate was reduced from 17% to 9%
12 months of various types of 5-FU-based che- (p = 0.002). OS and DFS were not reported sep-
motherapy [26]. A separate analysis of the arately for the RT and CRT groups. In the
Norwegian study where 5-FU + levamisole was QUASAR trial, 198 patients had preoperative
used for 12 months did similarly not reveal any RT and were then randomized to adjuvant che-
benefit in rectal cancer after surgery alone [13]. motherapy or not [27, 43]. In this subgroup,
An OS gain was seen in colon cancer stage III. In there was an obvious trend to benefit from adju-
addition, smaller studies showed no benefit in vant chemotherapy with hazard ratios for OS
DFS or OS [24, 28, 29]. and DFS close to 0.5. These differences were
not statistically significant due to the small
sample size.
22.3.2 Adjuvant Chemotherapy Early interim data from the ongoing PROCTOR/
Following Surgery and SCRIPT trial in which patients following short-
Postoperative RT or CRT course RT and immediate surgery are randomized
to 6 months folinic-acid-modulated 5-FU (n = 177)
Four moderately sized trials in this treatment set- or capecitabine (n = 183) or observation only and
ting showed no benefit in DFS or OS [9, 22, 37, joined with data (n = 107) from the Chronicle trial,
49]. In these trials, the adjuvant chemotherapy with randomization after preoperative CRT to
was 5-FU for 6–12 months. This treatment set- observation or adjuvant capecitabine and oxalipl-
ting was also part of the QUASAR trial (see atin, have been presented at a conference [53].
above), with 201 patients randomized [27, 43]. Based on these 470 patients, there were no signs
The hazard ratios indicated benefit from adjuvant of benefit in OS but numerically a minor advan-
chemotherapy for OS and DFS in this subgroup tage in terms of local recurrence and rate of dis-
of patients, although the differences were not sta- tance metastasis. The follow-up time of the
tistically significant. patients was not presented, but likely short since
some patients were recently included. The
PROCTOR/SCRIPT is still ongoing and has been
22.3.3 Adjuvant Chemotherapy expanded to also include patients having preop-
Following Preoperative erative long-course CRT.
RT and Surgery
22.3.5 Adjuvant Chemotherapy Before are positive. The overall data for this setting
and After CRT and Surgery support the notion that rectal cancer, in corre-
spondence with colon cancer, is possible to tar-
This setting could be considered experimental get with adjuvant chemotherapy. From a clinical
and is currently being studied, and no mature data practice point of view, however, this has limited
are available. Phase 2 trial data show high relevance since probably very few patients today
response rates in the rectal cancer primary from with more advanced rectal cancer go to surgery
chemotherapy with 5-FU/capecitabine and oxali- without preoperative (C)RT.
platin and better tolerance and compliance from In addition to being interesting from a princi-
adjuvant chemotherapy starting before CRT and ple point of view, this knowledge is of use in a
surgery vs. CRT, surgery and adjuvant chemo- situation in which a patient has been operated
therapy [10, 18]. without prior (C)RT based on favourable clinical
More relevant to the current issue of adjuvant and radiology findings at staging, but with unex-
effects is the randomized phase 2 Expert-C trial pected high-risk features in the histopathological
(n = 164) in which all patients with high-risk report. In this situation, adjuvant chemotherapy
operable RC were treated with 3 months of may be reasonable to consider as an alternative to
capecitabine combined with oxaliplatin (Capox), postoperative CRT since adjuvant chemotherapy
then had CRT with capecitabine followed by may provide both improved local and systemic
surgery and finally three more months of postop- control. If the high-risk features indicate a com-
erative Capox. The patients were randomized to parably high risk of local failure (e.g. crm+), it
addition of the EGFR antibody cetuximab to may be difficult for many to accept removal of
the pre- and postoperative chemotherapy and the the (C)RT component used for decades. If the
CRT or not. Efficacy data were presented at the features rather indicate high risk of failing sys-
2011 ASCO Conference [17]. Interestingly, in temically (e.g. extramural vascular invasion with
addition to significantly higher local tumour clear crm), adjuvant chemotherapy only maybe
response, addition of cetuximab also provided a considered acceptable. It is acknowledged,
statistically significant benefit in OS (hazard ratio though, that these data are not strong and are also
0.27; p = 0.035) and a trend towards better DFS unexpected from a pharmacological point of
(hazard ratio 0.81; p = 0.668) in the subset of view. A beneficial effect from adjuvant chemo-
patients with KRAS wild-type tumours. therapy on local recurrences is also supported by
population-based data [36] and in an analysis of
data from five European clinical trials [52].
22.4 Discussion The overall picture gets complicated when
(neo)adjuvant (C)RT has been used. For such
The level of scientific evidence in favour of therapy given postoperatively, most data show
benefit from adjuvant chemotherapy in rectal that addition of adjuvant chemotherapy pro-
cancer after curative surgery is considerably vides no major benefit, notably with the data
weaker than that in colon cancer. Not only are the from the QUASAR trial as an exception.
overall efficacy data far from convincing but they However, in practice, this situation is less rele-
often derive from old trials using adjuvant che- vant to discuss since there is now little support
motherapy schedules not in current use, and little for (C)RT after surgery [40, 51]. Most data
data are from treatment settings in which optimal indicate that when preoperative (C)RT has been
surgery and preoperative short-course RT or CRT given, the benefit from adding adjuvant chemo-
have been applied. therapy is likely to be very small or absent,
Adding 5-FU-based adjuvant chemotherapy again with the QUASAR trial as an exception.
to surgery alone seems to provide meaningful Although the Chronicle/PROCTOR/SCRIPT
benefit in terms of OS and DFS and perhaps also data are early and based on an interim analysis
local recurrence rate, although not all study data only, the lack of indication of a benefit from
22 Will Adjuvant Chemotherapy Improve Outcome After Preoperative Chemoradiation? 221
adjuvant chemotherapy is troublesome, given may be important in putative tumour ‘stem cells’,
the use in these trials of up-to-date neoadjuvant responsible for establishment and growth of
(C)RT, high-quality surgery and adjuvant che- metastasis. Furthermore, the pattern of metastatic
motherapy of current standard (5FU/leucovorin, spread differs between colon cancer and rectal
capecitabine or capecitabine/oxaliplatin). cancer, and theoretically, ‘stem cells’ deposited
By comparison with the efficacy of adjuvant in e.g., the lungs may be less drug sensitive than
chemotherapy in colon cancer and in rectal can- those in the liver or lymph nodes due to differ-
cer when adjunctive (C)RT has not been given, it ences in the interaction between tumour cells and
might be concluded that by adding (C)RT, which stroma [33, 38]. However, the finding of an adju-
has an obvious effect on small tumour deposits as vant effect in rectal cancer following surgery only
indicated by reduced local recurrence rate from does not support this possibility.
its addition to surgery, the effect from adjuvant Yet, another explanation to the small or absent
chemotherapy is in some way reduced. In the effect from adjuvant chemotherapy in rectal can-
case of CRT, the chemotherapy added to RT cer treated with preoperative (C)RT would be tim-
could theoretically have an adjuvant systemic ing of adjuvant chemotherapy, i.e. that adjuvant
effect although this is unlikely considering the chemotherapy is starting later than in colon can-
lack of benefit in OS and DFS from preoperative cer due to the time spent on the (C)RT and waiting
CRT compared with RT alone [6, 8] and the low for surgery and/or postoperative complications
total systemic exposure to chemotherapy in this leading to postponed start of adjuvant chemother-
setting compared with conventional adjuvant apy compared with the situation in colon cancer.
chemotherapy. This might be relevant since in colon cancer, the
Theoretically, the finding of an attenuated efficacy of adjuvant chemotherapy is attenuated
effect from adjuvant chemotherapy when given by time of start after surgery [5, 16]. However, the
after (C)RT could be explained if the untreated indication of a lack of effect from adjuvant che-
primary rectal cancer is an important source of motherapy also in the PROCTOR/SCRIPT study,
tumour cells that preoperatively spread and later in which the delay to adjuvant chemotherapy was
developed into metastases. However, in that case, likely small, argues against a major effect from
(C)RT should provide some benefit over no (C) timing. Another and related explanation could be
RT in terms of OS and development of metasta- the mostly lower compliance with the adjuvant
sis, which has not been observed, unless short- chemotherapy in rectal cancer compared with
course RT was given in the pre-TME era [21, 48]. colon cancer. In this context, presentation of study
On the other hand, the very complex view of the data both based on intention to treat and per pro-
primary tumour, metastasis and microenviron- tocol would be valuable. Although Swedish popu-
ment ecology emerging [38] may open for yet lation data show that OS after short-course RT,
unknown distant interactions between the pri- TME and adjuvant chemotherapy is significantly
mary and the metastases that speculatively could better than if adjuvant chemotherapy is not given
depend on the local treatment. [50], patient selection could have influenced the
Another possibility is a lower sensitivity of outcome since treatment allocation was not by
rectal cancer compared with colon cancer in the randomization.
adjuvant setting based on differences in tumour The relevance of the timing effect could be
biology. Similar activity of chemotherapy in approached by starting with the systemic rather
terms of tumour response rates and benefit in PFS than the local treatment in rectal cancer. The
and OS as well as the spectrum of drug activity in apparently favourable findings in the Expert-C
the metastatic setting argue against this possibil- trials indicate that this approach may be
ity. However, colon cancer differs from rectal beneficial [10, 17]. This approach seems fea-
cancer in several aspects relevant to tumour biol- sible and well tolerated [10, 18] and will be
ogy [1, 23, 39, 47], and although such differences investigated in the Nordic/Dutch RAPIDO
may not materialize in the metastatic setting, they trial, in which patients with poor prognosis
222 B. Glimelius and P. Nygren
rectal cancer will be randomized to conven- cancer are regarded as one disease entity essen-
tional CRT followed by surgery and optional tially separated only by an anatomical border.
adjuvant chemotherapy or short-course RT fol- Consequently, the role of adjuvant chemotherapy
lowed immediately by neoadjuvant chemother- in rectal cancer following (C)RT and surgery is
apy and finally surgery. conveniently and pragmatically extrapolated
Subgroup analyses of the EORTC 22921 trial from colon cancer and from the old, mainly US
have indicated that patients with tumour down- studies in rectal cancer where adjuvant chemo-
staging to pT0–2 compared with those with therapy with adjuvant chemoradiotherapy was
tumours remaining as pT3–4 following (C)RT had tested [41], without too much consideration of
better prognosis but they also showed benefit the evidence basis for this approach. The NCCN
from adjuvant chemotherapy [12]. However, this guidelines clearly state the adjuvant chemother-
effect from adjuvant chemotherapy seemed apy should be given to those at risk for recurrence
restricted to preoperative RT but not to CRT and [40]. In a recent exploration of the use of adju-
was, surprisingly, not related to the nodal status vant chemotherapy in a large US population
after treatment. These findings contrast to other registry, suboptimal use was noticed. It was con-
subgroup analysis on this issue [19] and the gen- cluded that even at specialty cancer centres, a
eral observations of better effect from adjuvant sizeable minority of rectal cancer patients treated
chemotherapy in colon cancer in more advanced with curative intent neoadjuvant CRT do not
disease [4, 35]. Additional methodological prob- complete postoperative chemotherapy. Strategies
lems with the EORTC trial subgroup analysis to foster adherence to the third and final compo-
were discussed by Bujko et al. [7]. Thus, although nent of curative intent treatment were considered
response to neoadjuvant (C)RT provides strong necessary [34]. However, for those with a more
prognostic information in rectal cancer, it cannot, puristic view on the scientific basis of cancer
based on current knowledge, be used to predict treatment, associated with considerable costs
the efficacy of adjuvant chemotherapy. both in terms of health-care funding and individ-
The notion that rectal cancer may successfully ual patient suffering from adverse effects, this
be targeted in the adjuvant setting, as shown in the approach is clearly disturbing.
early trials adding adjuvant chemotherapy to sur- In routine care, any treatment should be given
gery only, but that a substantial effect is somehow if it is proven that it is sufficiently effective and
lost or at least severely attenuated when combined that the negative effects and costs do not counter-
with preoperative (C)RT points to the use in adju- balance this. Since many patients with rectal can-
vant chemotherapy of drugs more active against cer recur, there is a need for adjuvant therapies
subclinical disease than 5-FU or its analogues that decrease the risk. After surgery alone, the
alone. The addition of oxaliplatin to 5-FU data indicate that adjuvant chemotherapy may
improves the adjuvant effect in colon cancer [4, have sufficient effects, but this is presently not
30, 35] and needs to be studied also in rectal can- the case after CRT. The answer to the question
cer. Unfortunately, effects in the metastatic situa- ‘will adjuvant therapy’ posed in the title is ‘well,
tion cannot be extrapolated to the adjuvant setting it should’. But, does it? No, we do not know.
as illustrated by the recent negative trial data on Should it be given? Basically not. Will it be
the VEGF and EGFR antibodies in colon cancer given? Well, in many, but not all health-care sys-
[2, 3, 14]. Thus, there is a need for preclinical tems it will, and even strongly recommended in
models of subclinical disease relevant to colon official guidelines. When the use was quality
and rectal cancer to optimize the selection of can- controlled, the doctors were almost ‘banned not
didate drugs to be included in clinical trials on the to have followed the guidelines’ [34]. In every
adjuvant effects in these tumour types. health-care system, doctors and patients must
In many, perhaps even most, centres treating weigh pros and cons in every clinical situation.
rectal cancer, adjuvant chemotherapy in this Considering the weak scientific evidence, with
tumour type is a non-issue; colon cancer and rectal comparably small gains in the positive trials and
22 Will Adjuvant Chemotherapy Improve Outcome After Preoperative Chemoradiation? 223
lack of signs of gain in other trials, it may actually adjuvant postoperative RT vs. postoperative RT plus
be very sound that not all patients get treatment, 5-FU and levamisole in patients with TNM stage II-III
resectable rectal cancer. J Surg Oncol 75:80–88
even if recommended. 10. Chua YJ, Barbachano Y, Cunningham D et al (2010)
The lack of convincing data showing a benefit Neoadjuvant capecitabine and oxaliplatin before
from adjuvant chemotherapy in rectal cancer chemoradiotherapy and total mesorectal excision in
argues for participation in well-designed clinical MRI-defined poor-risk rectal cancer: a phase 2 trial.
Lancet Oncol 11:241–248
trials in currently used treatment settings. 11. Cionini L, Manfredi B, Sainato A et al (2001)
Unfortunately, the trials ongoing in this field are Randomized study of postoperative chemotherapy
not designed to answer the fundamental question after preoperative chemoradiation in locally advanced
whether adjuvant chemotherapy provides any rectal cancer. Preliminary results. Eur J Cancer 37:
S300 (Abstr)
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since no non-treatment control arms are included. with curative resection of cT3–4 rectal cancer after
In this light, the PROCTOR/SCRIPT trial is preoperative radiotherapy or radiochemotherapy: does
important to finalize. anybody benefit from adjuvant fluorouracil-based
chemotherapy? J Clin Oncol 25:4379–4386
13. Dahl O, Fluge O, Carlsen E et al (2009) Final results of
a randomised phase III study on adjuvant chemother-
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49:1206–1216
Part VI
Q&As on Surgery
How to Evaluate the Quality
of Surgery? Suggestions 23
for Critical Reading of Surgical
and Pathological Reports
Lars Påhlman
based upon imaging as well as postoperative risk of damage of the nerves should be minimal.
tumour stage based upon pathological examina- However, if the tumour is growing outside the
tion exists. normal plane of dissection, the risk of nerve dam-
The registries have annual reports with data age is obvious. By registering such outcome
divided upon hospitals but also showing chang- together with the knowledge of tumour stage, it is
ing’s and trends in each country. Most of the reg- possible to increase the quality.
isters have been enlarged based upon the need for
new items to be register and studied. Once a new Conclusion
parameter is involved in the registration, i.e., Quality in surgery has become an important
lymph node retrieval, the first year registration topic in rectal cancer treatment. Lots of data
often shows unaccepted differences between support that provided surgery is done in an
units, but with transparent reports and discus- optimal way, one can reduce the use of radio-
sions among the surgical communities in the therapy and perhaps also reduce the use of
country, the next years’ registration will often chemotherapy. To have an immediate feed-
show an increase to the better, and within some back to the surgeon whether or not the surgi-
years it reaches acceptable levels. Subsequently, cal procedure has been done in an optimal
a quality register not only guarantees good assur- way, photo documentation of the specimen is
ance that the level of care is acceptable but also essential and grading by the pathologist of the
acts as a vehicle for quick introduction of new macroscopic view of the specimen is also
treatment standards. crucial. With a quality assurance programme,
The experience from the Scandinavian countries the whole treatment of rectal cancer can be
has led to the same project in many European coun- evaluated.
tries. In an effort to have similar programmes,
ECCO has sponsored together with European
Society of Surgical Oncology (ESSO) and Euro-
pean Society of Coloproctology (ESCP) a collabo- References
ration with all countries with quality registration,
the EURECCA project (European Registration of 1. Mc Ardle CS, Hole D (1901) Impact of variability
among surgeons on postoperative morbidity and mor-
Cancer Care) [10]. Countries involved so far, as
tality and ultimate survival. BMJ 302:1501–1505
national registries or regional, are Belgium, 2. Heald RJ, Husband EM, Ryall RDH (1982) The
Denmark, Germany, Italy, the Netherlands, Norway, mesorectum in rectal cancer surgery: the clue to pel-
Spain, Sweden and the UK. vic recurrence. Br J Surg 69:613–616
3. Enker WE, Thaler HT, Cranor ML, Polyak T (1995)
Other important end points to be evaluated are
Total mesorectal excision in the operative treatment of
specific complications which can be results of carcinoma of the rectum. J Am Coll Surg 18:
non-optimal surgical technique. Well-known 335–346
complications or merely dysfunctions are sexual 4. Moriya Y, Hojo K, Sawada T, Koyama Y (1989)
Significance of lateral lymph node dissection for
impairment, urinary dysfunctions and bowel
advanced rectal carcinoma at or below the peritoneal
problems [11, 12]. In all, this is a whole spectrum reflection. Dis Colon Rectum 32:307–315
of quality of life. To add this in a quality registra- 5. Wibe A, Møller B, Norstein J, Carlsen E, Wiig JN,
tion, prospective validated questionnaires have to Heald RJ, Langmark F, Myrvold HE, Søreide O,
Norwegian Rectal Cancer Group (2002) A national
be used.
strategic change in treatment policy for rectal cancer –
Regarding the sexual problems and also uri- implementation of total mesorectal excision as routine
nary impairments, modern more precise surgery treatment in Norway. A national audit. Dis Colon
will prevent such complications in the majority of Rectum 45:857–866
6. Påhlman L, Bohe M, Cedermark B, Dahlberg M,
the cases. Today, with good preoperative staging,
Lindmark G, Sjödahl R, Öjerskog B, Damber L,
surgeons should know if the normal plane of dis- Johansson R (2007) The Swedish rectal cancer regis-
section could be followed. If that is the case, the try. Br J Surg 94:1285–1292
232 L. Påhlman
7. Bülow S, Harling H, Iversen LH, Ladelund S, Danish CR07 and NCIC-CTGCO16 randomised clinical trial.
Colorectal Cancer Group (2009) Survival after rectal Lancet 373:821–828
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Laeger 171:2735–2738 bers of the EURECCA Consortium (2010) Improving
8. Kressner M, Bohe M, Cedermark B, Dahlberg M, quality of cancer care through surgical audit. Eur J Surg
Damber L, Lindmark G, Öjerskog B, Sjödahl R, Oncol 36:S23–S26
Johansson R, Påhlman L (2009) The impact of hospi- 11. Dahlberg M, Glimelius B, Graf W, Påhlman L (1998)
tal volume on surgical outcome for rectal cancer – a Preoperative irradiation for rectal cancer affects the
survey of the Swedish Rectal Cancer Register. Dis functional results after colorectal anastomosis –
Colon Rectum 52:1542–1549 results from the Swedish Rectal Cancer Trial. Dis
9. Quirke P, Steele R, Monson J, Grieve R, Khanna S, Colon Rectum 41:543–551
O’Callghan C, Sun Myint A, Bessell E, Thompson 12. Marijnen CA, van de Velde CJ, Putter H et al (2005)
LC, Parmar M, Stephens RJ, Sebag-Montefiore D Impact of short-term preoperative radiotherapy on
(2009) Effect of the plane of surgery achieved on local health-related quality of life and sexual functioning in
recurrence in patients operated with operable rectal primary recta caner: report of a multicentre trial.
cancer: a prospective study using data from the MRC J Clin Oncol 23:1847–1858
How Is Nerve-Sparing Surgery
Well Performed? 24
Zoran Krivokapic and Ivan Dimitrijevic
Goligher, Bernstein and Weinstein [2, 63, 67] with sphincter-saving procedures [13, 27, 31,
published the papers where significant percent- 41, 59, 66]. These results are in a way obvious
age of patients operated for rectal cancer had since the abdominoperineal resection (APR) is
sexual and urinary dysfunction. In one meta- more mutilant in its nature, and presence of a
analysis that dealt with quality of life of patients stoma has a significant psychological influence
operated for rectal cancer in the second half of on these individuals. Mr. Heald stressed that
the twentieth century, sexual dysfunction was injury to the neurovascular bundle of Walsh is
observed in 39% and urinary dysfunction likely to happen during the perineal act due to
occurred in 27% of patients [4]. Fortunately, with poor visibility and the fact that statistically more
the introduction and popularization of the TME, advanced tumours are found in this group of
the things changed for better [16]. Besides men- patients [15].
tioned oncological benefits, identification and As it is clearly apparent, the sex of patient
preservation of vegetative nerves has become significantly affects the percentage of nerve
easier [18]. By abiding the main principles of identification and preservation as well as patients’
TME technique, i.e. sharp dissection under the constitution (obese individuals, narrow ‘male’
direct control of vision, we have almost no bleed- pelvis) [56]. Neo-adjuvant therapy can also be a
ing, and by following the correct dissection plane, factor that influences nerve identification and
there is minimal risk of serious vegetative nerve preservation. Nevertheless, literature data are
damage. Additionally, we obtain adequate resec- inconsistent due to different inclusion criteria,
tion margins, especially important circumferen- and research methods and this subject deserve to
tial resection margin, good specimen and ability be further investigated [27, 32]. Tumour stage
to perform high percentage of sphincter-preserv- and localization as well as operation type also
ing operations. have significant influence on the degree of
Sympathetic vegetative nerve structures are identification and preservation of vegetative
generally situated more proximally and are easier nerves [27, 31]. The factor that significantly
to identify and preserve. According to literature affects nerve preservation and identification is
data, by conducting proper TME, identification surgeons experience and training in this field.
of these structures is possible in 80–94% [13] Learning curve showed to be independent factor
in males and in even 96% [21] in females. The that predisposed the degree of nerve preservation
situation with identification and preservation of and identification [27].
parasympathetic structures differs. They are Nevertheless, the good postoperative results
placed deep in the pelvis, in delicate fascial lay- published by highly specialized rectal surgeons
ers of closely situated pelvic organs and are much have not been achieved in larger studies [38, 43].
more difficult to identify and preserve. There is Concerning sexual function, age showed to be
a lot of discrepancy in literature data on this a very, if not the most, important predictive fac-
subject. The percentage of preservation and tor after rectal cancer operations [19, 29, 59].
identification of these structures varies between Patients over 60 years of age have a significantly
53% and 96% [21, 39, 44]. higher risk of loss of sexual function postopera-
In almost all studies published on this sub- tively than younger patients [13]. The difference
ject, the operation type proved to be a significant in the upper age limit between a number of stud-
factor of influence. In cases where surgeons pre- ies can explain various rates of sexual dysfunc-
formed the transection of mesorectum, situation tion reported.
was very good as presented by some [42]. On Some investigators, in order to further
the other hand, when performing more challeng- improve and facilitate the nerve preservation,
ing procedure, TME, the results tend to be attempted to employ neurostimulation and mea-
worse. Unfavourable functional results were surement of penile tumescence or intravesical
noted in patients where abdominoperineal resec- pressure. Using these methods, the percentage
tion (APR) was performed, compared to those of identification of pelvic vegetative nerves rises
24 How Is Nerve-Sparing Surgery Well Performed? 235
from standard 70–80% to almost 100% [7, 58]. engorgement of the clitoris and labia. Disruption
The initial results are promising but deserve fur- of the autonomic nerves in females may cause
ther research. dyspareunia and vaginal dryness. Reviewing the
Concerning all postoperative functional deficits literature, we see that postoperative sexual dys-
and recovery rates in the follow-up period, we can function is present in the range between 3% and
conclude that if preoperative function is intact, the 57% [19, 49]. Dyspareunia is the most common
likelihood of complete recovery is fair. symptom after rectal cancer surgery and some-
times even before the operation [13]. Disturbances
of the pelvic anatomy can explain some of the
24.3 Physiological Considerations female sexual problems. APR results in higher
incidence of dyspareunia and is almost always
The sympathetic and parasympathetic nervous present if the posterior wall of the vagina is
systems act as an integral system in the coordina- removed.
tion of urinary and sexual function. Sacral para- Urinary bladder is also innervated with both
sympathetic fibres carry the impulses that mediate components of the autonomic system. The base
dilatation of the vascular inflow to the cavernous of the bladder is supplied by sympathetic
bodies which results in erection. The neuronally impulses, and the detrusor muscle is innervated
triggered vasodilatation responsible for erection by parasympathetic fibres. These two systems
is mediated by nitric-oxide-induced relaxation of together with centres in the spinal cord and pons
the cavernosal sinusoids. The damage to these coordinate the cycle of filling and empting of the
structures results in impotence, the most severe bladder. Damage to the parasympathetic fibres
sexual deficit in men. causes non-coordinated action of the detrusor
On the other hand, sympathetic fibres are and overactive sympathetic stimulation of the
responsible for emission of semen from the semi- bladder base. As a result, we have the most com-
nal vesicles into the urethra. Sympathetic fibres mon consequence of the damaged vegetative
also innervate the vasa, prostate, urethra and the innervation, flaccid bladder with high intravesi-
internal urethral sphincter. Coordinated sympa- cal pressure. Patients in this situation experience
thetic activation of these structures, together with urinary retention. Infrequently, due to the isolated
somatically innervated bulbospongiosus and sympathetic denervation or a lesion of levator ani
ischiocavernosus muscles, results in ejaculation. nerve, which is a somatic structure, patients can
The sacral segment of spinal cord is responsible experience urinary incontinence [28, 62]. Urinary
for the coordination of the sexual response. dysfunction after rectal cancer operations is pres-
Damage to these structures most commonly ent in 4–28% of the cases [27, 37, 48]. In males,
causes the absence of ejaculation or a case of a urinary disturbances are rather frequent, occur-
retrograde one due to denervation of internal ure- ring in around 40%. On the other hand, urinary
thral sphincter. Male sexual dysfunction is pres- incontinence is infrequently reported [27, 37].
ent in around 10–35% of cases after rectal cancer
operations [13, 34, 39]. Enker reported that spon-
taneous postoperative erection was possible in 24.4 Anatomical Consideration
85% of the patients [9], and similar results were in the Context of Function
achieved by other specialized surgeons [14, 48]. Preservation
In women, parasympathetic impulses trigger
the release of vasoactive intestinal polypeptide 24.4.1 Pelvic Vegetative Nerve
from nerve endings in the vaginal wall that results Structures
in intensive vaginal transudation of fluid which
together with secretion of Bartholin glands allows 24.4.1.1 Sympathetic Innervation
good lubrication of vagina. As in males, parasym- The sympathetic impulses to the pelvis are gener-
pathetic impulses are responsible for vascular ated in the intermediolateral grey matter of the
236 Z. Krivokapic and I. Dimitrijevic
afferences exist, most commonly from a single fascia can sometimes be more obvious in patients
branch of the second, third or fourth sacral gan- thatunderwentneo-adjuvanttreatment.Nevertheless,
glion [40]. in most of the cases, this layer is thicker than the
mesorectal fascia [5].
24.4.1.4 Efferences of the Pelvic Plexus Histologically, it is constituted of collagen,
In females, the vaginal branches distally come out elastic and smooth muscle fibres. As mentioned,
of the top of the pelvic plexus through branches these longitudinal smooth muscle fibres are
leading to the bladder, vagina and the rectum. These accompanied by delicate nerve filaments [1, 55].
branches come from two stalks just beneath the Prostate and seminal vesicles in males and vagina
point where ureter crosses uterine artery. One trunk in females are situated anteriorly [1, 35].
that innervates bladder is distally, down to the ure- Posteriorly, mesorectal fascia, thin mesorectum
ter, divided into further two branches – lateral and and rectal wall are found. This structure is contin-
medial trigonal. The other trunk innervates vagina ued to the perineal body caudally [8].
and goes along with uterine artery. This branch, at On the matter of adherence of this structure to
the lateral edge of vagina, is divided into further the surrounding organs, there is no current con-
two fibre groups. Some of these fibres perforate the sensus. Sex differences are present, and generally
posterior vaginal wall and can be found in the rec- in females, it is less adherent to the anterior organs
tovaginal septum [40]. opposed to males, especially distally. Some
In males, the most prominent and important authors state that adherence is generally stronger
efferent of the pelvic plexus is the urogenital neu- to the anterior organs, but others have opposite
rovascular bundle. From its origin, at the most dis- opinion [5, 23].
tal part of the pelvic plexus, it goes posterolaterally According to Bill Heald and a number of other
to the prostate and continues laterally on the both authors [17, 45] Denonvilliers’ fascia is a part of
sides of the urethra. Approximate thickness of this the mesorectum anteriorly, thus suggesting that
structure is around 10–12 mm. It contains ganglia during the dissection, this structure should be left
as well as nerve fibres together with connective tis- on the mesorectal specimen. According to them,
sue. This structure is situated between two layers a distinct plane of dissection exists between sem-
of the lateral pelvic fascia (levator and prostatic inal vesicles and Denonvilliers’ fascia. Applying
fascia). The neurovascular bundle branches this approach mentioned, authors managed to
through parietal pelvic fascia and medially through maintain good sexual and urinary function post-
Denonvilliers’ fascia to the prostate and urinary operatively, which suggests that we can avoid
bladder. The rest of the fibres (cavernous nerves) damage to vegetative nerve structures if we fol-
pass around the base of the prostate base and con- low the so-called mesorectal plane [15, 36].
verge in a ‘pincer-shaped’ formation, close to ure- Others state that this structure has two leaves,
thra. Distally, these nerves pierce through pelvic suggesting that appropriate dissection plane
floor muscles and course to genital organs [6, 54]. should be through the Denonvilliers’ fascia [47].
Nevertheless, this structure is far from being well- Some more recent histological studies show
defined. Some authors [30] found distinct neuro- that this fascia is more adherent to the anterior
vascular bundle in only 48% of the cases. In the organs, and the reason for leaving it on the rectal
remaining 52%, nerve fibres were spread all along side is more oncologic than anatomic one, in cases
the lateral side of the prostate. of low anteriorly placed rectal carcinomas [35].
from the endopelvic fascia of the pelvic sidewall sacral plexus, separately from pudendal nerve.
that goes anteromedially as it approaches to the The levator ani nerve approaches levator ani mus-
rectum. Miles, Goligher and some other older cle from within the pelvis on the superior surface
authors suggested ‘clamping’ or ‘hooking on the of the pelvic floor. Its position makes this struc-
finger’ of this structure [11]. ture amenable to accidental damage during TME.
Also, it has been suggested that these liga- This nerve gives substantial innervation to levator
ments contain fatty tissue, nerves and vessels muscle as mentioned, and its injury can explain
(middle rectal artery), which present oncological certain proportion of postoperative faecal and uri-
danger for the rectal cancer patients; thus, these nary incontinence [61].
should be clamped near the lateral pelvic side-
wall [11]. This approach proved to be devastating
in the terms of preservation of pelvic vegetative 24.5 Important Points of Nerve
nerves, since according to recent studies, impor- Preserving TME
tant pelvic ganglia are contained in this area,
especially in its lateral third [6]. The basic concept of the TME procedure is to
With the advances in this field of surgery, follow embryologically defined layers. According
especially since the introduction of TME in 1982, to Mr. Bill Heald, the founder of this method, ‘the
by Bill Heald [18], situation changed. Heald and corollary to the perfect specimen and cure is
others state that there is no such structure and the perfect preservation of the layers surrounding
sharp dissection just close to mesorectal fascia is the mesorectum which, are formed by the auto-
adequate and oncologically sufficient. Resent nomic nerves and plexuses’ [15].
anatomical studies supported this opinion [25]. During the nowadays standard operation for
In addition, studies have shown that middle rectal rectal carcinoma of the middle and lower third
artery exists in only 25–50% of cases and its of rectum (TME), there are a number of points
diameter is rarely greater than 2 mm [25, 52], where a surgeon can easily damage some of the
which makes diathermy perfectly safe method in mentioned vegetative nerve structures. We will
transection of this structure. go through these steps and try to ascertain
mechanisms of vegetative nerve injury and their
prevention.
24.4.4 Pudendal and Levator Ani Nerve
Not only autonomic nerves play an important 24.5.1 Mobilization of the Left Colon
role in sexual and urinary function. Two somatic and Ligation of the Inferior
nerves are responsible for certain aspect of these Mesenteric Artery
functions. Those are pudendal nerve and levator
ani nerve. Proper mobilization of the left colon involves
In the infralevatory compartment, pudendal finding the right plane between two leaves of
nerve arises from S2–S4 roots of the sacral plexus Toldt’s fascia, leaving retroperitoneal surface
and runs through ischioanal fossa to the genital with gonadal vessels, ureter and preaortic sym-
area giving sensory and motor branches, i.e., dor- pathetic fibres intact. This is done by dividing
sal penis or clitoris nerve. In males, pudendal the white (Toldt’s) line of the sigmoid colon
nerve gives motoric impulses for ischiocaverno- from the peritoneum of the lateral abdominal
sus and bulbospongiosus muscle, important for wall (Fig. 24.2). By gently lifting upwards meso-
rigid phase of erection [6]. The damage to puden- colon together with so-called pedicle package,
dal nerve can cause faecal incontinence. Relatively, we reveal a correct dissection plane (Fig. 24.3).
recent papers have re-emphasized another somatic Performing this, we can easily identify and pre-
nerve that innervates levator muscles. That is leva- serve already mentioned two preaortic sympa-
tor ani nerve that arises from S3–S4 roots of the thetic trunks going around inferior mesenteric
24 How Is Nerve-Sparing Surgery Well Performed? 239
Fig. 24.11 Proper incision of the peritoneum reflection at Fig. 24.13 Specimen after performed TME with lower
the beginning of anterior dissection edge of Denonvilliers’ fascia transected in the level of the
lower third of prostate
to encompass peritoneal reflection that should transversely (Fig. 24.13). This is a crucial step in
remain on the specimen (Fig. 24.11). Entering this the preservation of delicate neurovascular bundles
plane enables us to clearly visualize anterior that present distal continuation of the inferior
organs, seminal vesicles and vagina. Good retrac- hypogastric plexus and practically invisible cav-
tion of these structures in most cases reveals avas- ernous nerves that pass anterolaterally to the rec-
cular, areolar tissue and relatively straightforward tum on the way through urogenital diaphragm
dissection plane distally which leaves shiny, before entering cavernous bodies [10, 16]. Once
smooth anterior side of the specimen (Fig. 24.12). again, in order to properly preserve neurovascular
This smooth surface on the specimen is actually bundles of Walsh, it is mandatory to be aware of its
Denonvilliers’ fascia. As one proceeds distally, correct anatomical position, especially in males
comes to a point where Denonvilliers’ fascia (Fig. 24.14). From the distal part of the pelvic
becomes adherent to the posterior capsule of plexus, it travels caudally, under the pelvic floor
the prostate. Here, fascia should be divided fascia. The neurovascular bundle pierces this
24 How Is Nerve-Sparing Surgery Well Performed? 243
the operation. Removing of the coccyx which is a [60]. This is a smooth muscle situated in the
standard part of this procedure enables the sur- levator hiatus, in the place where Denonvilliers’
geon to properly visualize neurovascular bundles fascia ends. It is connected to the external anal
and posterior part of the prostate, much easier sphincter, as well as with muscle layer of the rec-
than during standard abdominoperineal proce- tum. Cavernous nerves pierce this structure, and
dure [3, 22, 64, 65]. it is surrounded with tortuous anorectal veins. If
Additionally, in cases of very low rectal carci- we tend to dissect through this structure during
nomas when performing APR or intersphincteric the perineal act of APR, we can transect cavern-
resection, it is rather difficult to find a correct ous nerves and mentioned veins can be damaged.
plane or one can encounter venous bleeding in Afterwards, in an attempt to control the bleeding,
the area of anorectum passing levator hiatus. we can also do the damage to vegetative nerves
Some anatomical studies showed that this can be during the mass ligation of the anterior structures
explained by existence of rectourethral muscle (Fig. 24.15).
24 How Is Nerve-Sparing Surgery Well Performed? 245
24.5.7 Laparoscopic TME in the Context even with expert rectal surgeons. Thus, in
of Nerve Identification and words of Mr. Bill Heald, ‘specimen-oriented
Preservation surgery’ may be the clue. If we obtain a perfect
specimen, with no defects of extra tissue on the
In recent years, laparoscopic approach is gaining mesorectal fascia, it can be expected, with a
ground in this field of surgery. It would be logical certain amount of certainty, that functional
that better magnification facilitates the visualiza- result of the operation will be favourable. A
tion and identification of nerve structures within careful TME with proper reconstruction is a
the pelvis. A number of studies addressed the complex procedure, and with careful nerve
issue of postoperative sexual and urinary func- preservation takes 3–5 h according to the
tion after laparoscopic TME. A few authors patient’s and tumour characteristics; a conven-
achieved excellent results, of only 6% urinary tional APE was often completed in 1 h.
and sexual dysfunction [26]. Still, majority state
that postoperative urinary and sexual function
was worse compared to open technique. Quah
and co-workers noted significant percentage of References
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Is Laparoscopic Rectal Surgery
the Gold Standard? 25
David Jayne and Laeeq Khan
1.0
0.9
0.8
0.7
Proportion surviving
0.6 Open
0.5 Laparoscopic
Conversion
0.4
0.3
0.2
P–value for Longronk test = 0.0017
0.1
P–value for Wilcoxon test = 0.0004
0.0
0 6 12 18 24 30 36
Fig. 25.1 Three-year overall survival by actual procedure: open, laparoscopic and converted. A significant difference
is observed with worse outcomes for the converted patients
high conversion rate of 34% for laparoscopic- laparoscopic operation, a fi nding that makes
assisted surgery. This was a reflection of both a intuitive sense.
learning curve effect, as demonstrated by a fall Disappointingly, CLASICC failed to show
in conversion rates throughout the study period, any difference in quality of life between laparo-
but also the increased technical difficulty associ- scopic-assisted and open surgery, a feature that
ated with rectal cancer as compared to colon has also been reported in other trials. The reason
cancer surgery. The main reasons for conversion for this is unclear as the earlier recovery demon-
were excessive tumour fixity or uncertainty of strated by shorter hospital stays is a consistent
tumour clearance (41% of conversions), obesity finding. It is perhaps related to the quality of life
(26%), anatomical uncertainty (21%) and inac- instruments used, which may be insensitive to
cessibility of tumour (20%). Importantly, conver- subtle differences in physical and psychological
sion appeared to have a negative influence on well-being, or to the timing of the investigation,
early post-operative morbidity and mortality, missing early benefits which occur within the
with a significant difference in those patients who first 2 weeks following surgery. One area of con-
were converted and those who completed a lap- cern, specifically related to laparoscopic rectal
aroscopic resection (Fig. 25.1). Three factors cancer surgery, has been the reporting of impaired
were subsequently found to be independent pre- post-operative bladder and sexual function [5].
dictors for conversion to open surgery, namely, Although this is a recognized complication fol-
body mass index, male sex and extent of tumour lowing open surgery, with reported rates of blad-
spread from the muscularis mucosa [4]. Thus, the der and sexual dysfunction between 0–15% and
obese male patient with a locally advanced rectal 10–35%, respectively, the incidence of sexual
cancer is much less likely to undergo a successful dysfunction following laparoscopic surgery in
252 D. Jayne and L. Khan
male patients in particular seems to be increased cancer [8]. Significant benefits in favour of the
(overall sexual function: difference lap vs. open laparoscopic approach were found for time to
−11.18; 95% CI: −10.94, −0.74; p = 0.063). stomal function, first bowel movement, feeding
Adequate training in laparoscopic total mesorec- solids and length of hospital stay. Additional
tal excision with attention to preservation of the benefit was found for those undergoing laparo-
pelvic autonomic nerves is therefore important if scopic abdominoperineal resection in terms of
optimal functional outcomes are to be achieved. decreased post-operative analgesic requirements
In 2006, NICE updated its guidance for lap- and less wound infections. No difference was
aroscopic colorectal cancer surgery, stating ‘lap- found between the laparoscopic and open groups
aroscopic (including laparoscopically assisted) in extent of oncological clearance. In 2008,
resection is recommended as an alternative to Anderson et al. reported a meta-analysis focusing
open resection for individuals with colorectal can- on the oncological outcomes following laparo-
cer in whom both laparoscopic and open surgery scopic rectal cancer resection [9]. Over 3,000
are considered suitable’ [6]. This statement was patients from 24 studies were compared for dif-
qualified by the caveat that ‘laparoscopic colorec- ferences in oncological outcome between laparo-
tal surgery should be performed only by surgeons scopic and open surgery. At 3 years, no significant
who have completed appropriate training in the difference was seen between the two treatment
technique and who perform this procedure often groups: radial margin positivity was 5% (lap)
enough to maintain competence’. The NICE state- versus 8% (open), overall survival was 76% (lap)
ment failed to distinguish between laparoscopic versus 69% (open) and local recurrence was 7%
surgery for colon and rectal cancer, with the two (lap) versus 8% (open). The authors concluded
entities being merged under the same ‘colorectal’ that there was no oncological difference between
umbrella. This was taken by many surgeons as a laparoscopic and open resections for primary rec-
‘green light’ to progress with laparoscopic rectal tal cancer. This conclusion accords with the
cancer surgery and indeed was informally embod- recently published long-term results from the
ied into the 2006 Department of Health initiative CLASICC trial [10]. Initial concerns regarding
to promote laparoscopic colorectal cancer surgery the higher rate of circumferential margin involve-
in the UK [7]. ment following laparoscopic anterior resection
A summary of the published data on laparo- failed to translate into a difference in local recur-
scopic rectal cancer surgery up to 2006 is shown rence, overall survival or disease-free survival.
in Table 25.1 and includes a total of 44 studies. The most recent evidence to emerge is that
The conversion rates range from 0% to 33% with from the COLOR II study. This multi-centre study
only two studies reporting rates greater than 20%. involving 30 centres across the world and recruit-
Three studies reported a significant reduction in ing 1,103 rectal cancer patients over the period
morbidity with the laparoscopic approach, with 2004–2010 has recently presented its initial results
11 studies showing no significant difference; no at the European Society of Surgical Oncology
study reported an increase in morbidity from (ESSO) conference in Stockholm in 2011 (unpub-
laparoscopic surgery. The duration of surgery lished). Patients undergoing laparoscopic rectal
was consistently longer with the laparoscopic cancer resection had less blood loss but longer
approach, with no obvious differences in short- operations than those undergoing open surgery.
term survival measures. Conversion to open operation was still observed
Two meta-analyses specifically addressing in 16.4% of cases. There was no difference in the
laparoscopic rectal cancer surgery have attempted circumferential or longitudinal resection margins
to collate the available evidence. In 2006, Aziz or the number of retrieved lymph nodes. However,
et al. reported their meta-analysis, including 20 laparoscopic surgery had the advantage of earlier
studies and 2,071 patients with 44% undergoing recovery of bowel function, less analgesic require-
laparoscopic and 56% open surgery for rectal ment and shorter hospital stay.
Table 25.1 Published series for laparoscopic rectal cancer surgery
25
(continued)
Table 25.1 (continued)
254
Two other trials of laparoscopic rectal cancer they can be clinically justified in terms of
surgery are currently still in progress: a US trial cost-effectiveness given the capital cost of the
of laparoscopic-assisted versus open resection robotic system, remains to be seen. But, there is
for rectal cancer (ClinicalTrials.gov Identifier: an inevitability that new technologies and tech-
NCT00726622) and the Australasian A La Cart niques will continue to be incorporated into
trial (www.australiancancertrials.gov.au). The laparoscopic practice, enabling current bound-
results of these trials are eagerly awaited. aries to be surpassed with benefits to both
patients and health-care providers.
Conclusion
25.3 Future Developments Is laparoscopic surgery the current gold stan-
in Laparoscopic Rectal dard? Based on the current available evidence,
Cancer Surgery it is still probably a little too premature to make
such a bold statement. A gold standard is a
The last two decades have seen much improve- level that can be attained by the majority. It
ment in laparoscopic techniques and technol- cannot be judged on the results of personal
ogy. The use of modified approaches, such as series from enthusiastic centres of excellence,
medial-to-lateral dissection, combined with bet- but rather we must await the results of the large
ter instrumentation has facilitated the perfor- randomized clinical trials that are still yet to
mance of laparoscopic surgery, making it safer report. But there is no reason to believe that
and encouraging wider adoption. It is likely that they will show any real difference from that
this trend will continue, driven by increased already observed, i.e. the laparoscopic approach
patient demand, pressure from commercial for rectal cancer produces oncological results
sources and greater acceptance by health-care similar to open surgery, but with the advantage
providers. Current estimates of penetration for of better short-term outcomes. If this proves to
laparoscopic colorectal surgery are around be the case, then it will be safe to conclude that
30% in the UK and Australasia in 2011, so there a new gold standard for rectal cancer surgery
remains the potential for considerable growth, has been established.
particularly in rectal cancer. However, there
is probably a ceiling beyond which laparo-
scopic surgery in its current form cannot extend.
This is governed by the inherent limitations of References
laparoscopy, namely, the fulcrum effect of the
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ports, two-dimensional imaging and limited Technology Appraisal Guidance No 17: Guidance on
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some of these limitations. Currently, there is 2. The Clinical Outcomes of Surgical Therapy Study
Group (2004) A comparison of laparoscopically
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small randomized controlled trial testify to the Smith AMH, Heath RM, Brown JM, for the MRC
CLASICC trial group (2005) Short-term end-points
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cancer surgery, with initial indications of short- in patients with colorectal cancer (MRC CLASICC
term benefit with low conversion rates to open trial): multicentre, randomised controlled trial. Lancet
surgery and reduced rates of circumferential 365:1718–1726
4. Thorpe H, Jayne DG, Guillou PJ, Quirke P, Copeland J,
resection margin involvement. Whether these Brown JM, for the Medical Research Council Con-
indicators bear out in future long-term studies ventional versus Laparoscopic-Assisted Surgery in
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256 D. Jayne and L. Khan
influencing conversion from laparoscopically assisted 8. Aziz O, Constantinides V, Tekkis PP, Athanasiou T,
to open surgery for colorectal cancer. Br J Surg 95: Purkayatha S, Paraskeva P, Darzi AW, Heriot AG
199–205 (2006) Laparoscopic versus open surgery for rectal
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Guiloou PJ (2005) Bladder and sexual function fol- 9. Anderson C, Uman G, Pigazzi A (2008) Oncological
lowing resection for rectal cancer in a randomized outcomes of laparoscopic surgery for rectal cancer: a
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Br J Surg 92:1124–1132 J Cancer Surg 34:1135–1142
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105: Laparoscopic surgery for colorectal cancer. JM, Guillou PJ (2010) Five year follow-up of the
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sed March 2012
Is a Diverting Stoma Always
Necessary for a Low Anterior 26
Resection of a Rectal Cancer?
Geerard L. Beets
infection or pelvic fibrosis, and a substantial num- reversal and has its own morbidity in the form of
ber of patients will end up with some form of stoma-related complications and the decreased
definitive colostomy. Some older reports also sug- quality of life that is inherently associated with a
gested a worse long-term oncological outcome, stoma. A valid question is, therefore, whether all
with a higher rate of local recurrence. A recent patients should be given a diverting stoma or only
study on pooled data from five large randomized those at high risk for an anastomotic problem.
trials on rectal cancer showed a 5-year overall sur- Many papers have described risk factors for anas-
vival rate of 66% in patients who had an anasto- tomotic leakage, and the most important risk fac-
motic leak, compared to 74% in patients who had tor without question is the height of the
an uneventful anastomotic healing [2]. This 8% anastomosis: the lower the anastomosis, the
long-term survival difference was, however, not higher the chance of leakage. When the entire
due to a higher relapse rate but to a higher mortal- mesorectum is removed in a total mesorectal
ity in the postoperative period. excision, the anastomosis is always very low and,
therefore, at increased risk for leakage. Other risk
factors that are often mentioned in reports are
26.2 Rationale and Evidence peripheral vascular disease, male patients, meta-
for Diverting Stoma static or advanced disease, smoking, low albu-
min, diabetes, high age, blood transfusion and
A diverting loop ileostomy or colostomy has long technical mishaps during the operation. It is
been used by surgeons with the intention to both unclear whether or not neoadjuvant therapy
reduce the incidence and the severity of anasto- increases the risk for anastomotic problems. In
motic leakage. By decreasing the faecal load at the large randomized trials, the rate of anasto-
the site of the leakage, it is hoped that less bacte- motic leakage is generally the same in patients
rial contamination results in a less severe clinical with and without neoadjuvant therapy, while
course or even in a complete subclinical leakage. multivariate analyses of large cohort series some-
A recent Cochrane review of six randomized tri- times suggest an increased risk. In practice, it
als evaluating a routine diverting ileostomy or remains difficult to predict which group of
colostomy versus no diverting stoma after low patients is at risk, and given the evidence on the
anterior resection for rectal cancer shows a two- routine use of a diverting stoma in the random-
thirds reduction of clinical leak rate from 19.6% ized trials, it seems prudent to use a routine rather
to 6.3% and a three-fourths reduction in urgent than a selective policy.
reoperation rate from 16.1% to 3.9% [3]. The
reduction in mortality was not significant. Two
earlier reviews that included also nonrandomized 26.4 Ileostomy or Colostomy?
series basically had come to the same conclusion,
with the additional finding that in the nonran- An additional question is which diverting stoma
domized series, the mortality was significantly is to be preferred, ileostomy or colostomy. This is
lower in the patients who were given a diverting a topic for discussion among colorectal surgeons,
stoma [4, 5]. and strong personal opinions are often expressed.
It is more a matter of personal choice than a
choice based on evidence. There is a Cochrane
26.3 Routine or Selective Diverting review of five randomized trials and a meta-anal-
Stoma? ysis that adds seven observational studies. In the
Cochrane review, the only significant finding is a
Although a temporary diverting stoma dimin- higher rate of stoma prolapse with a colostomy
ishes the incidence and severity of anastomotic [6]. The other meta-analysis confirms this and
leakage, it does require a second procedure for also found an increased risk of infectious
26 Is a Diverting Stoma Always Necessary for a Low Anterior Resection of a Rectal Cancer? 259
complications with the colostomy [7]. The ileos- International Study Group of Rectal Cancer. Surgery
tomy, on the other hand, was more associated 147(3):339–351
2. den Dulk M, Marijnen CA, Collette L et al (2009)
with dehydration and late intestinal obstruction Multicentre analysis of oncological and survival
after closure. There is, therefore, no compelling outcomes following anastomotic leakage after rectal
evidence to prefer one to the other. cancer surgery. Br J Surg 96(9):1066–1075
3. Montedori A, Cirocchi R, Farinella E, Sciannameo F,
Abraha I (2010) Covering ileo- or colostomy in
Conclusion anterior resection for rectal carcinoma. Cochrane
A diverting stoma decreases both the incidence Database Syst Rev 12(5):CD006878
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1. Rahbari NN, Weitz J, Hohenberger W et al (2010) stomy versus loop colostomy for fecal diversion after
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Will Extralevator Abdominoperineal
Excision Become the New Gold 27
Standard?
27.2 How Does Preoperative Imaging Result 27.8 How Should Surgery in the Prone
in Better Surgery?..................................... 262 Position Be Performed? ............................ 267
27.5 What Are the Advantages and 27.11 Is a New Standard for
Limitations of Performing an Extralevator Abdominoperineal Excision
APE in the Supine Position? .................... 264 Necessary? ................................................. 270
I. Martijnse
Colorectal Surgery, Catharina Hospital Eindhoven,
The Netherlands
N. West • P. Quirke
Pathology and Tumour Biology, Leeds Institute of
27.1 Does a Patient After
Molecular Medicine, University of Leeds, Abdominoperineal Excision
United Kingdom Have a Worse Prognosis Than
R. Heald After (Low) Anterior Resection?
Pelican Cancer Foundation, Basingstoke,
United Kingdom The introduction of TME surgery led to the real-
C.J.H. van de Velde ization that the quality of surgery significantly
Colorectal Surgery, Leiden University Medical Center, influences the prognosis of rectal cancer patients
Leiden, The Netherlands
and has resulted in a huge improvement in sur-
H. Rutten (*) gery and its outcome [1]. On a population-based
Colorectal Surgery, Catharina Hospital Eindhoven,
level, an improved survival of more than 10%
Michelangelolaan 2 5623EJ Eindhoven,
The Netherlands was realized in countries adopting TME as the
e-mail: harm.rutten@cze.nl standard surgical technique [2, 3].
However, patients with low rectal cancer did [19, 20] In the MERCURY study, MRI could pre-
not seem to benefit from this improvement [4, 5]. dict extramural tumor spread to within 0.5 mm
After more than 20 years of widespread TME [21]. Even the current multislice CT does not
surgery, the difference between patients undergo- have the spatial resolution that is needed in low
ing APE or AR still persists [6–8]. It has been rectal cancer staging [22, 23]. Even though some
demonstrated that it is not the tumor biology question the use of MRI in low rectal cancer [24],
which heralds a worse outcome, but an increased most physicians agree that MRI is superior to
number of positive circumferential resection define the surgical planes for resection both in
margins (CRM) and iatrogenic perforations, both mid and low rectal cancer [25–27]. In modern
of which are avoidable and confer a poor progno- rectal cancer surgery, it is essential that the sur-
sis [9–13]. The latest analysis of the Dutch TME geon knows whether the tumor infiltrates through
study shows that when radical surgery is per- the muscularis propria in the anal canal to avoid
formed, APE patients share the same prognosis an intersphincteric resection, which would lead
as AR patients [14]. to an involved or threatened circumferential
Besides the change in surgical approach, the margin. In locally advanced rectal cancer in the
introduction of TME surgery has been associated lower rectum, MRI imaging to evaluate the rela-
with improved preoperative staging, proper selec- tion of the tumor to the levator muscles is equally
tion of preoperative treatment, and feedback on important for the surgical planning, and the com-
the quality of surgery by pathologists. parison of MRI before and after neoadjuvant
treatment may lead to different surgical options
[28]. A recent manuscript demonstrated that MRI
27.2 How Does Preoperative was able to predict long-term outcome in low
Imaging Result in Better rectal tumors, proving its validity in staging in
Surgery? rectal cancer [29].
intertwining muscular bundles anchoring the can start. The focus on the perineal dissection
anus in the perineum. At this point, the abdomi- and its standardization by beginning perineal dis-
nal phase can commence. section laterally and dorsally leaving the levator
Mobilization of the rectosigmoid and lympho- muscle on the specimen and then transecting the
vascular pedicle occurs according to the princi- anterior attachments in the described technique
ples of TME. During dissection, the mesorectal helps to avoid iatrogenic tumor perforations and
fascia is left intact and care is taken to avoid dam- involved margins.
age to the hypogastric nerve. On the anterior side
when the peritoneal flap is opened and
Denonvillier’s fascia is followed until the vesi- 27.7 What Are the Advantages
cles, sufficient dissection has been performed. and Pitfalls of Performing
On the posterior side, the correct plane is easy to an Extralevator APE
find. The final phase is a sharp dissection of the in the Prone Position?
remaining attachments through the abdominal
phase and removal of the specimen. Extralevator excision in the prone position is
When the surgeon does decide to start with the becoming increasingly popular. It is believed
abdominal phase prior to perineal dissection, the that this technique is easier to learn and that in
dissection must be limited. To avoid coning in this position superior exposure of the anatomy
toward the tumor, dissection should stop above can be achieved. Furthermore, it has been
the levator muscles after which the perineal phase hypothesized that the blood loss is less due to the
27 Will Extralevator Abdominoperineal Excision Become the New Gold Standard? 267
higher position of the venous plexus. However, lenging anterior side where the specimen remains
there is very limited evidence to support either attached. By rolling the specimen from side to
the prone or the supine approach. They both have side and applying gentle traction on the speci-
their advantages and disadvantages, and the men, the dissection continues along the correct
experience of the surgeon on either technique plane. From the perineal body onward, the con-
will determine the outcome. Standardization of necting muscles are divided. The most challeng-
technique is considered to be the most important ing point during the dissection is the 2 cm after
factor for radical surgery. cutting these connecting muscles before reaching
The main limitation of this technique is that a the prostate. This is where the ureter is in very
bimodal approach is not possible. In advanced close proximity to the plane of dissection, and
tumors, it is impossible to assess and dissect from care must be taken to avoid taking a false route.
both the abdominal and the perineal phase. The hypogastric nerves are identified and spared.
In front of the prostate, the plane of the fascia of
Denonvillier should be followed until the vesicles
27.8 How Should Surgery are reached. The specimen can now be removed.
in the Prone Position Excision of the ischiorectal fat is only neces-
Be Performed? sary in exceptional cases, for example, when
tumor infiltrates through the external sphincter-
Surgery always commences with the abdominal levator muscle funnel or when the tumor has per-
phase with either a conventional laparotomy or a forated or fistulated. Furthermore, when the anal
laparoscopic approach. Inspection of the abdo- skin is involved, a more radical excision should
men is performed, and the sigmoid and the rec- be considered. More ischioanal fat should then be
tum are mobilized along the TME planes. Once removed to achieve radical excision of the tumor,
the hypogastric nerves and the vesicles have been but the surgical technique remains the same.
identified on the anterior side, dissection from the
abdominal phase must be stopped. The incisions
are sutured and the patient is turned into prone 27.9 Which Surgical Technique
position. Care must be taken in positioning the Should Be Performed?
patient to avoid pressure ulcers.
Normal surgical preparation with disinfection
and covering with sterile drapes is performed. Recently the Cleveland Clinic published a man-
A rhombus-like incision is made around the anal uscript comparing the supine and prone posi-
skin and extended proximally above the sacro- tion. The type of surgery chosen was based on
coccygeal joint (Fig. 27.5). With diathermy, dis- the preference of the surgeon, which resulted in
section is performed on the lateral sides, and two comparable groups with similar patient
limited dissection is performed on the anterior characteristics. CRM involvement rates were
(perineal body) and the posterior side. Posteriorly, 14.6% and 9%, and the iatrogenic rectal perfo-
dissection is performed behind the os coccygis in ration rates were 2.4% and 4.6% for supine APE
order to remove this “en bloc” with the rectal and prone APE, respectively, and no difference
specimen to create extra space. Lateral dissection in oncological outcome was noticed [54].
takes place along the levator ani muscle until the Recently a paper from a Dutch referral center
mesorectum is reached. On the posterior side, the for advanced rectal cancer showed that stan-
dissection plane is relatively easy to find, and this dardization of the supine APE technique resulted
is followed until the mesorectum is encountered. in a perforation rate of 0.7% and CRM + (<1 mm)
The specimen is then everted from the perineal of 14%, keeping in mind that two-thirds of their
wound. Care must be taken to avoid tearing the patients had T4 tumors [56]. Excellent results
specimen by pulling with too much force. This have also been demonstrated with the prone
creates more space and a better view on the chal- APE technique [48, 57].
268 I. Martijnse et al.
An increased number of radical resections are vs. standard APE were 4.1% vs. 10.4% (relative
achieved by the en bloc removal of the distal rec- risk reduction 60.6%, p = 0.004) and 9.6% vs.
tum and levator muscles, therefore highlighting 15.4% (relative risk reduction 37.7%, p = 0.022),
the need of an extralevator excision more than respectively. The local recurrence rate was 6.6%
the positioning of the patient. A recent review vs. 11.9% (relative risk reduction 44.5%, p < 0.001)
of more extended perineal resections showed for the two groups [58].
that the rate of inadvertent bowel perforation These results set a new standard for APE.
and the rate of CRM involvement for extended Colorectal surgeons have to know their own results
27 Will Extralevator Abdominoperineal Excision Become the New Gold Standard? 269
Table 27.1 Three-point grading system for assessment of the plane of mesorectal dissection in TME/anterior resection
specimens for rectal cancer
Grade Short description Long description
Mesorectal plane Good surgery Intact smooth mesorectal surface with only minor irregularities. Any
defects must be no deeper than 5 mm. No coning of the specimen
distally. Smooth CRM on slicing
Intramesorectal plane Moderate surgery Moderate bulk to mesorectum but irregularity of the mesorectal
surface. Moderate distal coning. Muscularis propria not visible with
the exception of levator insertion. Moderate irregularity of CRM
Muscularis propria plane Poor surgery Little bulk to mesorectum with defects down onto the muscularis
propria and/or very irregular CRM. Includes infraperitoneal
perforations
and should strive that the quality of surgery is no tion rates. It helps to improve the quality of the
longer a prognostic factor. specimen produced by giving an objective feed-
Secondary endpoints such as nerve preserva- back to the surgeon.
tion and other postoperative complications will Within the Dutch TME and the UK CR07
eventually make the difference besides the ability trial, 57% and 52% of the anterior resection spec-
to teach and implement the principle of extraleva- imens were graded as being in the mesorectal
tor resection. plane, 19% and 34% were intramesorectal, and
24% and 13% were muscularis propria, respec-
tively [31, 62]. The CR07 trial showed that
27.10 What Role Do Pathologists Play through pathological feedback, CRM involvement
in the Treatment of Rectal rates fell to as low as 8%.
Cancer Surgery? For abdominoperineal excision, an addi-
tional grading system for the quality of the dis-
Pathologists have played an essential role in the section around the sphincters has been
improvement in rectal cancer outcomes. Besides developed. Besides grading the mesorectum,
tissue diagnosis and staging, the pathologist plays the plane of dissection around the anal sphinc-
a central role in the multidisciplinary approach. ters should also be graded as shown in
They give feedback on preoperative radiology Table 27.2. The levator ani muscle is left
and the quality of surgery. Furthermore, an evalu- attached to the mesorectum during extralevator
ation of the effectiveness of the administered excision that creates a more cylindrical speci-
neoadjuvant therapy can be made. This facilitates men. The extra tissue around the tumor results
internal auditing as well as a continued education in an increased radical resection rate and less
and improvement of all members of the MDT. perforations of the tumor (see Fig. 27.6). The
The involvement of the CRM has proven to be assessment of the plane of APE surgery is based
the most important prognostic factor for local on similar principles like the anterior resec-
recurrence within the pelvis. Pathologic feedback tions. Any defects must be no deeper than
during the era of TME has resulted in a significant 5 mm, and there should be no waisting of the
increase of radical resections [59–61]. specimen. The APE specimens should receive
A three-point grading system of the macro- two grades, namely one grade for the sphincter
scopic specimen was developed for the MRC and another for the mesorectum.
CLASSIC and CR07 trials and has been shown to In order for the pathologist to evaluate and audit
predict CRM involvement [31]. The recom- the quality of the MDT, their reports must be stan-
mended mesorectal grading system is described dardized. The specimen should be examined and
in Table 27.1. graded accordingly before fixation and slicing.
This grading system reports the plane of Photographs of the specimen provide a permanent
dissection besides the CRM status and perfora- record of the surgical quality. However, the macro-
270 I. Martijnse et al.
Table 27.2 Sphincter/levator grading according to the plane of surgery as assessed at the time of pathological dissec-
tion noting the presence and extent of any defects below the mesorectum in the sphincter/levator muscle complex
Grade Short description Long description
Extralevator plane Good surgery The specimen has a cylindrical shape due to the presence of levator
muscle removed en bloc with the mesorectum and sphincters. Any
defects must be no deeper than 5 mm. No waisting of the
specimen. Smooth CRM on slicing
Sphincteric plane Moderate surgery The specimen is waisting, and the CRM in this region is formed by
the surface of the sphincter muscles which have been removed intact
Intramuscular/submucosal Poor surgery The specimen is waisted and includes deviations into the sphincter
plane/perforation muscle complex, submucosa, and complete perforations
a b c
Fig. 27.6 Three APE specimens including an extralevator APE (a), a standard APE with classic surgical waist (b), and
a standard APE with a large anterior perforation (c)
excision for resectable rectal cancer: 12-year follow-up 29. Shihab OC, Taylor F, Salerno G et al (2011) MRI pre-
of the multicentre, randomised controlled TME trial. dictive factors for long-term outcomes of low rectal
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(2011) Prone or lithotomy positioning during an
Which Patients Do Benefit from
Extended Resections in Case of 28
Locally Advanced Rectal Cancer?
a b
Fig. 28.1 (a) Sagittal T2-weighted MRI slice showing a T4 (b) Transverse T2-weighted MRI slice showing the same
locally advanced rectal carcinoma which invades the blad- tumour, which invades the bladder (black arrowhead). The
der (black arrowhead) and the prostate (grey arrowhead). mesorectal fascia is invaded as well (white arrowhead)
deal with the usefulness of an intra-operative multicentre studies, have shown that the addition
radiation boost to further increase the therapeutic of oxaliplatin enhanced the downstaging effect of
ratio of the radiotherapy component. And last, the 5-FU-based neo-adjuvant treatment scheme
some thoughts about the use of the cellsaver to [10–16]. However, this increased downstaging
deal with the blood loss, which may be excessive did not always result in a better oncological
in these extended procedures, and its effect on outcome [15, 16].
oncological outcome. Nonetheless, the question is not: does neo-adju-
vant CRT work, but does intensified CRT work?
The Catharina Hospital Eindhoven is a national
28.2 What Is the Role of Neo- referral centre for primary unresectable T4 tumours.
adjuvant (Chemo-)radiation During the period of 1994–2010, a total of 504
in the Treatment of Primary consecutive patients without metastatic disease
Unresectable Patients? received four different neo-adjuvant treatment
schemes. In the early years, long-course radio-
To improve downstaging and downsizing of the therapy was the standard of treatment (RTH).
tumour, neo-adjuvant treatment became the stan- However, in 1998, the EORTC 22921 study intro-
dard of treatment in locally advanced rectal cancer. duced neo-adjuvant chemoradiation, consisting
Several studies have shown that neo-adjuvant long- of a bolus injection of 350 mg/m2 5-FU and leu-
course treatment schemes can effectively downstage covorin 20 mg/m2 (5-FU bolus) [1]. In 2003, the
and downsize tumours, which subsequently results CORE study commenced. It introduced two new
in a better oncological outcome [1–3]. However, principles: (1) continuous administration of 5-FU
there is no uniform definition of which scheme in the form of 825 mg/m2 capecitabine twice daily
should be used. The addition of a 5-FU-based radi- and (2) the addition of a second radiation sensi-
ation sensitizer resulted in increased downstaging, tizer in the form of 50 mg/m2 oxaliplatin once
compared to radiotherapy alone [1, 4, 5]. Since the weekly (CORE) [17]. In 2005, however, Dutch
introduction of 5-FU agents, bolus injections have guidelines changed and long-course radiotherapy
been replaced by continuous 5-FU administration with capecitabine twice daily only became the
[6–9]. Several studies, including two randomized standard of treatment (CAP). Therefore, selection
28 Which Patients Do Benefit from Extended Resections in Case of Locally Advanced Rectal Cancer? 277
0.08
0.9
0.06
Radicality of resection
0.8 R0
R1
0.04
Type of neo-adjuvant
0.7 treatment
RTH 0.02
5FUBolus
CAP
CORE 0.00
0.6
0 12 24 36 46 60 72 84 96 0 20 40 60 80
Months Months
Fig. 28.2 The left figure shows cancer-specific survival for the different neo-adjuvant treatment schemes after multi-
variate Cox regression analysis. The right figure shows the importance of radical resection
of the different neo-adjuvant treatment schemes ratios were 3.78, 2.73, 1.34 and 1.00 (p = 0.001)
was based on hospital policy rather than tumour and for downstaging 0.31, 0.44, 0.30 and 1.00
characteristics. All patients received 45–50.5 Gy (p < 0.0001). Toxicity rates between the CAP and
preoperative radiotherapy in 25 fractions and the CORE regimens did not differ significantly.
minimum waiting period was 8 weeks. In multivariate Cox regression analysis, the
The RTH, 5-FU bolus, CAP and CORE neo- CORE regimen remained significantly better for
adjuvant treatment schemes were administered to cancer-specific survival [18] (Fig. 28.2).
106, 137, 106 and 155 patients, respectively. R1 In previous papers, it has been shown that nega-
resections (tumour cells at the resection margin) tive circumferential resection margins remain of
occurred in 24.5%, 13.1%, 9.4% and 6.5% and paramount importance [19, 20]. Radical resec-
CRM+ (defined as tumour within 1 mm of the tion is a strong prognostic outcome parameter
circumferential resection margin) in 31.1%, [21–23]. Downstaging and downsizing before
21.9%, 14.2% and 8.4% after the different preop- surgery are essential to avoid positive resec-
erative treatments. No response to neo-adjuvant tion margins. Furthermore, pathologic complete
treatment was found in 57%, 44%, 49% and 27%, response (ypCR) is an important prognostic fac-
respectively. Pathologic complete response rates tor. Pathologic complete response rates vary in
(pCR) were 4.7%, 13.1%, 7.5% and 14.2%. In literature, ranging from 0% to 40% for combined
these challenging patients, intensification of the capecitabine and oxaliplatin regimens [13]. Any
neo-adjuvant treatment did lead to a more pro- response to neo-adjuvant treatment may also be an
nounced effect on downstaging. This could also important factor [3, 24–27].
be turned into a better oncological outcome. The interim results of two recent studies show
After multivariate regression analysis for R1, contradictory results [28, 29]. The NSABP04
CRM+ and any downstaging, the different neo- found no increase in pathologic complete response
adjuvant treatment schemes had a highly significant and an increase in toxicity when oxaliplatin was
impact on oncological outcome. Odds ratios for added. The CAO/ARO/AIO04, however, did find
having R1 resection for the RTH, 5-FU bolus, an increased pathologic complete response rate,
CAP and CORE group were 3.74, 1.94, 1.14 and without higher toxicity. The ACCORD study
1.00 (p = 0.003). For CRM+ resection, the odds showed an increase in radicality of resection and
278 R.L. Dudink et al.
tumour response but could not translate this into truly unresectable. Intraperitoneally metastasized
better oncological outcome [16]. However, the tumours have always been an exclusion criterion
Italian randomized STAR-01 phase III trial did for curative surgery for a long time, but nowa-
find a significant reduction of distant metastases days, there are curative options with HIPEC
when oxaliplatin was added [15]. For a definitive (hyperthermic intraperitoneal chemotherapy).
answer, the long-term results of these trials should The location of the tumour influences the
be awaited. However, these trials were multi- radicality of the resection and the consequent
institutional and the definition of locally advanced local recurrence rate. In both primary and locally
did not refer to unresectable T4 patients. In pri- recurrent rectal cancer, it has been shown that the
mary unresectable patients, intensified RCT may more dorsally the tumour is located, the higher
lead to better downstaging and hence increase the the irradical resection rate and local (re)recur-
chance for a radical resection [18]. rence rate is [30–34]. In these patients, often the
only chance for a radical resection is a sacral
resection.
28.3 Which Extended Resections Central and anterior tumours might require
Are Necessary to Achieve resection of the bladder and the prostate or semi-
a Radical Resection? nal vesicles in males and the vagina and uterus in
females. Lateral and dorsolateral tumours are
The main goal in curative surgery for both locally sometimes fixed to the pelvic sidewalls and can
advanced and locally recurrent rectal cancer is cause major bleeding during surgery.
achieving a radical resection. Radicality of the
resection is the most important factor which
influences local control and oncological outcome 28.4 Abdominosacral Resection
in general.
Only a thorough preoperative staging can A locally advanced dorsal rectal carcinoma and
provide the road map for a potential surgical especially the dorsal recurrent rectal carcinomas
intervention. A CT thorax/abdomen is neces- constitute a specific problem. When the dorsal
sary to exclude distant metastatic disease, as resection margin is threatened or involved, it is
most patients with distant metastases will be no not possible to achieve a radical resection with-
candidate for an extended resection (maybe with out an en bloc resection of the pelvic floor mus-
the exception of those with limited resectable cles, os coccyx or partial resection of the sacrum
metastases). An MRI scan of the pelvis is manda- (see Fig. 28.3).
tory, as delineation of tumour infiltration into the The sacral approach in prone position was
soft perirectal tissues is a prerequisite for surgi- originally described more than 100 years ago [35].
cal planning. Furthermore, the MRI is the best The combined abdominal and sacral approach
modality for local restaging to evaluate response was known as abdominosacral extirpation of the
to neo-adjuvant treatment, which may lead to rectum [35]. In its posterior approach, a much
less extended surgery. A PET scan may be help- wider resection is possible. The anterior approach
ful, especially in locally recurrent cases to dif- follows the rules of TME. Oncological outcome,
ferentiate between benign and malignant lesions. as described in literature, is disappointing. Five-
Preoperative discussion in a multidisciplinary year overall survival rates vary between 15% and
team with experience in the treatment of locally 30%, and local control rate varies between 15%
advanced and locally recurrent rectal cancer is and 40% [36–38].
essential to reach optimal treatment plans. Indications for abdominosacral resection
Tumours which invade the sacrum or the sacral (ASR) typically include invasion of the sacrum or
neural roots at the level of S2 or higher or tumours coccyx, tumour growth into the pelvic floor mus-
which extend more than a few centimetres beyond cles or lateral pelvic sidewalls and the need for a
the infrapiriform foramen will often be considered wider dorsal resection in order to achieve a radical
28 Which Patients Do Benefit from Extended Resections in Case of Locally Advanced Rectal Cancer? 279
a b
Fig. 28.3 (a) Sagittal T2-weighted MRI slice showing a pri- T2-weighted MRI slice showing the same tumour. The
mary locally advanced rectal carcinoma which invades the mesorectal fascia is clearly visible (black arrowheads) and is
sacrum and spinal canal (black arrowheads). (b) Transverse invaded by the tumour (white arrowhead)
a b c
Fig. 28.4 (a) Sagittal view of a wide field en bloc resec- sion [3]). (c) The dotted line shows the horseshoe-shaped
tion, indicated by the dotted line, of tumours with primar- circumferential margin at risk for irradical resection
ily latero-dorsal spread (Reproduced with permission [3]) (Reproduced with permission [3])
(b) Posterior line of transection (Reproduced with permis-
resection margin (Fig. 28.4) [39]. Double J-ureter sacral resections can also be performed in litho-
catheters can be helpful to identify and subse- tomy position. It is very helpful to identify the
quently avoid damage to the ureters. An ASR level of sacral transection by full thickness cut
starts with the abdominal phase. If the tumour through the sacrum with the osteotome (chisel)
growth only extends dorsally without threatening during the abdominal phase. The level of transec-
the ventral plane, TME rules can be followed, e.g. tion should be distal to the dura mater, which proj-
the ventral dissection plane will be guided by ects as far as mid S2 [36, 39].
Denonvilliers’ fascia. If the tumour invades ven- Before the patient is turned in prone position,
tral structures, e.g. the prostate in the male or the the abdominal phase can be completed by closure
uterus in the female, a more extended resection in of the abdomen and placement of the stoma.
the ventral plane is also necessary. The resection of A midline incision is made across the sacrum
the mid sacrum S2–S4 can be best done in prone from L5 to the perineum. The incision is contin-
position, as the venous plexus collapses in prone ued around the anus or scar after abdomino-
position and blood loss will be much less. Distal perineal extirpation (APE). The gluteus muscles
280 R.L. Dudink et al.
insertion from the sacrum, the sacrospinous and Table 28.1 Operative details of patients undergoing
sacrotuberous ligaments are transected near the sacral resection for T4 primary rectal cancer (n = 25) or
locally recurrent rectal cancer (n = 70).
sacrum. The levator ani muscles are in direct view
after this step and can be transected near their lat- T4-LARC LRRC
eral insertion at the obturator internus. The osteot- No. of patients No. of patients
Level of transection
omy performed during the abdominal phase may
S2 1 10
now be palpated. The sacral resection is com-
S3 5 33
pleted by a cut with the osteotome in the dorsal
S4 1 15
cortical wall in a V shape, in order to avoid dam- More distally 18 12
age to the sacral roots. The surgical specimen can Bladder resection
now be removed en bloc. An omentoplasty, which Total with ileal 20 9
has been mobilized during the abdominal phase conduit
can be used to fill the presacral space before clo- Partial 17 1
sure. In most cases, when no skin is lost, wound Urinary bladder flap 3 2
closure is primary. However, in case of a large right
defect, a myocutaneous rectus abdominis flap Urinary bladder flap 10 2
left
(VRAM) is rotated in the perineal wound [39].
Uterus extirpation
Other authors have advocated the use of (bio-) Without adnexes 0 1
meshes to create a new pelvic floor [40–42]. In With adnexes 40 16
our experience, prosthetic material was never nec- Vagina
essary for closure of the perineo-sacral defect. Posterior wall w/o 26 14
reconstruction
With reconstruction 10 5
28.5 Results Prostate
Capsule 29 6
From 1994 until 2010, we identified a group of Prostatectomy 3 6
369 patients who underwent surgery for T4 pri- Seminal vesicles
mary rectal cancer and 301 patients who under- Right only 13 0
Left only 8 0
went surgery for locally recurrent rectal cancer.
Both 20 3
For the analysis of the results, patients with peri-
Reconstruction
toneal carcinomatosis or distant metastasis were
VRAM w/o skin 11 4
excluded, resulting in a total of 336 patients with
VRAM with 14 7
T4-LARC (188 male, 147 female; mean age abdominal skin
60 years) and 212 patients with LRRC (126 male,
86 female; mean age 62 years) who were treated
with curative intent. achieved in 18 patients (72%), and R1 resection
Twenty-five patients with T4-LARC under- occurred in 7 patients (28%).
went sacral resection. Sacral resection was per- Post-operative complications typically incl-
formed by transection at either S2 (n = 1), S3 uded wound healing problems, superficial and
(n = 5), S4 (n = 1) or more distally (n = 18). All deep wound infections with or without wound
patients had preoperative long course of radio- dehiscence and abscesses (see Table 28.2).
therapy (23%) or radiochemotherapy (77%). Five-year cancer-specific survival is 68%.
Operative details are summarized in Table 28.1. Overall survival is 56%. Twenty-one percent of
Mean blood loss was 5,225 ml (200–18,000). patients develop local recurrence within 5 years
Packing of the small pelvis because of excessive of follow-up. Five-year metastasis-free survival
bleeding was performed in two patients (8%). is 69%, and relapse-free survival is 61%.
Intra-operative radiotherapy was administered in Seventy patients with LRRC underwent sacral
all but three patients. A radical resection was resection. In these patients, preoperative treatment
28 Which Patients Do Benefit from Extended Resections in Case of Locally Advanced Rectal Cancer? 281
Table 28.2 Post-operative complications in patients sacral resection (p = 0.191). There is no significant
undergoing sacral resection for T4 primary rectal cancer difference in the level of resection. Five-year
(n = 25) or locally recurrent rectal cancer (n = 70)
overall survival rates are 29% and 40%, respec-
T4-LARC LRRC tively (p = 0.217). Five-year local recurrence rates
No. of patients No. of patients are 46% and 43%, respectively (p = 0.379).
Wound infection 1 8
Metastasis-free survival rates are 47% and 50%,
Abdominal 1 8
infection/presacral
respectively (p = 0.442). Relapse-free survival
abscess rates are 24% and 39%, respectively (p = 0.025).
Abdominal 0 1 Ferenschild et al. report local control rates of
bleeding 88% for locally advanced rectal cancer and only
Wound dehiscence 2 1 10% for patients with recurrent rectal cancer,
Persisting ileus 1 3 with radicality of resection and lymph node posi-
Enterocutaneous 0 1 tivity being the only significant outcome factors
fistula
[36]. Three- and five-year overall survival rates
Abdominal sepsis 0 3
were reported at 46% and 30%, respectively [36].
Urinary leakage 0 1
Ureter obstruction 0 1
Typically, reported 5-year survival rates vary
Urinary retention 0 15 between rates of 18% and 37% [36]. Radicality
Urinary tract 0 2 of resection remains the most important prognos-
infection tic variable [36, 39, 43].
Severe pneumonia 4 1
DVT/pulmonary 0 1
embolism 28.6 Results After Pelvic
CVA 0 1 Exenteration
Death 0 1
Table 28.3 Post-operative complications in patients prostatectomy. Furthermore, the right seminal
with T4 primary rectal cancer (n = 336) or locally recur- vesicle was resected in 3 patients, the left semi-
rent rectal cancer (n = 212)
nal vesicle was resected in 5 patients and both
T4-LARC LRRC were resected in 27 patients. Mean operation
No. of patients No. of patients time was 380 min (170–660), and mean blood
Wound infection 29 19
loss was 6,607 ml (420–34,000). Intra-operative
Abdominal infection/ 26 23
presacral abscess
radiotherapy was administered in all but 13
Abdominal bleeding 6 3 patients. A radical resection was achieved in 124
Wound dehiscence 8 1 patients (59%), and R1 and R2 rates were 63
Persisting ileus 2 4 (30%) and 25 (11%), respectively. Packing of the
Enterocutaneous 2 1 small pelvic because of excessive bleeding was
fistula performed in 36 (17%) of patients. A hemostatic
Abdominal sepsis 6 6 balloon was placed in two patients (1%). Post-
Anastomotic leakage 10 3 operative complications are summarized in
Urinary leakage 1 3 Table 28.3.
Ureter obstruction 0 1 Five-year cancer-specific survival is 43%, and
Urinary retention 5 29
10-year cancer-specific survival for these patients
Urinary tract 4 4
infection
with locally recurrent rectal cancer is 34%.
Urosepsis 1 1 Overall survival rates are 36% and 20%, respec-
Severe pneumonia 10 3 tively. Local recurrence rates after 5 and 10 years
DVT/pulmonary 1 3 are 43% and 51%, respectively. Five-year metas-
embolism tasis-free survival is 49% and 44% after 10-year
CVA 1 1 follow-up. Relapse-free survival rates after 5-year
Death 2 2 and 10-year follow-up are 34% and 24%, respec-
tively. Radicality of resection is the most impor-
tant prognostic variable, in which there is no
because of excessive bleeding was performed in significant difference between R1 and R2 resec-
20 (6%) patients. A hemostatic balloon was placed tions (see Fig. 28.5).
in three patients (1%). Post-operative complica- A recent study, describing pelvic exentera-
tions are summarized in Table 28.3. tion for locally advanced and recurrent rectal
In these patients, 5-year cancer-specific sur- cancer, confirms that radicality of resection was
vival is 66% and overall survival is 53%. Local the only significant outcome factor in multivari-
recurrence and metastasis-free survival rates at ate analysis. An excellent 2-year overall sur-
5-year follow-up are 19% and 67%. Relapse-free vival rate of 80% for primary and 75% for
survival is 58%. recurrent tumours was reported. Nine percent
In the locally recurrent rectal cancer patients developed local recurrence [44]. Ferenschild
group, 26 underwent total bladder resection with et al. report 5-year local control rates for pri-
ileal conduit, four partial bladder resections were mary and recurrent rectal cancer at 89% and
performed and urinary bladder flap was per- 38%, respectively [45]. Five-year overall sur-
formed on either the right side (n = 7) or left side vival rates were reported at 66% and 8%, respec-
(n = 10). Extirpation of the uterus was performed tively. Completeness of resection was identified
either with (n = 38) or without extirpation of the as one of the most important prognostic factors
adnexa (n = 2). Partial extirpation of the vagina [45]. Harris et al. report a 3-year local recur-
was performed in 33 patients, 11 patients under- rence rate of 13% [40]. Surprisingly, there was
went extirpation of the vagina with subsequent no significant association between local recur-
vertical rectus abdominis muscle reconstruction. rence and circumferential margin involvement.
Resection of the prostate capsule was performed The authors report 5-year overall survival rates
in 12 patients and 16 patients underwent total of 48% and 33% for radical and irradical
28 Which Patients Do Benefit from Extended Resections in Case of Locally Advanced Rectal Cancer? 283
0.8
0.4
0.2
0.0
0 20 40 60 80 100
Months
Radicality of resection
R0 R0-censored
R1 R1-censored
R2 R2-censored
resected patients, respectively [40]. Wiig et al. (EBRT) and is feasible without increased toxicity
also emphasized the importance of a complete [47–49]. The theory behind IORT is that it
resection in salvage surgery for recurrent rectal reduced local recurrence rates by sterilizing
cancer. A 5-year survival for R0 patients at 53% microscopic residual tumour particles in a specific
compared to only 19% for R1 patients [46] was area. IORT is only applied on locally advanced
noticed. None of the R2 resected patients sur- rectal cancer (cT3+/T4) and in recurrent rectal
vived for 4 years (Fig. 28.5). cancer, as there is risk for remaining tumour
cells.
Historical studies suggest that IORT might
28.7 Is an Extra Intra-operative improve local control and survival [47, 50, 51].
Boost of Irradiation Effective Some studies suggest that it can only improve
to Reduce the Chance of Local local recurrence rates [52, 53], but some authors
Recurrence? find no benefit [54, 55], and some have even
abandoned IORT [56].
Intra-operative radiotherapy (IORT) is an entity The only way to quantify the effect is by
which is only practiced in a few specialized cen- analyzing the sites of local recurrence between
tres. It is administered as a boost of 10–15 Gy centres with a different policy in IORT applica-
after preoperative external beam radiotherapy tion. Most institutions using IORT-containing
284 R.L. Dudink et al.
multimodality treatment regimens deliver the boost surgery in high-volume referral centres special-
to the presacral space because this is the area con- ized in multimodality treatment is essential.
sidered most at risk [51] and because other areas Thus, we recommend the application of IORT
are difficult to cover with the applicator [57]. In in locally advanced rectal cancer, and data sug-
two studies reporting on patterns of local recur- gest that a boost to the area considered most at
rence after IORT, 59–67% of the local relapse risk is most effective in preventing local recur-
showed to develop outside the presacral IORT rences from developing.
radiation field [51, 57].
In our institution, the delivery of the boost is
to the area mostly considered at risk on the 28.8 Is There a Role for
basis of radiological and intra-operative the Use of the Cellsaver
findings. In a previous study, we questioned in Locally Advanced and
whether this approach leads to less outfield Locally Recurrent Rectal
local recurrences than the mentioned 59–67% Cancer Surgery?
in centres where IORT is only applied to the
presacral area. As mentioned before, blood loss may be consid-
From 1994 and 2006, 290 primary locally erable in locally advanced and recurrent rectal
advanced patients received intra-operative irradi- cancer because dissections planes often need to
ation. After 5 years 34 of the 290 patients devel- be extra-anatomically. Hence, allogeneic blood
oped local recurrence (13.2%). The subsites of transfusion is necessary in many cases.
the local recurrences were identified on MRI or Preservation techniques for the patient’s own
CT scan. Relating the patterns of local recurrence blood, or intra-operative cell salvage, has become
to the IORT-target, 47% of the local recurrences widely accepted and utilized in many braches of
developed outside the IORT-field [30]. This is surgery when substantial blood loss can occur.
less than in the few studies reporting on this sub- However, autologous blood transfusion has not
ject, in which the boost of IORT was given only been adopted widely in cancer surgery due to the
on the presacral area. fear of reintroducing viable tumour cells shed
Consequently, it might be suggested that an from the surgical site into the circulation. Based
IORT-boost specifically to the area at risk is more on this theoretical risk, the American Medical
effective in the prevention of local recurrence, Association Council on Scientific Affairs recom-
possibly because the area that causes tumour spill mended against autologous blood transfusion in
is sterilized. Also very suggestive that there is cancer surgery in 1986 [58].
effect of IORT is that 62% of the patients with an On the basis of these concerns, one could
irradical resection in this study [30] do not readily choose for allogeneic blood transfusion.
develop local recurrence. However, fresh autologous blood is superior to
Delivery of IORT to any specific area is tech- allogeneic blood in a number of areas. In the past,
nically very feasible. Normally, it can be deliv- a couple of studies suggested a relationship
ered through an abdominal access. However, the between perioperative blood transfusion and a
ventral area can be irradiated more adequately higher risk of recurrence of colorectal cancer
through the perineal wound. The only situation [59]. It is hypothesized that allogeneic blood
when IORT cannot be delivered is when there is transfusion has an immunosuppressive effect due
major blood loss during the operation and pack- to transfused allogeneic passenger leukocytes
ing is necessary. [59–61]. Furthermore, a dose-dependent relation-
IORT equipment is expensive and the logis- ship is suggested [59]. Allogeneic blood transfu-
tics are complex. Furthermore, non-metastasized sion is also associated with a higher risk of
locally advanced rectal carcinoma and local post-operative bacterial infections [61, 62].
recurrence are not very common. Therefore, for Furthermore, autologous blood has a higher
optimal treatment of these advanced cancers, 2,3-diphosphoglycerate (2,3-DPG) concentration
28 Which Patients Do Benefit from Extended Resections in Case of Locally Advanced Rectal Cancer? 285
Table 28.4 Five-year oncological outcome for the use of the cellsaver
Cancer-specific survival (%) Metastasis-free survival (%) Local recurrence rate (%)
Cellsaver No cellsaver p-value Cellsaver No cellsaver p-value Cellsaver No cellsaver p-value
All 74 57 0.001 70 61 0.036 12 22 0.007
patients
Q1 78 69 0.363 59 72 0.743 9 13 0.227
Q2 87 62 0.054 81 66 0.337 5 17 0.047
Q3 71 50 0.012 70 57 0.085 13 30 0.014
Q4 63 38 0.027 66 35 0.005 22 42 0.151
and thus lower oxygen binding affinity, resulting seems to be a survival benefit in patients with the
in better tissue oxygenation [63]. Experimental highest blood loss. The metastasis-free and local
studies have demonstrated that transfusion with recurrence-free survival rates show that the intro-
stored allogeneic blood results in less tissue oxy- duction of the cellsaver did not compromise onco-
gen consumption when compared to fresh autolo- logical outcome and is safe to use in these kinds of
gous blood [64]. patients (see Table 28.4 and Fig. 28.6).
Given these advantages, the cellsaver was The use of the cellsaver during oncological
used to collect, filter, wash and return the patient’s procedures remains controversial. However,
erythrocytes in order to maintain the circulating approximately 20–45% of patients with colorec-
red cell volume. After collection, the heparinized tal cancer develop metastases, which suggests
blood is being centrifugated, washed with a 0.9% that tumour cell dissemination is an early event in
saline solution and concentrated to hematocrit colorectal cancer. One study detected circulating
levels of 60–65%. The intra-operative red blood tumour cells in 41% of colorectal cancer patients
cell salvage (ICS) device was used with a leuco- in the preoperative stage [65]. Furthermore, it is
cyte depletion filter, which was replaced after suggested that surgical manipulation enhances
every two processed bowls. In case of contamina- the dissemination of malignant cells [65, 66].
tion by faeces or pus, ICS blood was not returned However, it has been estimated that only 0.01–
to the patient. If blood loss was excessive, plasma 0.000001% of circulating tumour cells have the
volume was replaced by moderate use of fresh potential to form metastatic lesions [58]. The
frozen plasma. most widely used technique to remove tumour
From 1994 until August 2010, data on 546 cells from the patient’s blood is the leucocyte
patients who have been treated for locally depletion filter. Several studies were not able to
advanced (n = 444) or recurrent (n = 102) rectal detect viable tumour cells after filtering the blood
cancer was collected prospectively. Four quartiles [67–69]. One study evaluated the effect of the use
representing the volume of blood loss were cre- of the cellsaver on local recurrence after radical
ated: Q1 less than or equal to 1,250 ml (n = 153), retropubic prostatectomy for prostate cancer.
Q2 1,251 ml up to 2,500 ml (n = 140), Q3 2,501 ml There was no statistical significant difference
up to 5,000 ml (n = 138), Q4 5,001 ml or more found for local recurrence rate [70].
(n = 115).
In these patients, mean blood loss was 3,697 ml,
3,110 ml for locally advanced rectal cancer 28.9 Which Patients Do Benefit from
patients and 6,209 ml for recurrent rectal cancer Extended Resections in Case
patients. Autologous blood was returned in 315 of Advanced Cancer?
patients (58%). Cancer-specific 5-year survival
for all patients and per quartile blood loss volume So, are extended resections including the sacrum
was higher when the cellsaver was used, compared or the pelvic organs worthwhile in offering the
to those without cellsaving (see Table 28.4). There patient a chance for cure? It depends on different
286 R.L. Dudink et al.
0.4
Cellsaver used
0.2
No
Yes
No−censored
Yes−censored
0.0
0 10 20 30 40 50 60
Months
1.0
0.8
Cum survival
0.6
0.4
Cellsaver used
0.2
No
Yes
No−censored
Yes−censored
0.0
0 10 20 30 40 50 60
Months
28 Which Patients Do Benefit from Extended Resections in Case of Locally Advanced Rectal Cancer? 287
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Can Standard Surgical Procedure
Reliably Be Avoided in Major 29
Responders After Radio(chemo)
therapy?
Contents Abbreviations
29.1 Introduction
pCR. As it is well known from many studies survival, overall survival, and cancer-specific
[3, 5, 15, 16, 19, 25, 27, 35, 36, 40, 41, 49, 55, survival were 98.8%, 84.7%, 91.6%, and 95.6%,
61], the rate of pCR after neoadjuvant RCT in respectively. Yeo and the Korean Radiation
rectal cancer ranges between 8% and 35% Oncology Group in 2010 reported clinical data of
(Table 29.1). Pathological complete response has 304 ypT0N0 rectal cancer patients following pre-
a very important prognostic value and is associ- operative RCT and curative radical resections
ated with very good results in terms of local con- between 1993 and 2007 [63]. After a median
trol, disease-free survival (DFS), and overall follow-up of 43 months, 5-year DFS was 88.5%
survival (OS) [9, 14, 20, 52, 57, 58] (Table 29.2). and OS was 94.8%. In a recent pooled analysis
These good results have been confirmed in a large published in Lancet Oncology [37], Maas et al.
multicenter study published in 2008 by Capirci identified 27 articles, based on 17 different data-
and the Gastro-Intestinal Working Group of the sets, for long-term outcome of patients with and
Italian Association of Radiation Oncology. This without pCR after RCT and TME. Four hundred
study collected 566 patients with pCR (pT0N0) eighty-four of 3,105 (15.6%) included patients
after neoadjuvant therapy and surgery with TME had a pCR. After a median follow-up for all
for locally advanced rectal cancer with no evi- patients of 48 months, 5-year crude DFS was
dence of metastases at the time of diagnosis [12]. 83.3% for patients with pCR (with a disease
After a median follow-up of 45.6 months, locore- recurrence occurred in 61 patients) and 65.6% for
gional recurrence occurred in 7 patients (1.2%) those without pCR (p < 0.0001). The adjusted
and distant metastases in 49 patients (8.9%). hazard ratio for pCR for failure was 0.54 (95%
Overall, 5-year rates of local control, disease-free confidence interval: 0.40–0.73), indicating that
patients with pCR had a significantly increased
probability of disease-free survival. Even after
Table 29.1 Rate of pCR after RCT for extraperitoneal
rectal cancer adjustment for other relevant prognostic factors,
pCR still had a significant impact.
Authors Patients % pCR
Luna-Pérez et al. [36] 120 25
Hiotis et al. [25] 488 10
Mehta et al. [40, 41] 62 35 29.2 Role of Total Mesorectal
Sauer et al. [55] 405 8 Excision After Pathological
Wiltshire et al. [61] 135 21 Complete Response
Bosset et al. [5] 572 13
Gambacorta et al. [19] 102 27
Hughes et al. [27] 143 18 Total mesorectal excision was introduced by
Pucciarelli et al. [49] 235 24 Heald and colleagues [24] in 1982, and this tech-
Coco et al. [15, 16] 272 21 nique is based on the concept that an adequate en
Beddy et al. [3] 126 21 bloc clearance of the rectal mesentery, including
Lindebjerg et al. [35] 135 19 its blood supply and lymphatic drainage, would
Table 29.2 Oncologic outcome in patients who obtained pCR after RCT
Median FU
Authors Patients pCR (%) (months) 5-year LC 5-year DFS 5-year OS
Theodoropoulos et al. [58] 88 16 (18) 33 100 100 100
Garcia-Aguilar et al. [20] 168 21 (13) 37 100 95 95
Rödel et al. [52] 344 40 (12) 41 100 86 NS
Chan et al. [14] 120 32 (27) – 100 97 97
Stipa et al. [57] 200 60 (30) 39 96 NS 90
Bujko et al. [9] 131 22 (17) 48 95 91 NS
FU follow-up, LC local control, DFS disease-free survival, OS overall survival, NS not stated
29 Can Standard Surgical Procedure Reliably Be Avoided in Major Responders After Radio(chemo)therapy? 293
minimize possible disease relapse. Early experi- term RT: sensation of incomplete evacuation is
ence by Heald et al. (on 100 cases) documented reported in a range varying from 35% to 69% and
very good results in terms of local recurrence rate urgency between 16% and 42%; incontinence to
also without the benefit of adjuvant RT [24]. flatus, soiling, and incontinence to solid stools
Actually, TME is considered the gold standard of are reported, respectively, in a range varying from
treatment for extraperitoneal rectal cancers in 25% to 68%, from 20% to 50%, and from 7% to
Europe and in the USA. 14%, with almost 25% of cases which need to
While generally the value of TME is out of wear a pad [7, 18, 38].
doubt, there is much more concern about its role There are evidences in literature that TME
in pathological complete responders patients. It compromises urinary function (from 10% to
raises the question of what can be the contribu- 70%) and sexual function (from 13% to 70%)
tion of a TME in improving results in this specific too, even if nerve-sparing techniques or laparo-
group of patients and if it is reasonable to imag- scopic approach are employed. About urinary
ine to improve the prognosis by removing a functional outcome, the Dutch Colorectal Cancer
healed organ. Study Group [47] on 306 patients reported a rate
On the other hand, what is definitely known is of 39% of urinary incontinence with 57% of the
that TME is associated with a significant postop- patients wore pads because of urinary inconti-
erative morbidity and mortality rate, respectively nence. Moreover, 70% of patients needed to uri-
between 20% and 35% and between 1% and 4% nate again within 2 h, 53% referred urgency, and
[48, 51]. The most frequent postoperative com- 47% complained an incomplete bladder empty-
plication after TME is anastomotic leakage. Leak ing. Concerning sexual disorders after TME,
rates following TME are reported in the range of Sartori et al. [54] reported a reduced sexual desire
15–20% compared with a 5% or less after colonic and impaired spontaneous erectile function in
and intraperitoneal rectal anastomoses [48]. almost half the cases, respectively in 47.1% and
The anterior resection syndrome, including 41.1%; about one-quarter (23.5%) of patients
dysfunction as incontinence, urgency, incomplete still had not the possibility of penetration.
rectal evacuation, inability to defer defecation, Keeping in mind all these considerations about
and clustering of bowel movements, is consid- the possible complications after a TME, there is
ered a consequence of TME and low rectal anas- more than a suspect that this operation in pCR
tomoses. Loss of the physiological rectal reservoir patients (Fig. 29.1) could be an overtreatment. At
and alteration of anus-rectal physiology are the same time, the real problem nowadays is how
responsible for compromised anorectal function. can we identify patients with a pCR before a
In 2007, our institution published functional gas- standard surgical resection and how reliable is
trointestinal results [15, 16] of 100 patients our diagnosis of clinical complete response
treated with neoadjuvant long-term RCT and (cCR).
anterior resection with TME, from 1996 to 2003.
After 1 year from surgery, sensation of incom-
plete evacuation was reported in 58% of cases, 29.3 Wait and See Policy
necessity to return to the bathroom <15 min in
37%, and inability to evacuate completely Long-term results of “wait and see” approach
<15 min in 35%; urgency was referred in 31% of have been firstly reported by Habr-Gama and
cases. Incontinence to flatus was reported in 46% colleagues in 2004 [22] on selected group of
of cases, soiling in 19%, and incontinence to patients with radiological and clinical evidence
solid stools in 5% with 14% of patients needed of of CR after neoadjuvant RCT. Two hundred
wearing pad. In 29% of cases, these functional sixty-five patients with distal resectable rec-
gastrointestinal disorders affected normal social tal cancer were treated with preoperative RCT
and physical lifestyle. These poor functional (RT at a dose of 50.4 Gy in 1.8 Gy fractions
results after TME are also present after short- for six consecutive weeks plus concomitant CT
294 C. Coco and G. Rizzo
The excitement born by Habr-Gama’s results The pathologic complete response rate among
and the necessity of a systematic prospective trial clinical complete responders was 25% with 75%
induced the Royal Marsden Hospital (Sutton, of cCR patients which had persistent foci of
Surrey, UK) and Pelican Cancer Foundation tumor that were not detectable on preoperative
(Basingstoke, Hampshire, UK) to start a pilot examination. Moreover, 55 patients (59.1%)
study investigating a nonoperative approach for preoperatively defined as cCR were affected by a
complete responders patients [45]. pT ³2 cancer and 16 (17.2%) had positive nodes
at pathological staging. On the contrary, 27 of
395 patients clinically classified as not com-
29.4 Definition and Value plete responders were ypT0N0 at pathological
of Clinical Complete Response examination.
In the study of Kim and colleagues in 2001
[29], all patients underwent sigmoidoscopy and a
At present, the criticisms existing about the digital rectal examination to evaluate clinical
“wait and see” approach are mainly due to the response after RCT and endorectal ultrasound
difficulties in identifying with certainty pCR was done after RCT in 12 of the 26 patients. In
patients. We must assume that what appears to the study of Onaitis et al. [46], clinical restaging
be a cCR is equal to a pCR, but this is not true after treatment consisted of proctoscopic exami-
in many times and we still not have nowadays a nation and often computed tomography scan. In
uniform accepted definition of cCR. Schell’s experience [56], digital rectal examina-
Several studies have investigated how cCR tion, endoscopy, computed tomography scan, and
is correlated with pCR. In Table 29.3 are endorectal magnetic resonance or endorectal
reported some who evaluated the ratio between ultrasound were utilized to define cCR.
cCR and pCR [25, 29, 46, 56, 64]. The ratio In last years, new diagnostic techniques con-
varies between 25% and 77%. This large vari- curred to refine the definition of cCR. Diffusion-
ability depends on the fact that the definition of weighted imaging (DWI) has shown promising
clinical complete response as “no evidence of results in the assessment of treatment response to
disease” is often vague and not homogeneous. neoadjuvant therapy. A recent multicenter com-
The largest, published in 2002, was a retro- parative study [30, 31] evaluated the accuracy of
spective review of the clinical and pathologic DWI in addiction to standard rectal MRI for
characteristics of 488 patients, from the Memorial selection of complete responders (only for ypT0)
Sloan-Kettering prospective colorectal database, after RCT. A total of 120 patients with locally
who received preoperative chemoradiation fol- advanced rectal cancer from three university hos-
lowed by resection for primary rectal cancer [25]. pitals (Maastricht University Medical Center,
Definition of cCR was based on the absence of Catholic University of Sacred Heart in Rome,
detectable tumor on preoperative digital rectal and University Hospital of Leuven) underwent
examination and proctoscopy; pCR was defined RCT followed by a restaging MRI, consisting of
as the absence of cancer cells in the resected standard T2W-MRI and DWI. Three independent
specimen. A cCR was achieved in 93 patients readers first scored the standard MRI only for the
(19%) and pCR rate among all patients was 10%. likelihood of a CR, after which DWI images were
Table 29.3 Ratio between Authors Patients cCR (%) Ratio pCR/cCR (%)
cCR and pCR
Kim et al. [29] 95 22/95 (23%) 17/22 (77%)
Onaitis et al. [46] 141 30/141 (21%) 18/30 (60%)
Hiotis et al. [25] 488 93/488 (19%) 23/93 (25%)
Schell et al. [56] 74 11/74 (15%) 8/11 (73%)
Zmora et al. [64] 109 47/109 (43%) 15/47 (33%)
296 C. Coco and G. Rizzo
added and the scoring was repeated. Histology surgeons (58%) would not consider conservative
was the standard reference. A pCR occurred in 25 management of patients with a complete response
patients (20.8%). The accuracy for three readers and even more (69%) expressed that they would
improved from 76%, 68%, and 58%, using only never discuss nonoperative management in
MRI, to 80%, 80%, and 78%, respectively, after patients with rectal cancer who are fit for curative
addiction of DWI (p-value: 0.39, 0.02, and 0.002). surgery.
Positive predictive value increased, after adding In conclusion, cCR is an evolving concept,
DWI, from a range of 0–56% to 62–81%, and but, at the current time, even using the latest avail-
negative predictive value increased from 79–85% able imaging diagnostic techniques, we have
to 88–90%. In this study, authors did not evaluate always a 15–20% of error in identifying pCR. In
lymph nodes. Standard MRI accuracy for lymph these patients with a major clinical response, we
node post-RCT is high and, in our institution, is are in a dilemma. Should we wait and see or
reported as 86.8% on the basis of morphologic should we perform a TME? The first option seems
criteria [1]. The only study [30, 31] specifically too little but at the same time the second one
focused on DWI for staging of rectal cancer seems too much.
nodes after RCT already showed good results for
standard MRI only (negative predictive value:
94–95%) and reported no clear benefit after addi- 29.5 Role of Local Excision After
tion of DWI (negative predictive value: Major Clinical Response
92–93%). to Neoadjuvant Treatment
Positron emission tomography (PET) demon-
strated high accuracy defining the response to Historically, local excision was considered in
RCT. Nearly the same multicenter study group rectal cancer patients as an alternative to radical
has recently developed predictive models for resection if patients were unfit for major surgery
pathologic complete response based on clinical or refused a permanent stoma. When used alone,
data (including age, gender, clinical tumor and local excision of rectal tumors was associated
nodal stage, and tumor location and tumor length with a high recurrence rate, but the key for an
based on MRI or endoscopy if MRI was unavail- appropriate use of local excision for rectal cancer
able) and on PET-based data (maximal tumor is the patient selection [2]. So, during the last
diameter, gross tumor volume, and maximal and 25 years, local excision as curative procedure
mean SUV values within the gross tumor vol- was accepted only for highly selected rectal can-
ume) [60]. Sequential PET-CT data in combina- cer patients who presented with a T1 (sm1 or
tion with clinical variables seem to significantly sm2) nonmucinous adenocarcinoma, with small
increase the performance of prediction models size (less than 4 cm), exophytic, mobile, moder-
for pathologic complete response with an accu- ately or well differentiated histology, and without
racy of 86 ± 5%. vascular, lymphatic, or perineural invasion [2].
Further complicating the situation is the fact Traditional local excision (Fig. 29.2), usually
that there is not a standard interval of time from performed using transanal surgical techniques
the end of RCT when the diagnosis of cCR should (Parks, Mason, Francillon, etc.), is performed
be done. This can vary from 4 weeks up to under general or regional anesthesia; the tumor
1 year. should be removed with a 1-cm margin of normal
In 2010, a questionnaire was sent to members mucosa around the tumor; the resection should
of the Association of Coloproctology of Great be a full-thickness excision, and the perirectal fat
Britain and Ireland regarding investigations, clin- should be seen clearly. Tumor fragmentation
ical management, pathological assessment, and should be avoided. The excised specimen should
oncological outcome in rectal cancer patients be oriented and pinned before fixation. Short-
with a complete response to neoadjuvant RCT term postoperative complications (including uri-
[62]. A total of 122 consultants responded: most nary retention, bleeding, and pelvic sepsis) are
29 Can Standard Surgical Procedure Reliably Be Avoided in Major Responders After Radio(chemo)therapy? 297
infrequent, and most patients are discharged from Local excision of rectal cancers after RCT,
the hospital within 48 h of the operation. The especially using TEM, is increasingly being
introduction of transanal endoscopic microsur- described in the literature. The first docu-
gery (TEM) by Buess in 1983 [6] was an impor- mentation was in 1990 in a study conducted
tant technical advance in the local excision of in Comprehensive Rectal Cancer Center of
rectal cancer. For the TEM technique (Fig. 29.2), Philadelphia [39]. Fourteen patients, unable to
a large operating proctoscope with a stereoscopic tolerate radical surgery or with completely disap-
telescope is used, specially designed instruments peared tumor after irradiation, were treated with
are introduced through the proctoscope, and the preoperative RT (for a total dose of 45 Gy) and
rectum is insufflated with CO2, which maintains full-thickness local excision by transanal, trans-
exposure. This method, compared with the tradi- sphincteric, and transsacral techniques. Follow-up
tional transanal approach using Park’s retractor, observation ranged from 24 to 48 months with a
permits good exposure of the operative field with median of 31 months. Local recurrence devel-
stereoscopic magnified endoscopic vision that oped in three patients (21%), and 3-year actuarial
allows extremely precise dissection and permits local recurrence rate was 23%. Actuarial Kaplan-
a complete full-thickness excision to be per- Meier survival at 3 years was 61%. The Italian
formed with an appropriate margin (ablation with Lezoche’s group has the largest number of pub-
1 cm of surrounding free margin and with the lications on the subject. In 2002, this group of
largest amount of adjacent perirectal fat) [10]. study evaluated the results of preoperative high-
Moreover, TEM enables extension of local exci- dose RT (50.4 Gy) and TEM in 35 patients with
sion to tumors located in the mid-upper rectum pre-RT T2N0 rectal cancer [32]. The tumors were
that are not amenable to removal by standard responsive (50% or more reduction of the diam-
transanal techniques [10]. TEM is technically eter) to preoperative RT in 82.8% of cases. Low
difficult and requires a significant investment responsiveness or unresponsive patients were
in equipment and training for competent per- submitted to radical surgery with TME. After a
formance [2]. median follow-up of 38 months, only one local
298 C. Coco and G. Rizzo
recurrence (2.85%) was noted and the probabil- in node-positive patients. In the first [11], 47
ity of surviving at 96 months was 83%. A larger patients underwent by traditional local excision
publication [33] from the same group included for a relatively small (median diameter: 4 cm),
data from a 15-year experience of the technique low (median distance from anal verge: 4 cm) rec-
on 151 patients with N0 rectal cancer (88 T2 and tal cancer. After long-term RCT (RT doses of 45,
63 T3) who underwent to TEM after preoperative 50.4, or 52.5 Gy with concurrent 5-fluorouracil-
high-dose RT. The definitive histology was 34 based CT), 49% of patients obtained a pCR, and
(22.5%) pT0, 23 (15.2%) pT1, 68 (45.0%) pT2, in 36%, only a microscopic disease was observed.
and 25 (16.3%) pT3. No pT0 patients did not go At a median follow-up of 63 months, five patients
to radical surgery with TME. For the patients (10.6%) developed local recurrence. None of the
with pre-RT T2, the probability of local failure LE patients who developed local recurrence have
was 6% and 5% for T3 patients. The probability died of rectal cancer. Thirteen patients (27.7%)
of metastasis was 3% for pre-RCT T2 patients were pre-RCT N1; of these, 3 (23.1%) developed
and 4% for T3 staging. The rectal cancer-specific a local recurrence versus 2 (5.9%) of the 34
survival rate at the end of the follow-up period patients with pre-RCT N0 disease; this difference
was 90% for pT2 and 77% for pT3 patients. In was relevant but not statistically significant
2008 results were published from a randomized (Fisher exact test, p = 0.1213), probably due to
study [34] that was performed to compare the the small number of N1 patients observed. In
oncologic results obtained by TEM and those contrast, the second study [44] did not find that
by laparoscopic TME resection in the treatment nodal positivity before RCT was associated with
of T2N0, G1–2 rectal cancer after neoadjuvant increased rates of local recurrence but, after a
therapy (high-dose 50,4 Gy RT combined with median follow-up of 64 months, the rate of local
continuous infusion of 5-flurouracil). The study recurrence was high in both groups: 15% in node-
enrolled 70 patients: of these, 35 were random- negative and 18% in node-positive patients. The
ized to TEM and 35 to TME. At pathological major criticism of this technique remains the
exam, there were 11 (32%) pT0 in TEM group impossibility to radically remove all the mesorec-
and 10 (29%) in TME group. After a median tal fat and, consequently, we have no direct path-
follow-up of 84 months, two local recurrences ological information about mesorectal lymph
(5.7%) were observed after TEM and one (2.8%) nodes status. Even when a tumor that has under-
after TME. Distant metastases (2.8%) occurred gone significant pT downstaging after RCT is
in one case each after TEM and TME. The prob- resected with clear margins, lymph node may
ability of survival for rectal cancer was the same still be involved [8, 21, 42, 50] (Table 29.4).
(94%) for TEM and TME. The main reason for performing local excision
As nodal positivity is an accepted adverse (in cCR patients) instead of radical surgery with
prognostic factor after RCT, the majority of stud- TME is to preserve the anatomical and functional
ies have assessed the value of TEM after RCT integrity of the rectum, avoiding a permanent
primarily in patients who were node negative colostomy and some of the bowel, bladder, and
before treatment on the assumption that they sexual dysfunction secondary to radical surgery
would remain so after RCT. Only two studies and improving quality of life. Although it seems
[11, 44] investigated the role of TEM after RCT reasonable, few studies have assessed this con-
29 Can Standard Surgical Procedure Reliably Be Avoided in Major Responders After Radio(chemo)therapy? 299
cept formally. Cataldo PA and colleagues [13] Table 29.5 Rate of lymph node metastasis in ypT0
prospectively evaluated functional outcome on patients
39 patients who underwent TEM (without pre- or Authors # ypT0 # pN+ % N+
postsurgical RCT) by a completed preoperative Crane et al. (2003) [17] 84 1 1.2
and postoperative (6 weeks) survey including Read et al. [50] 42 1 2.3
fecal incontinence severity index, fecal inconti- Bedrosian et al. [4] 45 4 8.8
nence quality of life, number of bowel move- Pucciarelli et al. [49] 56 1 1.8
Tulchinsky et al. [59] 17 1 5.8
ments per 24 h, and ability to defer defecation.
Coco et al. [15] 56 1 1.8
There was no change in any of these parameters
Maas et al. [37] 509 26 5.1
when preoperative and postoperative data were
Total 809 35 4.3
compared. To date, no published data exist about
quality of life after TEM for rectal cancer previ-
ously treated with RCT. In our institution from thickness excision of the rectal wall disk pre-
2000 to 2008, 21 patients underwent TEM after viously containing the rectal cancer can assess
RCT for rectal cancer and no needed further radi- indeed the pathologic response of the primary
cal surgery. After 1 year, all patients were asked tumor (ypT) with an accuracy of nearly 99%.
by a questionnaire on evacuation and continence. This result in assessing pathological response
No patients referred more than three daily bowel of T can be reached with a very low morbidity
movements, sensation of incomplete evacuation, rate and with good functional results. We still
necessity to return in bathroom, or inability to have the problem to have no direct pathologi-
completely evacuate within 15 min. Only one cal information about mesorectal lymph nodes,
patient (4.8%) refers urgency. If compared with but we can have data on this aspect in a round-
an historical series of 100 patients who under- about way. In 2007, our group have published
went radical surgery with TME [15, 16], these an analysis of 272 consecutive rectal cancer
symptoms were statistically less frequent. The [15] submitted to neoadjuvant RCT and surgery
median evacuation score was 24.5 (score varied with TME, to prospectively evaluate the correla-
from 0 to 28; the highest value corresponds to tion between pathological response of primary
better function), significantly lower than patients tumor and mesorectal lymph node involvement.
who underwent TME (16.1; p-value: 0.004). A pCR was recorded in 56 patients (20.6%),
Continence score in TEM patients results to be and lymph node metastases were found in 72
significantly lower than TME series (18.6 vs. patients (26.5%). When a pCR of primary tumor
13.7; p < 0.001; score varied from 0 to 20; the (pT0, TRG1) occurred, the rate of lymph node
highest value corresponds to better function): involvement has been less than 2% (1.8% in our
only two patients (9.5%) referred incontinence to series). Despite at univariate analysis also clini-
flatus after TEM; no patients reported soiling, cal pretreatment N-stage was statistically corre-
incontinence to solid stools, necessity of a pad, or lated with the risk of pathological lymph node
lifestyle limitations after RCT and TEM. metastasis, at multivariate analysis, the best
Local excision after neoadjuvant treatment predictors of pathologic lymph node involve-
of rectal cancer can be seen under two different ment were only ypT stage (p = 0.0013) and TRG
points of view. It can be considered as a minimal (p = 0.0011). Table 29.5 reports a collective
treatment of residual disease or it can be consid- review of recent papers [4, 15–17, 37, 49, 59]
ered just a diagnostic tool. If we consider local published on this topic. If we sum all the series,
excision and especially TEM, not as a therapeu- we can see that on 809 pT0 patients, only 35
tic choice but as the most effective diagnostic (4.3%) had a lymph node involvement. So we
tools we have today to confirm a pathological can consider local excision after a major clini-
complete response after neoadjuvant RCT, we cal response as the best diagnostic tool to patho-
have probably in our hands the most safe way to logically confirm the complete response of the
avoid unnecessary radical resections. The full- primary tumor after RCT and to estimate with
300 C. Coco and G. Rizzo
a very high accuracy (near 96%) the mesorectal erative chemoradiation for locally advanced rectal
nodal involvement. If pathological examination carcinoma. J Gastrointest Surg 8:56–62
5. Bosset JF, Calais G, Daban A et al (2004) Preoperative
of surgical specimen after TEM reveals the pres- chemoradiotherapy versus preoperative radiotherapy
ence of residual neoplastic diseases, patients in rectal cancer patients: assessment of acute toxicity
should be advised to undergo a standard surgical and treatment compliance. Report of the 22921 ran-
resection with total mesorectal excision because domised trial conducted by the EORTC radiotherapy
group. Eur J Cancer 40:219–224
of the higher risk of lymph node involvement. 6. Buess G, Theiss R, Hutterer F et al (1983) Transanal
endoscopic surgery of the rectum – testing a new
Conclusions method in animal experiments. Leber Magen Darm
Pathological complete response after RCT is 13:73–77
7. Bujko K, Nowacki MP, Oledzki J et al (2001)
increasingly reported and identifies a group of Sphincter preservation after short-term preoperative
patients with favorable prognosis in which radiotherapy for low rectal cancer – presentation of
major surgery is probably useless. On the own data and a literature review. Acta Oncol 40:
other hand, a radical resection with TME has a 593–601
8. Bujko K, Nowacki MP, Nasierowska-Guttmejer A
high rate of short- and long-term morbidity. et al (2005) Prediction of mesorectal nodal metastases
Major clinical response is an evolving concept after chemoradiation for rectal cancer: results of a
not easy to define and not truly reliable in pre- randomised trial: implication for subsequent local
dicting pCR. “Wait and see” policy appears excision. Radiother Oncol 76:234–240
9. Bujko K, Kolodziejczyk M, Nasierowska-Guttmejer
today still controversial, and reported results A et al (2010) Tumor regression grading in patients
are contrasting. with residual rectal cancer after preoperative chemo-
If a major or complete clinical response radiation. Radiother Oncol 95:298–302
after a neoadjuvant treatment occurs, full- 10. Burghardt J, Buess G (2005) Transanal endoscopic
microsurgery (TEM): a new technique and develop-
thickness local excision, rather by TEM, ment during a time period of 20 years. Surg Technol
should be considered as the best diagnostic Int 14:131–137
tool we have today to confirm the tumor 11. Callender GG, Das P, Rodriguez-Bigas MA et al
response. The accuracy of the pathological (2010) Local excision after preoperative chemoradia-
tion results in an equivalent outcome to total mesorec-
definition of tumor response after a local exci- tal excision in selected patients with T3 rectal cancer.
sion is near 99% and, in ypT0 patients, is pos- Ann Surg Oncol 17:441–447
sible to predict the absence of lymph node 12. Capirci C, Valentini V, Cionini L et al (2008)
involvement with an accuracy of nearly 96%. Prognostic value of pathologic complete response
after neoadjuvant therapy in locally advanced rectal
Clinical trials to confirm validity of an organ- cancer: long-term analysis of 566 ypCR patients. Int J
sparing approach after local excision diagno- Radiat Oncol Biol Phys 72:99–107
sis of ypT0 are required. 13. Cataldo PA, O’Brien S, Osler T (2005) Transanal
endoscopic microsurgery: a prospective evaluation of
functional results. Dis Colon Rectum 48:1366–1371
14. Chan AK, Wong A, Jenken D et al (2005) Post-
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Part VII
Q&As on Pathology
What Is the Correct Procedure
for Handling the Surgical Specimen? 30
Nigel Scott
under the guidance of the Royal College of polyps, ulcers or colitis; and an assessment of the
Pathologists. Since 1998, the Royal College of completeness of mesorectal excision. The latter
Pathologists minimum data set has provided a is particularly important when trying to gauge
detailed, evidence-based set of instructions for the quality of surgery and in recent studies has
colorectal cancer reporting, widely available on been shown to be an important prognostic factor
the college website [54]. This was last revised in for both loco-regional recurrence and survival.
2007 and is now the standard against which all Mesorectal grading is described in more detail
UK pathology reports are judged. The introduc- below. Additionally, in the case of APR speci-
tion of a reporting proforma to accompany or mens, distance from tumour to dentate line is
replace free text reports has also had a major recorded. Although not widely used at present, a
impact on the completeness of pathological new grading system has recently been proposed
reporting in the UK as demonstrated by numer- to reflect the extent of surgical dissection at the
ous audits [7]. Proformas are increasingly help- level of the anal canal and ano-rectal junction.
ful in the construction of large population This has not yet entered general practice in the
databases by cancer registries, and we would UK but is described briefly in section 30.3.5 for
strongly encourage their use. completeness.
Tumour dimensions may be difficult to mea-
sure accurately when the tumour-bearing bowel
30.2 Specimen Dissection is left unopened; however, tumour size is not an
and Sampling important prognostic factor. Moreover, length
and width can usually be estimated adequately
30.2.1 Specimen Dissection from the tumour slices after dissection.
and Macroscopic Assessment The mesorectal surface (circumferential resec-
tion margin, CRM) is painted with India ink
Ideally, the resection specimen should be received (or an appropriate alternative), and the tumour-
fresh and unopened. Digital pictures are taken of bearing segment is sliced in the transverse plane
the front and back to demonstrate the quality of at 3–5-mm intervals. Slices through the tumour
mesorectal excision and any significant perito- and surrounding mesorectum are laid out in order
neal pathology, e.g., tumour perforation. The rec- on a white board, with proximal and distal ends
tum is opened from both ends along the anterior identified, and photographs taken (Fig. 30.1). It is
margin to within 5–10 mm of the tumour. It may at this stage that tumour dimensions and macro-
not always be possible to see the tumour clearly, scopic type can be recorded. Slices where tumour
especially after chemoradiotherapy, but if the invades closest to the CRM (either by direct
bowel is cut a few millimetres at a time and a spread or within lymph nodes or vessels) are pho-
finger inserted into the lumen to palpate the tographed individually (Fig. 30.2).
tumour edge, it is usually possible to avoid cut- Following a systematic examination of the
ting into the lesion. The opened rectum is then tumour slices, the maximum distance of tumour
pinned to a cork board and immersed in formalin invasion outside muscularis propria is recorded
for 48–72 h. If the tumour is more than 1 or 2 cm as well as the closest point of approach to the
long, a formalin-soaked paper wick can be inked circumferential margin. The location of
threaded through the lumen to facilitate fixation. cancer in the bowel wall is described as involving
Prior to dissection, the specimen is examined anterior, left, right and posterior quadrants or
macroscopically and its external appearance with reference to a clock face (as viewed from
described. This includes the type of operation per- below), e.g., ‘tumour located between 2 and 7
formed, e.g., abdominoperineal excision or ante- o’clock’. It should also be recorded where the
rior resection; length of bowel resected; location CRM is threatened, e.g., ‘tumour invades to
of tumour with respect to distal resection margin within 2 mm of the CRM at 3 o’clock’.
and peritoneal reflection; any peritoneal abnor- The mesorectum proximal and distal to the
malities, e.g., tumour perforation; coincidental luminal cancer is sliced in a similar way to look
30 What Is the Correct Procedure for Handling the Surgical Specimen? 307
Anterior
Proximal
Fig. 30.1 Digital image of slices through tumour and mesorectum for presentation at a multidisciplinary team meeting
be emphasised too much that good histology will Grade is mainly determined by the extent of gland
never compensate for inadequate macroscopic formation. In the WHO grading system, tumours
examination and an intelligent purposeful are divided into low- and high-grade categories,
approach to selection of tissue blocks. It may take the latter corresponding to poorly differentiated
30–45 minutes for the proper dissection of a rec- carcinomas in a three-tier system. In the UK, the
tal cancer excision specimen, but the extra effort Royal College of Pathologists has proposed that
taken will be more than paid back by the quality colorectal adenocarcinomas are graded accord-
of the report. ing to the dominant pattern of differentiation,
The list of pathological prognostic factors whereas WHO advises that grade is based on the
which could be included in a report is large. Core least differentiated component [13, 54]. Both
data items of key importance to the correct man- have been shown to correlate with tumour stage
agement of patients, quality control of diagnosis and prognosis.
and surgery and prediction of disease recurrence
are more limited however, and include tumour
site, tumour size, relationship to anal canal and 30.3.2 Direct Tumour Spread
peritoneal reflection, distance to nearest longitu- and pT Stage
dinal resection margin, mesorectal grade, tumour
type, tumour grade, presence of vascular invasion, All pathological reports on rectal cancer must
pT stage, pN stage, total number of lymph nodes describe the maximum extent of direct tumour
harvested, pR stage and CRM involvement. spread through the bowel wall and provide
While some of these features have already the correct TNM stage. Use of Dukes stage is
been mentioned in the preceding section, a more optional. In the UK, carcinoma is only diagnosed
detailed description is given below including evi- when neoplastic cells invade through muscularis
dence from clinical and pathological studies mucosae into submucosa. Neoplastic glandular
which supports their inclusion as important data proliferations confined to the mucosa are, by
items in the pathologist’s report. common convention, regarded as dysplasia. The
only exception to this rule occurs following neo-
adjuvant therapy where, very occasionally, small
30.3.1 Histological Typing and Grading islands of adenocarcinoma are left behind in the
mucosa after extensive tumour regression in the
Four blocks of tumour are sufficient to type and remainder of the specimen. In this circumstance,
grade most rectal carcinomas. Typing is per- the TNM category pTis can be used. While
formed according to the fourth edition of the intramucosal adenocarcinoma clearly exists, it
WHO Classification of Tumours of the Digestive is doubtful whether this stage of carcinogenesis
System [13]. Over 90% are adenocarcinomas and can be consistently recognised using morpho-
most are either well or moderately well differen- logical criteria alone (except where the tumour is
tiated. Rarer types of carcinoma encountered in poorly differentiated and invades as single cells),
the rectum include signet ring cell carcinoma, and the risk of lymph node metastasis in such
adenosquamous carcinoma, squamous cell carci- early disease is widely regarded as negligible if
noma, neuroendocrine carcinoma and undiffer- it exists at all [16]. pT stage is described in the
entiated carcinoma. Mucinous adenocarcinomas seventh edition of the TNM system as: pT0 – no
are defined as tumours in which over 50% of the evidence of primary tumour, pTis – carcinoma in
tumour volume is made up of extracellular mucin situ: intraepithelial or invasion of lamina propria,
pools and can be either low or high grade. This pT1 – adenocarcinoma confined to the submu-
type is more commonly seen in the colon. cosa, pT2 – invasion of muscularis propria, pT3
Tumour grade reflects how well differentiated invasion through muscularis propria into perirec-
the carcinoma is i.e., the degree to which it tal fat, pT4a – tumour perforation of the visceral
resembles normal rectal (glandular) epithelium. peritoneum and pT4b – direct tumour invasion
310 N. Scott
into other organs or structures [43]. The latter and threatened CRM [46]. Routinely measuring
includes invasion of the levator ani muscle in extramural invasion is therefore, not only a record
advanced low rectal cancers. Other organs com- of a valuable prognostic factor but can be used to
monly invaded by aggressive rectal tumours and audit the quality of magnetic resonance imaging.
included in en bloc excisions or pelvic exentera-
tions include the urinary bladder, seminal vesi-
cles, prostate gland, vagina and uterus. Invasion 30.3.3 Circumferential Resection
of these structures should always be confirmed Margin Involvement
by microscopic examination. Occasionally, only
fibro-inflammatory changes are seen in the adhe- In 1986 Quirke and colleagues from Leeds, UK,
sion between a rectal cancer and excised uterus described the results of the first systematic exam-
or bladder. The prognosis in these patients is bet- ination of the circumferential or radial resection
ter than if carcinoma were present, and unless margin of the rectum [29]. In this seminal paper
there is convincing evidence of previous tumour they showed a strong relationship between CRM
perforation at this site, the final pT stage should involvement (CRMI) and local recurrence in the
be pT1–3 rather than pT4. Rectal perforation is pelvis. Eleven out of 13 patients (85%) with CRMI
seen in 10–20% of operations and may be either eventually developed a loco-regional recurrence
spontaneous or iatrogenic. Surgical perforation compared with 3% of those with clear margins.
is particularly likely to occur during an APR Prior to this publication most pathologists’ atten-
procedure. In an analysis of the Dutch TME- tion had been concentrated on the distal mural
radiotherapy trial, perforation was documented resection margin. Subsequent studies from Leeds
in 13.7% of APR specimens and 2.5% of ante- and elsewhere, including large population-based
rior resections, although not all of these occurred series and data from randomised controlled trials,
through the tumour and therefore, would not all confirmed the prognostic significance of tumour
qualify as pT4 [27]. Both iatrogenic and spontane- at the CRM, defined as carcinoma 1 mm or less
ous perforations are associated with an increased from the resection line, the most recent publica-
risk of tumour recurrence however, and must be tions reporting local recurrence in approximately
documented in the pathology report. 20% of CRM-positive cancers compared with
In addition to pT stage, it is now common 10% if the margin was uninvolved. As well as
practice in the UK to measure the maximum being one of the best pathological predictors of
extent of direct tumour spread outside the muscu- local recurrence, CRM positivity is also predic-
laris propria in millimetres. This is usually per- tive of distant metastasis, disease-free survival
formed at the time of macroscopic examination and overall survival. In a series of 141 patients
and then confirmed microscopically. Where the undergoing curative surgery for rectal cancer in
muscularis propria is destroyed by carcinoma, an Leeds between 1985 and 1990, CRMI was the
estimate is made by extrapolating the line of the strongest independent prognostic factor together
muscle wall from adjacent bowel. Several studies with lymph node status [2]. Reported series
show that advanced pT3 tumours which have where preoperative radiotherapy or chemoradio-
invaded further outside the bowel wall have a therapy has been used likewise show CRMI to be
higher risk of local recurrence and poorer survival an important prognostic factor, even after neoad-
than more superficially invasive lesions [9, 21]. juvant therapy [25].
This is found to be true for both node-positive and An analysis of the relationship between sur-
node-negative groups. In 2007, the Mercury study vival, recurrence rates and tumour distance from
group found that MRI scans were highly accurate the CRM has generally supported the validity of
in measuring this parameter preoperatively [20]. the 1 mm definition with the exception of a single
Subsequently, this has led to the proposition that study from the Dutch TME-radiotherapy trial
patients could be selected for preoperative radio- which suggested that a 2-mm cut-off was more
therapy on the basis of MRI determination of effective in defining a poor prognostic group [24, 28].
extent of extramural spread, vascular invasion It is clear, however, that within the group of
30 What Is the Correct Procedure for Handling the Surgical Specimen? 311
metastasis to the liver [23, 45]. In a minority of increase the rate with which invasion is seen.
specimens, invasion of large veins can be recog- Routine use of an elastin stain to highlight the
nised macroscopically in tumour slices, but in vein wall has been evaluated in several studies
most cases the diagnosis is made microscopi- and not only increases detection rate but
cally. The frequency with which vascular improves reproducibility of diagnosis between
involvement is seen varies according to tumour different pathologists [1, 50]. Elastin stains are
stage and grade and the method of detection. particularly helpful where a small vein is com-
Reported rates vary between less than 20% and pletely occluded by the invading tumour and its
60% or more. Increasing the number of tumour wall partially destroyed (Fig. 30.5). Even with-
blocks examined and taking sections parallel out these techniques however, extramural venous
rather than perpendicular to the bowel wall may invasion (EMVI) should be seen in over 25% of
314 N. Scott
cases and must always be reported. A recent nodes containing metastases will be large and
large population-based study showed that the easily found; 45–50% of involved nodes are
5-year survival of patients with stage II disease <5 mm in diameter [3]!
(Dukes stage B) and EMVI was significantly Most pathologists will identify nodes by a
worse than that seen in patients with a single combination of thin slices through the mesorec-
metastatic lymph node [23]. EMVI therefore, tal and mesocolic fat, visual inspection and
helps to identify a group of patients with ‘high- palpation. Fat clearance techniques and lymph
risk’ Dukes B cancers who may benefit from node enhancement solutions e.g., GEWF, can
adjuvant chemotherapy. enhance the lymph node yield but have not yet
been widely adopted, presumably owing to cost,
the greater time required and perceived difficulty
30.3.8 Lymph Node Metastasis of incorporating such techniques into a busy cut-
and pN Stage up schedule. There is also little evidence that
these methods increase the frequency with which
Rectal adenocarcinomas are metastatic to regional patients are classified as having nodal metasta-
lymph nodes contained within the surgical speci- ses (pN1/pN2) despite substantially improving
men (mesorectal, superior rectal artery and inferior overall lymph node yield. Similarly, while there
mesenteric artery nodes) in 35–50% of patients. are one or two studies suggesting that more posi-
Lateral pelvic lymph nodes (also regarded as tive nodes can be found by cassetting individual
regional nodes in the TNM classification) may lymph nodes separately, processing the entire
be involved by tumour in as many as 10–25% of node for microscopic examination, serial slicing
patients with pT3/pT4 cancers lying distal to the larger nodes and examining smaller nodes at three
peritoneal reflection, but it is unusual in European or more levels, the evidence is still insufficient
and North American surgical practice for the sur- to make clear recommendations on this subject
geon to perform a lateral pelvic lymph node dis- [49]. For the time being most pathologists will
section, and these nodes are rarely seen by the embed only a fraction of larger nodes and exam-
Western pathologist. ine a single section at a single level.
It is essential that time and effort are spent on Macroscopic (and microscopic) tumour nod-
finding as many lymph nodes as possible in the ules may occasionally be found in the mesorectal
resection specimen. The total number of lymph fat unassociated with residual lymph node struc-
nodes found and the number containing metasta- tures. These have been variously called satellite
ses should always be reported. Although pNX is tumour deposits and mesorectal microfoci [12,
applied only to cases where no lymph nodes at all 33]. In some cases there is convincing evidence
can be found, the UICC guidelines advise that in that these deposits have arisen as a result of
most cases 12 or more nodes should be identified. perineural or vascular spread; in other instances,
Evidence from several studies indicates that the it is surmised that they represent lymph nodes
frequency of lymph node positivity increases outgrown by metastatic tumour deposits. While
with the number of lymph nodes found and that these lesions are clearly associated with more
patients staged as node negative (TNM stage II) advanced cancers and reduced survival, incorpo-
on the basis of a small lymph node harvest (the rating them into the TNM staging system has
exact figure varies between studies) have a caused considerable controversy. Older iterations
significantly worse survival outcome than those have regarded them as lymph node deposits
where larger numbers of negative nodes are found if 3 mm in size (fifth edition) or, alternatively,
[23, 48]. While there are other potential explana- when they possess the rounded outline of a node,
tions for this relationship, it seems very likely irrespective of size (sixth edition) [41, 42]. The
that failure to sample an adequate number of current seventh edition removes these
nodes in the surgical specimen risks understaging qualifications and places them in a distinct cate-
the patient’s disease. The pathologist needs to be gory of lymph node metastasis i.e., pN1c [43]. In
aware that it cannot be taken for granted that the UK, the Royal College of Pathologists has
30 What Is the Correct Procedure for Handling the Surgical Specimen? 315
advised retaining the fifth edition of the TNM complete regression has not occurred, the patholo-
system for routine reporting, but it is question- gist needs to sample the remaining cancer widely
able whether all pathologists are able or willing enough to allow accurate assessment of lesser
to apply these rules consistently. A recently pub- degrees of tumour response and provide reliable
lished pathological review of colorectal cancers staging. In our experience regression can vary quite
from the UK and Sweden showed that reporting markedly between different parts of the same
of these lesions was most reproducible using cri- tumour, a fact which may be missed if only limited
teria described in the fifth edition and that the sampling is performed. While there is no univer-
result of successive changes to the classification sally agreed protocol for sampling tumours follow-
has been to increase the proportion of pN1/pN2 ing neoadjuvant treatment, Quirke has suggested
cases in these particular series from 34% using that where no residual tumour is visible macro-
the fifth edition to 43% using the seventh [26]. scopically, the whole tumour site should be sliced
at 5–8-mm intervals and processed for microscopy
[30]. If tumour cells are still not seen after com-
30.3.9 Examination of the Specimen pletely embedding the lesion, each block is to be
After Neoadjuvant Radiotherapy examined at three levels. Where macroscopic
tumour persists, at least four blocks should be sam-
Over the past 10–15 years it has become common- pled including one large (whole mount) block.
place for surgery to be performed after a period of It is also widely recognised that identification
preoperative radiotherapy with or without con- of lymph nodes is more difficult following preop-
comitant chemotherapy. This usually takes the erative radiotherapy and lymph node harvests are
form of either short-course radiotherapy adminis- significantly reduced. It is our experience, how-
tered over 5 days followed by resection a week ever, that it is still possible to find more than 12
later or chemoradiotherapy given over several nodes in most cases if a careful examination is
weeks with a delay of 6–8 weeks before surgery. performed. Interestingly, a recent study suggests
After short-course radiotherapy and early surgery that the relationship between low lymph node
the pathologist will see acute radiation proctitis in numbers and poorer survival in stage II cancers
the peritumoural mucosa but little or no evidence described for patients treated by surgery alone
of tumour regression. Results from the Dutch does not hold true after radiotherapy [34]. This
TME-radiotherapy trial found a modest increase in needs to be validated however.
the frequency of poorly differentiated mucinous Reporting of T and N stage CRMI, histologi-
tumours following this regimen but no evidence of cal type and grade, peritoneal involvement and
downstaging [19]. In contrast, chemoradiotherapy vascular invasion is identical to that for the
with delayed surgery will produce complete untreated specimen except that the prefix ‘y’ is
tumour disappearance (ypT0 ypN0) in 10–20% of used to denote that staging has been performed
cases and lesser degrees of regression in many of after preoperative radiotherapy, e.g., ypT2 ypN1.
the others. In these specimens it may be difficult to Tumour regression grade (TRG) should also be
identify the tumour macroscopically or reliably reported, although its exact role in patient man-
differentiate residual carcinoma from post-radio- agement is still debated. There is good evidence
therapy fibrosis. While there is some correlation that TRGs are prognostic, but it is not clear if
between macroscopic appearances and degree of they offer any additional information that is not
regression, in up to a third of cases where there is a provided by TNM stage and CRM status. Despite
good clinical response i.e., minor mucosal abnor- this many oncologists will request tumour regres-
mality or ulcer scar, residual malignant cells can sion grading as a measure of the tumour’s radio
still be demonstrated microscopically [5]. In these and chemosensitivity and the likelihood of
cases it is important that the pathologist performs a response to future chemotherapy. The most com-
sufficiently thorough examination to confirm com- monly employed TRG is that developed by
plete tumour regression which has been shown Mandard et al. for oesophageal cancer [18].
to have a very good prognosis [51, 53]. Where Dworak described a similar system for colorectal
316 N. Scott
Table 30.1 Tumour regression grading: comparison of three commonly used classifications
Mandard et al. [18] TRG 1 TRG 2 TRG 3 TRG 4 TRG 5
No residual Rare residual Fibrosis Residual cancer Absence of
cancer cancer cells outgrowing outgrowing regressive changes
residual cancer fibrosis
Royal College of TRG 1 TRG 2 TRG 3
Pathologists [54]
No residual Minimal residual No marked regression
tumour cells, tumour. Occasional
mucus lakes microscopic tumour
only foci identified with
difficulty
Beddy et al. [4] TRG 1 TRG 2 TRG 3
No cancer cells, single cells or Residual cancer Fibrosis outgrown by cancer or no
small groups of cancer cells outgrown by fibrosis with extensive residual
fibrosis cancer
cancer, and more recently, Beddy et al. and the meetings that we understand which pieces of
Royal College of Pathologists have proposed a information are important for clinical decision
simpler classification with three grades instead of making and where the uncertainties lie. The
five [4, 10]. These have the advantage of being recent emphasis on quality control of diag-
more reproducible but still retaining prognostic nosis and treatment and the introduction of
significance. Three of these TRG classifications national guidelines with explicit recommenda-
are described and compared in Table 30.1. tions for surgical and pathological audit have
Regressed primary tumours and lymph created a new role for pathologists who must
node metastases may leave behind areas of now describe and record features which not
inflammation, fibrosis, calcification and pools of only have a prognostic function, and guide the
mucin. These are not to be regarded as evidence selection of adjuvant treatments, but are also a
of residual tumour unless tumour cells are actu- measure of the quality of surgery performed.
ally seen and do not count towards ypT stage, If the pathologist is to achieve these aims
ypN stage or CRM involvement. It may be neces- there must be a standardised, evidence-based
sary however, to examine multiple levels through approach to examining the rectal cancer speci-
an area of mucin accumulation before one can be men and an agreed minimum data set which is
sure that no malignant cells are present, and very collected on every case. In this chapter, I have
occasionally immunohistochemistry is required set out to describe what I believe to be the most
to distinguish between tumour cells and mac- important elements of rectal cancer reporting
rophages. In a series of 108 patients undergo- and the evidence, as it currently stands, for
ing long-course chemoradiation at the Memorial their inclusion in the pathologist’s report.
Sloan-Kettering Cancer Centre, acellular mucin
pools were found in 15% of irradiated cancers
[38]. Follow-up confirmed that the presence of
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What Is the Prognostic
Value of (y)pT and (y)pN? 31
Nadine Ectors
Table 31.1 TNM classification of malignant tumours (seventh edition) – digestive system tumours: colon and
rectum
T Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ: intraepithelial or invasion of lamina propria
T1 Tumour invades submucosa
T2 Tumour invades muscularis propria
T3 Tumour invades subserosa or into non-peritonealized pericolic or perirectal tissue
T4 Tumour directly invades other organs or structures and/or perforates visceral peritoneum
T4a Tumour perforates visceral peritoneum
T4b Tumour directly invades other organs or structures
N Regional lymph nodesa
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1–3 regional lymph nodes
N1a Metastasis in one regional lymph node
N1b Metastasis in 2–3 regional lymph nodes
N1c Tumour deposit(s), i.e. satellitesb in the subserosa, or in non-peritonealized pericolic or perirectal soft
tissue without regional lymph node metastasis
N2 Metastasis in four or more regional lymph nodes
N2a Metastasis in 4–6 regional lymph nodes
N2b Metastasis in seven or more regional lymph nodes
M Distant metastasis
M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confined to one organ (liver, lung, ovary, non-regional lymph node(s))
M1b Metastasis in more than one organ or the peritoneum
Changes in TNM7 compared to TNM6
a
Regional lymph nodes of the rectum: superior, middle and inferior rectal (haemorrhoidal), inferior mesenteric, internal
iliac, mesorectal (paraproctal), lateral sacral, presacral and sacral promontory (Gerota). Metastasis in nodes other than
those listed above (e.g., external iliac or common iliac nodes) is classified as distant metastasis
b
Tumour deposits (satellites), i.e. macroscopic or microscopic nests or nodules, in the pericolorectal adipose tissue’s
lymph drainage area of a primary carcinoma without histological evidence of residual lymph node in the nodule, may
represent discontinuous spread, venous invasion with extravascular spread (V1/2) or a totally replaced lymph node
(N1/2). If such deposits are observed with lesions that would otherwise be classified as T1 or T2, then the T classification
is not changed, but the nodule(s) is recorded as N1c. If a nodule is considered by the pathologist to a be a totally replaced
lymph node (generally having a smooth contour), it should be recorded as a positive lymph node and not as a satellite,
and each nodule should be counted separately as a lymph node in the final pN determination
(first publication in 1940) is nowadays the most been modified over the years, up to the seventh
universal cancer staging system. The T (tumour), N edition, attempting to follow the pace of progress
(node) and M (metastasis) staging system classifies and evidence-based developments in oncology
tumours according to the anatomic extent. Tumour (Table 31.1) [39, 40].
staging according to the TNM system is currently
accepted as the strongest prognostic parameter for
different types of cancers, including rectal cancers. 31.2 ‘pT’: Pathologic Classification
Staging provides clinically applicable prognostic of Primary Tumour Extent
information for individual patient management
as well as standardization allowing interpreta- Tumour extent is classified as Tis, T1, T2, T3 and
tion and comparison of evidence-based data at a T4. Changes and discussions relate to sub-
much broader scale. The TNM classification has classification.
31 What Is the Prognostic Value of (y)pT and (y)pN? 321
Unlike other organs, for colorectal carcino- recently [25]. According to the SEER analyses,
mas, ‘carcinoma in situ’ (pTis: Carcinoma in situ: prognosis for patients with pT4a is (10–20%
intraepithelial or invasion of lamina propria) 5-year survival) better than prognosis for pT4b,
includes lesions limited to the epithelium with an independently of the N category [10].
intact basement membrane as well as invasive For rectal cancer, invasion of the external
lesions extending into the mucosal lamina pro- sphincter is classified as pT3, while invasion into
pria up to but not through the muscularis muco- the levator ani muscle(s) is classified as pT4 [43].
sae (intramucosal carcinoma). The underlying
argument being that the lamina propria of the rec-
tum contains extremely few lymphatics. However, 31.3 ‘pN’: Pathologic Classification
the direct link between the number of lymphatic of Lymph Node Involvement
vessels and the associated risk of lymph node
metastasis has been questioned recently [34]. Invasion in regional lymph nodes is classified as
In pT1 tumours (invasion through the mus- N0, N1 and N2. The risk of metastasis to regional
cularis mucosae into the submucosa but not lymph nodes correlates with the T category and
into the muscularis propria), the frequency of other parameters (e.g. grade).
lymph node metastasis relates to the depth of The number of positive lymph nodes affects
invasion, i.e. the superficial (2%), middle (8%) prognosis for most TN categories of rectal can-
and deep (23%) thirds of the submucosa [12, cer. The categories pN1 (1–3 positive regional
34]. This sub-classification is especially useful LN) and pN2 (³4 positive regional LN) remained
for the assessment of local excisions of early unchanged in TNM7. However, both were sub-
lesions. classified in a and b based on numbers of involved
Tumour extension into the muscularis propria lymph nodes (Table 31.1). Patients staged pN1a
(pT2), into the subserosa or the non-peritoneal- (1 positive regional LN) were shown to have a
ized pericolic or perirectal tissue (pT3) and into 3–10% better 5-year relative and observed sur-
other organs or structures and/or perforating vis- vival compared to pN1b (2–3 positive regional
ceral peritoneum (pT4) has been subject to split- LN), while pN2a (4–6 positive regional LN) have
ting and lumping manoeuvres in, e.g. the TNM a 5–20% better 5-year survival than pN2b (³7
and Japanese staging systems. For example, the positive regional LN) [10]. Nevertheless, some
sub-classification of pT3 was included in the authors persist arguing on the basis and validity
third edition of the TNM supplement (2003) and of the cut-off values for sub-classification.
is included in the Japanese classification [44]. A high-quality, i.e. complete ‘total mesorectal
Data confirming the impact of pT3 sub- excision’ (TME), specimen includes the primary
classification on prognosis of patients with rectal tumour as well as all regional lymph nodes [1,
cancer exist; however, it did not find wide accep- 24, 33]. The accuracy and predictive value of
tance probably because of discussions on the stage II (pT3,T4-N0M0) assignment are directly
basis and validity of the cut-off values for sub- proportional to the quality of the TME, i.e., the
classification and the lack of standardized meth- inclusion of all regional lymph nodes and the
ods of assessment [25]. More recently, TNM7 pathological examination of the specimen, i.e.
introduced differentiation between pT4a and the retrieval and harvest of all regional lymph
pT4b, which was previously also addressed in the nodes. The minimal acceptable harvest has been
third edition of the TNM supplement (2003) [44]. set at 12 lymph nodes [5, 6, 36]. However, ‘lymph
Multivariate analysis having demonstrated that node retrieval in rectal cancer is dependent on
involvement of the serosa by tumour (pT4b) is an many factors – the role of the tumour, the patient,
important independent prognostic factor imply- the surgeon, the radiotherapist, and the patholo-
ing an increased risk of distant metastasis and a gist’, not in the least the pathologist [4, 18].
shorter median survival time [17]. Whether the Although these authors tend to settle for a median
risk incurred in pT4a differs significantly from of at least 8 lymph nodes, a number of studies
pT4b and how they relate has been questioned indicate that examination of increased numbers
322 N. Ectors
of lymph nodes is, in itself, associated with an prognostic significance of apical-node metasta-
increased survival advantage (e.g. 18). Moreover, sis around the inferior mesenteric artery (IMA)
it has been shown in rectal cancer that lymph remains unclear [16]. Therefore, ‘Western’ prac-
node metastasis are often found in small lymph tice does not advocate (systematic) extensions of
nodes (<5 mm diameter) [43]. lymphadenectomies.
More recently, the debate has moved away Metastasis to non-regional lymph nodes, e.g.
from the exact number of lymph nodes towards external iliac or common iliac nodes, is classified
the lymph node ratio (LNR) as an even better as distant metastasis (M1).
indicator of prognosis [2, 3, 8, 15, 24, 30]. If the
LNR can be considered as a prognostic factor, it
may have the advantage to be less dependent on 31.4 SLN: Sentinel Lymph Nodes
the number of retrieved lymph nodes than stage
[7]. Moreover, in a systemic review, it was pointed Sentinel lymph node mapping is the standard
out that marked heterogeneity exists within stage nodal staging technique in patients with breast
III patients and LNR may prove useful to stratify cancer without gross nodal involvement. This
outcome in those patients [2]. Although data look procedure allows to adapt the extent of the resec-
promising, both publications as well as the SEER tion on a case by case basis and thus to avoid
analysis concluded that further evidence is needed unnecessary extensive surgery, i.e. axillary
[2, 7, 10]. Independently of the potential of LNR, lymphadenectomy, to decrease the rate of com-
it is crucial that the pathology report should plications and side effects and to improve quality
clearly indicate the number of positive lymph of life. The concept is based on the existence and
nodes as well as the total number of lymph nodes understanding of an orderly and sequential drain-
examined. age of lymphatic fluid, carrying tumour cells
Since the fifth edition of the TNM (1997), the from the primary tumour through lymphatic ves-
classification of positive lymph nodes according sels and lymph nodes ultimately into the blood
to the location along (named) arteries (introduced circulation. The procedure consists of preopera-
as pN3 in TNM4) has been discarded, this in con- tive injection and tracing of a marker (blue dye,
trast to the actual Japanese classification [35]. No radiocolloids) in order to identify and dissect a
major impact towards patient management is to sentinel lymph node. The lymph node is sub-
be expected. jected to a preoperative extensive pathological
The regional lymph nodes of the rectum are investigation including multiple serial levels with
superior, middle and inferior rectal (haemor- (in a second time) special/ancillary techniques
rhoidal), inferior mesenteric, internal iliac, (immunohistochemistry, qRT-PCR).
mesorectal (paraproctal), lateral sacral, pre- Recently, a number of articles, including sys-
sacral and sacral promontory (Gerota). The ‘total tematic reviews and meta-analysis, have addressed
mesorectal excision’ – which ideally should the issue in rectal cancer [1, 42]. However, the
include all regional lymph nodes – is described underlying surgical motive is not applicable in
in Japanese literature as a ‘limited resection’. rectal cancer: involvement of a sentinel lymph
A Japanese ‘standard resection’ and an ‘extended node will not change the extent of the resection
resection’ include lateral extensions, i.e. respec- on a case by case basis, i.e. the en bloc resection
tively a dissection along the parietal pelvic fascia of the primary rectal cancer including the regional
and the internal iliac artery and a dissection of the lymph nodes; it is the total mesorectal excision,
internal iliac vessels preserving the superior vesi- the cornerstone for locoregional control of rectal
cal artery and obturator nerve [1]. Wide pelvic cancer. Moreover, in rectal cancer, sentinel lymph
lymphadenectomies – which do include lymph nodes have been shown not to be representative
nodes along the internal iliac artery – correlate of involvement of the locoregional lymph nodes
with increased morbidity and a limited, selective, in an important percentage of patients. Finally,
improvement of prognosis [45]. Similarly, the skip metastasis or aberrant metastasis has been
31 What Is the Prognostic Value of (y)pT and (y)pN? 323
noted. Therefore, the drainage of lymphatic fluid ing, implying that this additional staging in other-
in rectal cancer is not sufficiently ‘orderly and wise ‘pN0’ patients may improve identification
sequential’. Theoretically, mapping of the lym- of potential candidates for adjuvant therapy, how-
phatic drainage of an individual rectal cancer ever, up till now without proven benefit [42].
could be taken into consideration when consider- The available data do not provide unequivocal
ing extended lymphadenectomies. Unfortunately, evidence to support classifying micrometastasis
specifically, the lateral lymphatic drainage is as positive lymph nodes, let alone to prescribe
extremely variable. In conclusion, sentinel lymph adjuvant therapy.
node mapping in rectal cancer should be consid-
ered as investigational and does not belong to the
routine clinical practice [13, 20]. 31.6 In Between ‘T’ and ‘N’ and
Close to ‘V’: Tumour Deposits
31.5 Isolated Tumour Cells (ITC) Tumour deposits are defined, in the TNM staging
and Micrometastasis system, as irregular discrete tumour deposits in
perirectal fat away from the leading edge of the
A micrometastasis is defined, in the TNM staging tumour and showing no evidence of residual
system, as a metastasis measuring more than lymph node tissue, but within the lymphatic
0.2 mm and less than or equal to 2.0 mm in diam- drainage of the primary tumour, are considered
eter. Isolated tumour cells (ITC) are defined as peritumoural deposits nodules. The finding of
single tumour cells or small clusters of tumour tumour deposits (satellites or numerous other
cells measuring 0.2 mm in diameter or less. The synonyms) has always confronted pathologists
latter are usually identified by special techniques, with uncertainty concerning the underlying etio-
e.g. immunohistochemistry. pathogenic mechanisms and thus the impossibil-
According to TNM6 and 7, micrometasta- ity to classify them in a prognostic staging
sis should be classified as such (abbreviations: systems, i.e. as T or N factor or neither of them.
mi or mic) and staged as lymph node positive The changes in definitions of tumour deposits
(e.g. pN(mi)), owing to their possible malignant and interpretations in the fifth, sixth and seventh
potentiality [37, 39]. In contrast, isolated tumour editions of the TNM classification clearly dem-
cells (ITC) are considered insignificant and thus onstrate this problem [35, 37, 39]. Unfortunately,
should not be taken into account as lymph node these issues have direct implications concerning
metastasis (pN0). It is explicitly stated that spe- staging and thus treatment of individual patients.
cial techniques (e.g. multiple tissue levels, immu- Tumour deposits were first acknowledged
nohistochemistry, qRT-PCR) to detect ITCs are in TNM5 (1997) [35]. The ‘3-mm rule’ stated
not recommended for the routine examination of that tumour deposits 3 mm or larger in diameter
regional lymph nodes. The pathological report should be regarded as a positive lymph node.
should clearly mention the number of lymph The implementation of the ‘3 mm rule’ was not
nodes involved by micrometastasis and ICTs. evidence-based, acknowledged post-factum, but
The presence of micrometastasis in colorectal had the advantage of being an ‘objective’ crite-
cancer has been previously investigated, but there rium [40]. The next edition of the TNM staging
has been no consensus in relation to their prog- system (TNM6 2002) introduced controversial
nostic significance, which in part is surely due to changes [37]. The ‘3 mm rule’ was withdrawn,
the nature of the studies themselves and other and the definitions of lymph nodes as well as
technical aspects [19]. The prognostic significance vascular invasion were revised. A tumour nodule
of ITCs is still unproven. Some authors of articles in the pericolic/perirectal adipose tissue without
concerning sentinel lymph node mapping do state histological evidence of residual lymph node in
that the main advantage of the sentinel procedure the nodule is classified in the pN category as a
could well be the improvement of the cancer stag- regional lymph node metastasis, as the nodule has
324 N. Ectors
the form and smooth contour of a lymph node. do not know if adjuvant therapy in patients sub-
If the nodule has an irregular contour, it should jected to stage migration, following onto these
be classified in the T category and also coded as interpretations, has a true benefit. Therefore, in
V1 (microscopic venous invasion) or V2 if it was a number of European countries, it was decided
grossly evident, because there is a strong likeli- that the definitions in TNM5 are the most repro-
hood that it represents venous invasion. This ducible and thus should be adhered to, especially
interpretation elicited major concerns on repro- as far as tumoural deposits are concerned [26, 28].
ducibility and thus interobserver variability on the Therefore, it is advisable to indicate the number
one hand and discussion on biological and clini- of TNM version used (e.g. v5, v6, v7) [41].
cal underlying evidence on the other hand. These As a reminder, the objectives for cancer stag-
concerns have been discussed and published in ing were defined by the International Union
great length by Philip Quirke and other European Against Cancer (UICC) TNM Committee almost
pathologists [11, 26]. The paragraph related to the 50 years ago in this order: to aid the clinician in
tumour deposits, and consequently lymph node planning treatment, to give some indication of
and vascular invasion, has been rewritten, but not prognosis, to assist in evaluating the results of
necessarily clarified, in the most recent edition treatment, to facilitate the exchange of informa-
of the TNM staging system (TNM7 2009) [39] tion between treatment centres and, last but
– tumour deposits (satellites), i.e. macroscopic admittedly not least, to contribute to continuing
or microscopic nests or nodules, in the pericol- investigation of human malignancies [9].
orectal adipose tissue’s lymph drainage area of a
primary carcinoma without histological evidence
of residual lymph node in the nodule, may repre- 31.7 CRT: y(pT) and y(pN)
sent discontinuous spread, venous invasion with
extravascular spread (V1/2) or a totally replaced Y(pT) and y(pN) refer to a primary tumour and
lymph node (N1/2). If such deposits are observed lymph nodes that have been previously treated by
with lesions that would otherwise be classified as means of CRT.
T1 or T2, then the T classification is not changed, Neoadjuvant combined treatment in rectal
but the nodule(s) is recorded as N1c. If a nodule cancer is associated with significant tumour
is considered by the pathologist to a be a totally response and downstaging. Minimal residual dis-
replaced lymph node (generally having a smooth ease has been shown to have a better prognosis
contour), it should be recorded as a positive than gross residual disease. Thorough pathologi-
lymph node and not as a satellite and each nodule cal assessment of rectal resection specimens after
should be counted separately as a lymph node in chemoradiation is mandatory (e.g. sampling pro-
the final pN determination. Again, this interpre- tocols, grading systems for tumour response (see
tation elicited major concerns on reproducibility Part VII)) [42] [44].
and thus interobserver variability on the one hand The College of American Pathologists (CAP)
and discussion on biological and clinical under- recommends that (1) tumour regression should
lying evidence on the other hand [21, 27, 40]. In be assessed only in the primary tumour, lymph
the meantime, the literature on tumoural deposits node metastases should not be included in the
has been thoroughly reviewed concluding that, assessment and (2) acellular pools of mucin in
indeed, tumoural deposits have an adverse prog- specimens from patient receiving neoadjuvant
nostic factor [20]. In a comparative study of two therapy are considered to represent completely
independent study populations, it was confirmed eradicated tumour and are not used to assign pT
that tumoural deposits should be taken into stage or counted as positive lymph nodes [43].
account in staging patients with colorectal cancer The latter statement has received scientific sup-
[22]. However, numerous questions remained to port from a recent publication addressing
be addressed as to the definition and reproducibility specifically this issue [32].
and thus interobserver variability before applica- After neoadjuvant chemoradiation and total
tion in the TNM classification. Moreover, we still mesorectal excision, lymph node positivity is
31 What Is the Prognostic Value of (y)pT and (y)pN? 325
associated with significant worse survival time orectal cancer: a systemic review. Ann Surg Oncol
and time to local recurrence. Neoadjuvant treat- 17:2847–2855
3. Chin CC, Wang JY, Yeh CY,et al (2009) Metastatic
ment is a well-documented cause of limited lymph node ratio is a more precise predictor of prog-
lymph node retrieval (<12) [4, 18]. Lymph node nosis than number of lymph node metastases in stage
ratio has been proposed as an alternative prog- III colon cancer. Int J Colorectal Dis 24:1297-1302
nostic parameter and may possibly show to be a 4. Chou JF, Row D, Gonen M et al (2010) Clinical and
pathologic factors that predict lymph node yield from
better independent staging method than absolute surgical specimens in colorectal cancer. Cancer
count especially when limited numbers of lymph 116:2560–2570
nodes have been retrieved [8]. Moreover, 5. Compton CC, Fielding LP, Burgart LJ et al (2000)
specifically in this setting, the absolute number of Prognostic factors in colorectal cancer; College of
American Pathologists consensus statement 1999.
lymph node retrieved may have a less important Arch Pathol Lab Med 124:979–994
impact on prognosis [14]. 6. Compton CC, Greene FL (2004) The staging of col-
The consequent application of the TNM7 in orectal cancer: 2004 and beyond. CA Cancer J Clin
the setting of patients with rectal cancer treated 54:295–308
7. Dekker JWT, Peeters KC, Putter H et al (2010) Metastatic
with neoadjuvant chemoradiation will imply that lymph node ratio in stage III rectal cancer, prognostic
a number of patients with tumour regression and significance in addition to the 7th edition of the TNM
residual tumour foci, interpreted as tumoural classification. Eur J Surg Oncol 36:1180–1186
deposits, will be classified in the node positive 8. Doll D, Gertler R, Maak M et al (2009) Reduced
lymph node yield in rectal carcinoma specimen after
group, rightly or wrongly [22]. neoadjuvant radiochemotherapy has no prognostic
relevance. World J Surg 33:340–347
Conclusions 9. Gospodarowicz MK, Miller D, Groome PA et al
The TNM classification is a worldwide bench- (2004) The process of continuous improvement of the
TNM classification. Cancer 100:1–5
mark for reporting the extent of cancer and is 10. Gunderson LL, Jessup MJ, Sargent DJ et al (2010)
a major prognostic factor in predicting the Revised tumor and node categorization for rectal can-
outcome of patients and thus a valuable aid cer based on surveillance, epidemiology, and end-
in planning treatment of individual patients. results and rectal pooled analysis outcomes. J Clin
Oncol 28:256–263
Mandatory continuous improvement of the 11. Horvath SM, Morgan JM, Williams GT (2006) The
TNM classification should be evidence-based. new (6th edition) TNM classification of colorectal
The prognostic values of ‘T’ and ‘N’ are facts, cancer: a stage too far. Gut 53:A21
no more, no less. However, the prognostic 12. Kikuchi R, Takano M, Takagi K, et al (1995)
Management of early invasive colorectal cancer: risk
values of various subcategories do not always of recurrence and clinical guidelines. Dis Colon
achieve the same standards of evidence- Rectum 38:1286–1295
based. Communication between the oncology 13. Kim JW (2011) The clinical usefulness of the sentinel
community and those involved in the TNM lymph node in rectal cancer: do we believe in it ? J
Korean Soc Coloproctol 27:51–52
classification in order to create a structured 14. Klos CL, Shellito PC, Rattner DW et al (2010) The
process for introducing changes is essential effect of neoadjuvant chemoradiation therapy on the
for success. prognostic value of lymph nodes after rectal cancer
surgery. Am J Surg 200:440–445
15. Kobayashi H, Mochizuki H, Kato T,et al (2011)
Lymph node ratio is a powerful prognostic index in
patients with stage III distal rectal cancer: a Japanese
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What Is the Prognostic Value
of CRM Involvement? 32
Iris D. Nagtegaal
In this chapter, I will demonstrate that the CRM Lymph node metastases in the CRM were associ-
is a very good prognostic marker, a surrogate ated with a lower than expected local recurrence
endpoint, as well as a quality indicator. rate; however, only 42 of these patients have been
described [4, 6].
gained. By judging the quality of the surgery per- numbers of positive margins, although there was
formed by evaluating the completeness of more downstaging in the radiochemotherapy arm
mesorectal excision, we proved the direct rela- (p < 0.001) [14]. From the frequencies in the non-
tion between CRM + and quality of surgery. In randomized neoadjuvant studies, no conclusions
two large randomized multicenter trials [10–12], can be drawn about the efficiency of regimens to
we demonstrated that if the mesorectum is reduce positive margins, due to the variability in
removed as a whole (i.e., the resection margin is inclusion criteria, treatment schemes, and lack of
on the mesorectal plane), very few positive mar- pathology quality control.
gins are present and local recurrence rates are
very low [10–12]. In contrast, when the plane of
resection is on the muscularis propria, CRM 32.4 The Prognostic Value
involvement is common and local recurrence of CRM Involvement
rates are high. The plane of resection can explain
why, in a few cases (1.1% [6], 2.0% [4]), positive High local recurrence rates ranging from 25% to
CRMs are present in TNM stage I tumors. 50% in the past have markedly reduced in recent
years, due to changes in surgical approach com-
bined with neoadjuvant therapy. The recognition
32.3 Incidence of CRM Involvement of CRM involvement as one of the main causes of
local recurrence has led to the global introduction
Large differences exist between centers with of TME, resulting in fewer positive margins and
regard to the number of CRM + patients, percent- less residual disease. Since predictive values
ages ranging from 1% to 28% in curatively oper- depend strongly on the prevalence of local recur-
ated patients. Various factors should be taken into rence, the role of CRM was expected to be less
account when reviewing these percentages. The prominent after the introduction of the TME pro-
percentage of CRM + patients is dependent on cedure. However, this does not appear to be the
patient selection, performance of preoperative case owing to the variability of the quality of
imaging, preoperative long-course therapy, surgi- TME. Due to the lower local recurrence rates,
cal technique, and skill of the pathologist. both the sensitivity and the positive predictive
Frequencies of CRM involvement in single cen- value of circumferential margin involvement have
ter studies should thus be treated with caution. decreased. However, after TME treatment, local
On the other hand, less variability is present in recurrence can be predicted with a high specificity
the population-based studies, ranging from 8% to (92%) and a high negative predictive value (95%),
13%. In these studies, there is a difference in which are both clinically relevant [15].
patient selection as well, reflected by differences A recent review [7] evaluated the prognostic
in the number of node-positive patients ranging value of the CRM in a meta-analysis of 17,568
from 21% to 40%. patients, described in the literature between 1985
Randomized neoadjuvant trials give insight to and 2006. From these analyses, it became very
mechanisms by which negative CRMs can be clear that CRM is an important predictor of local
obtained. Short-course 5 × 5 Gy does not influence recurrence. In 4,899 patients treated with surgery,
the percentage of positive margins, as could be only a positive resection margin increased the
expected by the lack of downstaging due to this risk of local recurrence (HR 2.0, 95% CI
regimen. When comparing short-course radio- 1.4–2.9).
therapy with long-course chemoradiation, there The addition of neoadjuvant therapy (varying
is a difference, 13% versus 4% involved margins, from short-course radiotherapy to long-course
p = 0.017 [13]. In this study, downstaging is radiochemotherapy depending on national guide-
observed as well, 48% versus 32% TNM III lines and patient selection based on diagnostic
(p = 0.007). The addition of 5FU/folinic acid to imaging) was expected to compensate for poor
long-term radiotherapy does not decrease the surgical performance and to diminish the role of
330 I.D. Nagtegaal
the CRM. However, when comparing neoadju- significant relation with CRM, both in the neoad-
vant studies with non-neoadjuvant studies, a juvant setting as well as in the patients treated
significant difference in hazard ratio is observed: with surgery alone (n = 6,148, HR 1.7, 95% CI
6.3 (95% CI 3.7–16.7) versus 2.0 (95% CI 1.4– 1.3–2.3). A recent study investigated the value of
2.9). In other words, in contrast to the expecta- CRM for survival in a multivariate model and
tions, a positive CRM is a more powerful predictor found that CRM is more important than T-stage.
of local recurrence in patients treated with neoad- In combination with lymph node status, CRM
juvant therapy. One could argue that this might status provides a better prognostic model than the
be due to the fact that patients treated with neoad- current TNM system [17, 18].
juvant therapy are usually patients with locally
advanced tumors. CRM involvement can be seen Conclusions
as tumor resistance to therapy and indicate a lack The circumferential margin has been around
of downstaging. Indeed, when downstaging for over 25 years. Although the treatment of
occurs, the distance of tumor to the CRM rectal cancer has changed significantly over
increases in some but not all studies [14, 16]. those years, achieving large improvements in
However, in patients treated with 5 × 5 Gy, no prognosis, the prognostic value of the CRM is
downstaging occurs, and still the hazard ratios still there. A positive margin after neoadjuvant
are 3.8 and 2.3 (no neoadjuvant therapy, 95% CI therapy implies a major increase in local recur-
3.3–5.6 and 1.9–3.0) versus 10.0 and 5.3 (5 × 5 Gy, rence risk. In addition, CRM + increases the
95% CI 6.7–25.0 and 3.6–10.0). Thus, the effect risk on development of distant metastases and
of CRM involvement was significantly more pro- decreases overall survival, both in univariate
nounced in the patients who were treated with as in multifactorial analyses.
neoadjuvant therapy, without the downstaging. In addition, a free CRM can be used as a sur-
To monitor the effects of neoadjuvant treat- rogate marker for effectiveness of neoadjuvant
ment on the histology of the tumor, various tumor therapy. CRM evaluation, together with grad-
regression grading systems (TRG) have been ing of the quality of surgery, is the most impor-
employed over the years. These pathological tant quality indicator for surgical treatment.
evaluations are based on the relative amount of
tumor cells present and the desmoplastic reac-
tion. The definitions used in the different studies
vary and reproducibility is poor. Despite these References
disadvantages, TRG has been suggested as a sur-
rogate and early outcome parameter for neoadju- 1. Quirke P, Durdey P, Dixon MF, Williams NS (1986)
Local recurrence of rectal adenocarcinoma due to
vant trials. When comparing the value of CRM
inadequate surgical resection. Histopathological study
with TRG [7], four independent studies demon- of lateral tumor spread and surgical excision. Lancet
strate superiority of CRM above TRG in a multi- 2:996–999
variate model. 2. Heald RJ, Ryall RDH (1986) Recurrence and survival
after total mesorectal excision for rectal cancer. Lancet
All studies that included the development of
1:1479–1482
distant metastases as a separate outcome vari- 3. Kapiteijn E, Marijnen CAM, Nagtegaal ID et al (2001)
able (total n = 2,267) show a significant differ- Preoperative radiotherapy combined with total
ence in prognosis between the CRM + and the mesorectal excision for resectable rectal cancer.
N Engl J Med 345(9):638–646
CRM − patients (HR 2.8, 95% CI 1.9–4.3). No dif-
4. Nagtegaal ID, Marijnen CAM, Klein Kranenbarg E,
ference is observed between the patients treated van de Velde CJH, van Krieken JHJM (2002)
with or without neoadjuvant therapy. Circumferential margin is still an important predictor
The relation of CRM involvement and patient of local recurrence in rectal carcinoma: not one mm
but two mm is the limit. Am J Surg Pathol 26(3):
survival is not clear from all studies, probably
350–357
due to lack of statistical power. However, when 5. Bernstein TE, Endreseth BH, Romundstad P, Wibe A
all studies are summarized, there is a clear and (2009) Circumferential resection margin as a
32 What Is the Prognostic Value of CRM Involvement? 331
prognostic factor in rectal cancer. Br J Surg 96(11): therapy. Preliminary results of the MRC CR07 trial.
1348–1357 J Clin Oncol 24(18s):A3512
6. Birbeck KF, Macklin CP, Tiffin NJ et al (2002) Rates 13. Bujko K, Nowacki MP, Nasierowska-Guttmejer A
of circumferential resection margin involvement vary et al (2004) Sphincter preservation following preop-
between surgeons and predict outcomes in rectal can- erative radiotherapy for rectal cancer: report of a ran-
cer surgery. Ann Surg 235(4):449–457 domised trial comparing short-term radiotherapy vs.
7. Nagtegaal ID, Quirke P (2008) What is the role for the conventionally fractionated radiochemotherapy.
circumferential margin in the modern treatment of Radiother Oncol 72(1):15–24
rectal cancer? J Clin Oncol 26(2):303–312 14. Bosset JF, Calais G, Mineur L et al (2005) Enhanced
8. Ueno H, Mochizuki H, Shinto E, Hashiguchi Y, Hase K, tumorocidal effect of chemotherapy with preoperative
Talbot IC (2002) Histologic indices in biopsy speci- radiotherapy for rectal cancer: preliminary results –
mens for estimating the probability of extended local EORTC 22921. J Clin Oncol 23(24):5620–5627
spread in patients with rectal carcinoma. Cancer 15. Wibe A, Rendedal PR, Svensson E et al (2002)
94(11):2882–2891 Prognostic significance of the circumferential resec-
9. Nagtegaal ID, Van Krieken JH (2007) The multidisci- tion margin following total mesorectal excision for
plinary treatment of rectal cancer: pathology. Ann rectal cancer. Br J Surg 89(3):327–334
Oncol 18(9):ix122–ix126 16. Rullier E, Goffre B, Bonnel C, Zerbib F, Caudry M,
10. Nagtegaal ID, van de Velde CJH, van der Worp E, Saric J (2001) Preoperative radiochemotherapy and
Kapiteijn E, Quirke P, van Krieken JHJM (2002) sphincter-saving resection for T3 carcinomas of the
Macroscopic evaluation of rectal cancer resection lower third of the rectum. Ann Surg 234(5):633–640
specimen: clinical significance of the pathologist in 17. Nagtegaal ID, Gosens MJ, Marijnen CA, Rutten HJ,
quality control. J Clin Oncol 20(7):1729–1734 van de Velde CJ, van Krieken JH (2007) Combinations
11. Nagtegaal ID, van de Velde CJH, Marijnen CAM, of tumor and treatment parameters are more discrimi-
van Krieken JH, Quirke P (2005) Low rectal cancer; a native for prognosis than the present TNM system in
pathologists’ call for a change of approach in abdomi- rectal cancer. J Clin Oncol 25(13):1647–1650
noperineal resection. J Clin Oncol 23:9257–9264 18. Gosens MJ, van Krieken JH, Marijnen CA et al (2007)
12. Quirke P, Sebag-Montefiore D, Steele R et al (2006) Improvement of staging by combining tumor and
Local recurrence after rectal cancer resection is treatment parameters: the value for prognostication in
strongly related to the plane of surgical dissection and rectal cancer. Clin Gastroenterol Hepatol 5(8):
is further reduced by preoperative short course radio- 997–1003
What Is the Prognostic
Value of TRG? 33
Fabio M. Vecchio
Contents Abbreviations
33.1 Definition and Grades of TRG ..................... 333
CRT Chemoradiotherapy
33.2 Prognostic Significance of TRG ................... 336
CSS Cancer-specific survival
References ................................................................. 337 DFS Disease-free survival
m-RCRG Modified version of rectal cancer
regression grade
RCPath Royal College of Pathologists
RCRG Rectal cancer regression grade
TRG Tumor regression grade
ypTNM TNM staging after neoadjuvant
therapy
Tumor regression was assessed by examining the No response (%) Grade response 0
residual cancer cells and scoring both cytologi- 1–33 Grade response 1
cal changes and stromal changes. On the basis of 34–66 Grade response 2
the combination of these findings, tumor regres- 67–95 Grade response 3
sion was classified according to the five grades, 96–99 Grade response 3+
reported in Table 33.1. 100 Grade response 4
The main advantage of Mandard’s TRG was that
regression was assessed only by comparing the pro- In the conclusions of their study, Ruo et al.
portion of residual carcinoma to scarring by a very found that a marked response to preoperative
simple and reproducible method. In fact, this method radiotherapy ± chemo was clinically associated
was promptly applied also to rectal cancer treated with fewer recurrences and good long-term out-
with preoperative CRT. In 1997, Dworak et al. come, but was not an independent predictor of
adopted a very similar grading of regression exam- recurrence-free survival.
ining the surgical specimens of 17 patients with rec- Wheeler et al. quantified the histologic regres-
tal carcinoma after CRT [2]. Like Mandard et al., sion of rectal cancer after irradiation in a study on
they designed five regression grades, but defined 42 patients. They proposed a 3-point rectal can-
and named them in a different way. Dvorak TRG cer regression grade (RCRG).
varies from grade 0 with no regression to grade 4 RCRG 1 was characterized by “good” radio-
with no tumor cells (see Table 33.1, showing the responsiveness with sterilization or only micro-
correspondence between the Mandard and Dworak scopic foci of adenocarcinoma remaining. In
TRG systems). In 17 specimens studied by Dworak, RCRG 2, macroscopic disease was present asso-
no case of total regression was observed after stan- ciated with marked fibrosis. Finally, RCRG 3
dardized pathological workup, i.e., embedding of indicated a “poor” response with abundant mac-
the whole suspicious area in paraffin blocks and step roscopic disease and little or no fibrosis. Wheeler
sectioning, if necessary. They pointed out that the stressed the importance of determining RCRG
demonstration of residual tumor depended mainly by the consideration that as radiotherapy reduced
on the accuracy of the pathological technique. the number of viable cells present in field of
In 2002, two other different regression grad- treatment, it seemed appropriate to use a patho-
ing systems were proposed by Ruo and by logic staging system that measured tumor regres-
Wheeler [6, 10]. Ruo et al. analyzed the long- sion in addition to the traditional TNM staging
term prognostic significance of selected clinico- after neoadjuvant therapy (ypTNM). Tumors
pathologic factors, including the extent of with the same ypT stage may have different
pathologic response in 69 patients with locally TRG because ypTNM staging does not differen-
advanced rectal cancer. They recorded rectal can- tiate tumors with quite different responses to
cer response as percentage histologic response, CRT. In these cases, RCRG may aid prediction
ranging from no evidence of treatment effect of prognosis.
(0%) to a complete response with no viable tumor Rodel et al. in 2005 evaluated prognostic
identified (100%) by a 6-point grading scale: significance of TRG on surgical specimens of
33 What Is the Prognostic Value of TRG? 335
Table 33.2 Dworak and Rodel TRG Table 33.3 Mandard TRG and Ryan and Vecchio
modifications
Dworak TRG Rodel TRG
Definition Score Definition Mandard Ryan Vecchio
No tumor cells (total 4 Complete regression score score score
regression) Absence of tumor cells 1 1 1
Very few (difficult to 3 Good regression Residual cancer cells 2 2
find) tumor cells in >50% of tumor mass scattered through the
fibrotic tissue fibrosis
Dominant fibrotic 2 Moderate regression Fibrosis outgrowing 3 2
changes with few tumor with fibrosis residual cancer cells
cells or groups (easy to ³25–50% of tumor Residual cancer cells 4 3 3
find) mass outgrowing fibrosis
Dominant tumor mass 1 Minor regression Absence of regressive 5
with obvious fibrosis with fibrosis <25% changes
of tumor mass
No regression 0 No regression
Complete pathologic response edition of dataset guidelines for colorectal can-
Intermediate pathologic response cer reporting. The system defined the following
Poor tumor response
categories:
(A) No residual tumor cells and/or mucus lakes
only
385 patients treated with preoperative CRT [5]. (B) Minimal residual tumors, i.e., only occa-
They defined a 5-point TRG derived from Dworak sional microscopic tumor foci, are identified
scale with some modifications (see Table 33.2). with difficulty
Rodel incorporated Dworak TRG 3 and 2 in TRG (C) No marked regression
3 and split Dworak TRG 1 in TRG 2 and 1. TRG In 2009, Bateman et al. proposed a modified
0 and 4 remained unmodified. On this basis, version of Wheeler RCRG (m-RCRG) in which
Rodel grouped TRG by a 3-grade system. They the key change was the inclusion of a more
reported that 5-year DFS after CRT and curative detailed definition of each category (Table 33.4)
resection was 86% for TRG 4 with no tumor cells [1]. In their study performed by reviewing the
(complete pathologic response), 75% for grouped rectal excision specimens from 54 patients,
TRG 2 + 3 with regression ³25% of tumor mass Bateman et al. compared the utility and reproduc-
(intermediate pathologic response), and 63% for ibility of three different TRG scoring system: the
grouped TRG 0 + 1, with regression <25% of Mandard TRG, the modified RCRG, and RCPath
tumor mass (poor tumor regression). Cancer Dataset method. They concluded that all
In 2005, Ryan et al. proposed a modified three scoring systems were usable in a diagnostic
Mandard score with a 3-point TRG in which TRG setting and all with acceptable degrees of interob-
1 grouped the Mandard TRG 1 and TRG 2, TRG server agreement. The authors favored the use of
2 was equivalent to Mandard grade 3, and TRG 3 m-RCRG for the assessment of rectal cancer
grouped the Mandard TRG 4 and TRG 5 (see specimens after neoadjuvant therapy because the
Table 33.3) [7]. In their study based on 60 patients m-RCRG system provided the optimum balance
with a mean follow-up of 22 months, the Authors between applicability and the accurate recording
emphasized that TRG 1 and 2 could be consid- of low, moderate, and high tumor regression.
ered a complete pathologic response and that the They also suggested that regression grade scoring
modified 3-point TRG had the advantage of bet- must be entirely based on the microscopic pres-
ter reproducibility, with similar prognostic ence of residual tumor, rather than including mac-
significance. roscopic features suggestive of residual tumor.
Another method of grading the degree of Finally, in 2010, Vecchio et al. examined the
tumor regression post CRT in rectal cancer was relationship between TRG and 10-year outcomes
the system proposed in 2007 by Royal College of in 502 patients with locally advanced rectal cancer
Pathologists (RCPath) included within the 2nd treated with preoperative RCT [9]. They proposed
336 F.M. Vecchio
Table 33.4 Wheeler RCRG and Bateman m-RCRG multivariate analysis, only ypN (p < 0.001) and
RCRG 1 Sterilization or only microscopic foci of TRG (p = 0.005) significantly predicted improved
adenocarcinoma remaining, with marked DFS. Moreover, TRG predicted the incidence of
fibrosis positive nodes (p < 0.0001). Vecchio et al. con-
m-RCRG 1 The macroscopic features may be varied.
cluded that, given the ability of TRG to predict
Microscopy reveals no tumor epithelium
or scattered foci of malignant epithelium those patients with N+ disease, it might be help-
comprising <5% of the overall area of ful, in combination with other clinicopathologic
abnormality. Mucin pools may be present factors, in selecting patients for a more conserva-
but do not contain malignant epithelium
tive procedure following CRT such as local exci-
RCRG 2 Marked fibrosis, but macroscopic disease
present
sion rather than radical surgery.
m-RCRG 2 The macroscopic features may be varied. Rodel et al. evaluated TRG on surgical speci-
Microscopy reveals a combination of mens of 385 patients with 5-year outcome and
viable tumor epithelium and fibrosis. concluded that complete and intermediate patho-
Malignant epithelium comprises 5–50% logic response suggested improved DFS after
of the overall area of abnormality
preoperative CRT. They found that complete
RCRG 3 Little or no fibrosis with abundant
macroscopic disease regression of the primary tumor was associated
m-RCRG 3 The macroscopic and microscopic with better control of disease in lymph nodes
features may not be significantly different (ypN positive, 10%) and a minor risk to develop
to cases in which neoadjuvant therapy has distant metastases (DFS, 86%). Intermediate
not been given. Over 50% of the area of
tumor regression was associated with intermedi-
abnormality comprises malignant
epithelium. Some fibrosis may be present ate risk of lymph node involvement (ypN posi-
but no more than that commonly seen as tive, 32%) and an intermediate prognosis (DFS,
desmoplastic stroma in cases where no 75%). Patients with tumors showing poor tumor
neoadjuvant therapy has been given
regression also had more advanced ypT catego-
ries, higher incidence of nodal involvement (ypN
a simplification of Mandard score in three grades positive, 42%), and unfavorable outcome (DFS,
(see Table 33.3): 63%). In their study, Rodel et al. did not find any
TRG 1: Complete regression with absence of significant relationship of TRG to specific pre-
tumor cells. treatment characteristics, such as the cT and cN
TRG 2: Incomplete regression with fibrosis categories, and hypothesized that tumor regres-
predominant on cancer cells. sion after preoperative CRT was a multifaceted
TRG 3: Absent or poor regression with resid- phenomenon that appeared to be associated with
ual cancer outgrowing fibrosis. smaller, less aggressive disease and may also cor-
respond to the molecular tumor profiling regulat-
ing treatment response. There is evidence that
33.2 Prognostic Significance of TRG positive lymph nodes, after preoperative CRT
indicating an aggressive potential of the malig-
Apart from the chosen method, tumor regression nant cells associated with resistance toward CRT,
after preoperative RCT has been found to have suggest an unfavorable prognosis irrespective of
prognostic significance [5, 8]. Vecchio et al. any TRG of the primary tumor [5]. In a recent
examined the relationship between TRG and out- paper, Min et al. investigated the clinical impact
come in 144 patients with rectal cancer treated of TRG after preoperative CRT for locally
with preoperative CRT and with a median follow- advanced rectal cancer especially in lymph node
up of 72 months. They quantified TRG in five negative patients [4]. They studied a group of 178
grades according to Mandard score and com- patients who had cT3–T4 tumors and examined
bined TRG 1–2 and TRG 3–5. They found that the prognostic significance of TRG in comparison
TRG was a predictor for local failure, metasta- with histopathologic staging. They found that
ses-free survival, DFS, and overall survival. By TRG was an independent prognostic factor for
33 What Is the Prognostic Value of TRG? 337
the cancer-specific survival (CSS) of the ypN0 3. Mandard AM, Dalibard F, Mandard JC et al (1994)
patients and that TRG had a stronger impact on Pathologic assessment of tumor regression after pre-
operative chemoradiotherapy of esophageal carci-
the CSS of ypN (−) patients (p = 0.002) than on noma. Cancer 73:2680–2686
that of the ypN (+) patients (p = 0.521). 4. Min BS, Kim NK, Pyo JY et al (2011) Clinical impact
An accurate prediction of CSS requires both of tumor regression grade after preoperative chemora-
information on the number of residual cancer diation for locally advanced rectal cancer: subset
analyses in lymph node negative patients. J Korean
cells (by TRG) and on their location in rectal wall Soc Coloproctol 27:31–40
and perirectal tissue (by ypT stage). Therefore, 5. Rodel C, Martus P, Papadoupolos T et al (2005)
TRG determination is the logical complement to Prognostic significance of tumor regression grade
traditional ypTNM staging when considering after preoperative chemoradiotherapy for rectal can-
cer. J Clin Oncol 23:8688–8696
patients for further adjuvant therapy. As TRG 6. Ruo L, Tickoo S, Klimstra DS et al (2002) Long-term
defines the amount of residual cancer cells after prognostic significance of extent of rectal cancer
preoperative CRT, further investigations are man- response to preoperative radiation and chemotherapy.
datory in order to define the quality of neoplastic Ann Surg 236:75–81
7. Ryan R, Gibbons D, Hyland JMP et al (2005)
cells and their behavior, especially in patients Pathologic response following long-course neoadju-
without lymph node metastasis. Identification of vant chemoradiotherapy for locally advanced rectal
factors indicating a more aggressive phenotype cancer. Histopathology 47:141–146
and/or resistance toward CRT may contribute to 8. Vecchio FM, Valentini V, Minsky BD et al (2005) The
relationship of pathologic tumor regression grade
improve the prognostic value of TRG and to (TRG) and outcomes after preoperative therapy in rec-
allow tailoring of treatment. tal cancer. Int J Radiat Oncol Biol Phys 62:752–760
9. Vecchio FM, Barba MC, Gambacorta MA et al (2010)
Pathologic tumor regression grade and 10-year out-
References comes in 502 patients with rectal cancer treated with
preoperative therapy. Mod Pathol 23(Suppl):171
10. Wheeler JM, Warren BF, Mortensen NJ et al (2002)
1. Bateman AC, Jaynes E, Bateman AR (2009) Rectal
Quantification of histologic regression of rectal cancer
cancer staging post neoadjuvant therapy – how should
after irradiation. Dis Colon Rectum 45:1051–1056
the changes be assessed? Histopathology 54:713–721
2. Dworak O, Keilholz L, Hoffmann A (1997) Pathologic
features of rectal cancer after preoperative radiochemo-
therapy. Int J Colorectal Dis 12:19–23
Part VIII
Q&As on Multidisciplinary Team Management
What Are the Recommendations
to Ensure a Successful 34
Multidisciplinary Team
in Rectal Cancer?*
34.1 Introduction
adherence to evidence-based guidelines, better best practice guidelines [12]. Hence, preparation
staging at diagnosis and improved treatments. costs alone come to around £50 million per annum,
In the UK, multidisciplinary team-working is and attendance time will cost a similar amount.
associated with improved 5-year survival in col- Multidisciplinary teams also require good and
orectal cancer [9]. The presence of microscopic timely communication between primary, second-
tumour cells within 1 ml of the circumferential ary and tertiary care; good data collection for the
surgical resection margin (CRM) in the patho- benefit of the individual patient, audit and
logical specimen post surgery is the endpoint research; encouragement of recruitment into clin-
most strongly associated with local recurrence in ical trials; assurance that good practice guidelines
rectal cancer and doubles the risk of developing are adhered to; optimising the use of resources;
distant metastases. Improvements in surgical and hopefully improving the working lives of
technique have dramatically altered the risks of a staff. Hence, MDT meetings pose difficulty for
positive CRM [10]. An increased efficacy for more rural and remote areas particularly when
preoperative CRT followed by surgery after a specialist centres offer regional services – which
delay of 6 weeks to allow downstaging over has driven the use of teleconferencing.
SCPRT and immediate surgery has already been
demonstrated in a randomised trial, where the
involvement of the CRM was reduced from 13% 34.4 What Are the Primary
to 4% [11]. In the study by Burton et al., the Functions of an MDT?
authors showed that in one network, 16/66 (26%)
of patients not discussed by the MDT had a posi- The primary functions of an MDT are generally
tive CRM (£1 mm). In contrast, those discussed agreed to be:
in an MDT preoperatively achieved a negative 1. To discuss all new and recurrent active col-
CRM (>1 mm) in 113/116, i.e. 96% of cases. orectal cancer patients
2. To act as a specialist forum to discuss complex
cases and make clinical decisions
34.3 What Are the Challenges 3. To act as a specialist forum to integrate psy-
Facing MDTs? chosocial, emotional, sexual and financial
issues that may affect the patients
There is wide variation in the knowledge, skills 4. To register patients on relevant cancer regis-
and perspectives of members of multidisciplinary tries and databases
teams – and in particular the chair or MDT lead. 5. To encourage recruitment into relevant and
Multidisciplinary team-working also highlights available clinical trials
the paradox that an evidence base is mandated for 6. To improve practical techniques (imaging,
individual clinical decisions, but not for overall surgical, chemotherapeutic, radiotherapeutic
organisational decisions. In addition, there are and pathological) through review and positive
substantial constraints in terms of time and feedback
resources for a large and varied number of health- 7. To support clinicians in hard-pressed
care professionals (surgeons, physicians, radiation circumstances
and medical oncologists, radiologists, patholo- 8. To promote optimal medical management and
gists, dieticians, clinical nurse specialists and pal- care that is both up-to-date and appropriate
liative care specialists) who are required to attend
such additional meetings to discuss cancer care
and multidisciplinary forum. MDT meetings use 34.5 What Are the Markers
resources. For the 174 colorectal MDTs in the of a Successful MDT?
UK, attendance involves over 100,000 person-
hours each year. In addition, preparation time for There is no such thing as a perfect MDT.
radiologists may take 2 h and pathologists 2.4 h However, there are several markers that can be
prior to MDT meetings in line with Royal College used to gauge the success of MDTs. The
344 S. Shah et al.
‘Improving Outcomes Guidance’ (IOG) defines aspx?rid=136) [15]. The recommendations below
the composition of teams and their working are a combination of the views highlighted in this
practices (e.g. having protocols for referral and report as well as additional views.
treatment). The IOGs provide measurable stan-
dards in many settings, and adherence is assessed
using a detailed peer review process. However, 34.7 Health-Care Professionals:
analysis of data collected in the second round of The Team
peer reviews, conducted between 2004 and 2007,
which reviewed 174 colorectal MDTs, showed 34.7.1 Representation and Attendance
that there was considerable variation in MDT
functioning according to the predefined stan- It is essential that the there is representation
dards (National Cancer Peer Review Programme from members of the all relevant disciplines. In
2004–2007) [13]. The reviewers found a highly the case of rectal cancer, this includes surgeons,
committed workforce, despite acknowledged oncologists, radiologists, pathologists, clini-
gaps in the provision of services. Compliance to cal nurse specialists and MDT coordinators.
the range of expertise in the MDT, i.e. a named Although attendance should be regular, and
core membership was 88%. MDTS adhered least part of the job plan for these individuals, allow-
well with aspects of team-working that require ances should be made for absences and suit-
additional resources, expertise and time such as able cover available. There should be a regular
participating in audits, conducting patient expe- attendance register with details of arrival and
rience surveys and service improvement. This departure from meetings. Additionally, indi-
partly reflects the shortage of some core staff vidual members should strive to be present for
including oncologists [14]. We also have varia- discussion of patients in whose care they have
tion in the provision of clinical nurse specialists, been involved.
who often fail to play as important a role as in Our own colorectal MDT meets for 2.5 h
the day to day clinical setting. weekly. The personnel present includes surgeons,
Finally, the decisions made by MDTs regard- gastroenterologists, clinical oncologists, several
ing patient treatments and subsequent treatment specialist radiologists (gastrointestinal diagnos-
outcomes provide another way of measuring the tic/interventional) with different skills (MRI/CT/
level of success of an MDT. However, factors ultrasound), pathologists, clinical nurse special-
that affect the quality of clinical decisions made ists, stoma nurses, palliative care nurses, doctors
by multidisciplinary cancer teams (MDTs) are in training and MDT coordinators. Intermittently,
poorly understood and rarely investigated [7]. our dietician and anaesthetists also attend. All are
required formally to sign in their attendance.
All members of the team should be allowed to the programme to enhance understanding of how
raise their views and initiate discussions into the team members can work together to improve clini-
management of patients. In a study from Lamb cal outcomes.
et al. [16], it was felt that ‘most participants (in Currently, the National Cancer Action Team
the MDT) thought that the discussion was not (NCAT) has a training initiative in some networks for
balanced equally across groups and sometimes MDT lead to address this issue. There are now plans
not open enough’. to run workshops aimed at MDT chairs and partici-
A study of colorectal cancer teams in the UK pants to further improve performances at MDTs.
suggests there is a positive impact of multidisci-
plinary team-working on the working lives of
team members [17, 18]. Providing patient care in 34.7.4 The Meetings
multidisciplinary teams was reported as the pre-
dominant source of job satisfaction by all team It is important that meetings take place in a fixed
members [18]. An observational study of UK place and at a fixed time during core hours to
breast cancer teams also suggests team-working ensure maximal attendance. The environment
has a positive impact on the mental health of can- should be clean, quiet and of a reasonable size to
cer team members [19]. Working in teams may accommodate all team members comfortably.
be beneficial for psychological well-being and to Additionally, suitable equipment should be pres-
avoid burnout [20]. ent to view radiological images, histopathologi-
cal slides and any other test results. Access to
relevant databases should be available to ensure
34.7.3 Is There a Role for Training? prompt data entry (Figs. 34.1 and 34.2). Ideally,
these should all be set up and running prior to the
Educational initiatives should address the start of the meeting.
significant shortfalls in training multidisciplinary An important aspect that is often forgotten is
team members in the core skills required for effec- the prompt availability of IT technical support, in
tive team-working, including communication skills, the event of any malfunctioning of equipment.
team-working, handling complaints and leader-
ship. The Pelican MDT Development Programme
originally provided a national initiative which 34.7.5 Is Videoconferencing
attempted to improve clinical outcomes in col- a Good Idea?
orectal cancer by training all UK MDT colorectal
teams in best clinical practice. The Programme Effective team-working needs a culture that is
was intended to be a unique team-based residential shared within the team, mutual respect and an
training programme, attended by the whole MDT, understanding of each others’ roles. This is the
including surgeons, oncologists, radiologists, oil which lubricates the working of an MDT.
pathologists, clinical nurse specialists and MDT Remote working is necessary with some large
coordinators. The programme focussed on train- teams to accommodate different hospitals and the
ing individual professional groups in imaging, normal working practices of the individuals con-
different potential treatment modalities (chemo- cerned. However, our experience is that techno-
therapy, radiotherapy and surgery), optimising the logical delays, frequent equipment failures and
information obtained from the pathologist and the loss of normal social interactions of face-to-
supportive care. The MDT was encouraged to dis- face meetings do tend to hinder achieving a
cuss and formulate treatment plans, in response to shared team culture.
MDT review of imaging [21] and pathology [22]. It is much more difficult to pick up social cues
Similarly, the programme encouraged reflection which facilitate the activity and development of
on the clinical roles of the individual key team the functioning team [23]. Often, several people
members to emphasise a team-based culture within attempt to speak at once, and then all pause at
346 S. Shah et al.
Figs. 34.1 and 34.2 A regular weekly multidisciplinary team meeting in the UK involving pathologists, surgeons,
radiologists, gastroenterologists, clinical oncologists, colorectal clinical nurse specialists and palliative care nurses
once and finally try to speak again at the same However, newer systems, which make use of
time, which makes for a very staccato decision- wireless Internet connections and virtual servers may
making process. Interactions appear impersonal, provide a suitable solution to these problems and, in
and the group may not fully function. There is so doing, make meetings more efficient, particularly
some evidence that the exchange of information where members have to travel large distances
via virtual teams is less effective than in face- to attend meetings. There are a number of these
to-face meetings [24]. being trialled in various centres across Europe.
34 What Are the Recommendations to Ensure a Successful Multidisciplinary Team in Rectal Cancer?* 347
34.7.6 The Patients’ Perspective inclusion of patients into weekly MDTs, a list
of patients for discussion should be made avail-
Evidence for the benefit of multidisciplinary able to all those involved in advance of the
team-working from the patients’ perspective meeting. This is particularly important for radi-
may be inferred from the results of NHS patient ologists and histopathologists for whom pre-
surveys. However, patients do not attend, and meeting preparation is essential to ensure
their preferences are rarely discussed [7, 8]. The efficient discussions at the meeting itself. There
overall experience of care for cancer patients in should be a minimum set of criteria that is pre-
the UK improved between 2000 and 2004 sented regarding each patient, ideally by the
according to analysis of patient experience sur- individual team member who has made the deci-
veys undertaken by the Picker Institute (Picker sion for inclusion at the meeting. Furthermore,
Institute) [25]. Although many factors are likely any relevant imaging/pathological specimen
to have been responsible (including the impor- should be available.
tance given to patient experience in national Following the meeting, appropriate steps should
policy, stronger leadership at national and local be in place to ensure any recommendations are
levels, the provision of funding, the influence of carried out, and the patient and their GP are
charities and the power of information obtain- informed at the earliest opportunity. If appropriate,
able from the Internet), those cancers where onward referral should be made in a timely man-
team-working was at a more developed stage ner, with all the relevant information enclosed.
(breast, colorectal and lung cancer) showed more
striking improvements than urological cancers
where guidance that included providing care 34.7.8 Data Collection
within multidisciplinary teams was not published
until much later in 2002. A clear database for use in MDTs should be avail-
It is important to remember that the patient is able, which keeps a record of patient demograph-
the central figure in the MDT discussion. With this ics, clinical information as well as the discussion
in mind, it is important to have a good knowledge regarding the patient at the MDT. This is a manda-
of the patient’s comorbid status and their personal tory requirement for MDTs in the UK and provides
preferences with regard to treatment options. access, both prospectively and retrospectively, to
A study by Blazeby [5] showed that 15.1% of treat- data that can be used for research and audit. It also
ment decisions made at upper GI MDT meetings helps identify patients that may be suitable for
were not implemented, with the most common rea- ongoing trials. This process also allows for effec-
sons for this related to lack of information concern- tive follow-up of patients and their outcomes fol-
ing patients’ wishes or comorbid disease. lowing treatment (Fig. 34.3).
It is recommended that MDTs take place weekly. Following meetings, it is important to review pro-
It is important that there are clear guidelines on cesses at regular intervals and assess the deci-
what patients are suitable for discussion at MDT sions made retrospectively. This may reinforce
meetings, as well as at what stage in their diag- the decisions made and highlight the perfor-
nostic/treatment journey they should be dis- mances of individual MDTs. At the same time,
cussed. In general, any new patient with a these may highlight discordance between MDT
diagnosis of colorectal cancer, all patients with recommendations and actual treatment decisions –
a cancer resected and patients with recurrence in this case, it is important to review the available
or metastatic disease are appropriate for discus- data and assess why this discordance arose, and
sion. Following an appropriate cut-off time for try and improve on particular areas.
348 S. Shah et al.
60%
50%
40%
30%
20%
10%
0%
ae
st
gy
ng
ta
G
ea
yn
ec
lo
Lu
er
Br
ro
G
or
pp
U
ol
U
C
Fig. 34.3 Overall compliance to quality measures for MDT in peer review assessment
34.8 What Are the Next Steps? communication of these decisions) may improve
the quality and patient-centredness of decision-
There is evidence that the introduction of multidis- making by multidisciplinary teams.
ciplinary team meetings has led to more rigorous
decision-making processes and has improved out-
comes for patients with cancer as well their experi- 34.9 What Is the Future of MDT
ence of care. Yet, some teams work more effectively Working?
than others. There is also a suggestion that partici-
pation in multidisciplinary teams meetings may It is clear from the evidence presented that MDTs
increase team members’ job satisfaction. are here to stay and now make up a substantial
Randomised trials are unlikely to be able to amount of time and effort for all concerned;
examine the added value in terms of effectiveness indeed, a large proportion of peer review out-
of multidisciplinary teams because they now comes are based around MDT functionality.
form routine clinical practice. However, there is Many MDTs have core members who primarily
evidence for a wide variation in the quality of work at geographically distance sites, and hence
cancer multidisciplinary teams. Therefore, there attending every MDT they are required to is not
is a need to identify dysfunctional teams and possible. Hence, the concept of videoconferenc-
improve their performance. Hence, reliable mea- ing has gathered support. Although some research
surements of MDT functioning and the opportu- may show that this style of working may not be
nity to demonstrate the differences in outcomes effective, it is here to stay. A natural progression
for teams classified as ‘high’ or ‘low’ performers for MDTs therefore is to embrace current and
would be useful. developing technology; the majority of mobile
More formal proformas to standardise all phone companies have ‘health’ sections and all
aspects of multidisciplinary team-working are producing state-of-the-art communication
(such as reporting of diagnostic imaging, sum- portals which facilitate efficient videoconferenc-
marising patient management decisions and the ing functionality. Current technology will allow
34 What Are the Recommendations to Ensure a Successful Multidisciplinary Team in Rectal Cancer?* 349
members to not only log in from their parent sites, 3. Taflampas P, Christodoulakis M, de Bree E, Melissas
but they will be able to communicate effectively, J, Tsiftsis DD (2010) Preoperative decision making
for rectal cancer. Am J Surg 200(3):426–432
see images in higher resolution and include any 4. Augestad KM, Lindsetmo RO, Stulberg J, Reynolds
information that is part of a patient’s electronic H, Senagore A, Champagne B, Heriot AG, Leblanc F,
record. They will even be able to log in from any- Delaney CP, International Rectal Cancer Study Group
where in the world on a secure line. It may even (IRCSG) (2010) International preoperative rectal can-
cer management: staging, neoadjuvant treatment, and
be possible to ‘tap’ into another specialist MDT impact of multidisciplinary teams. World J Surg
to get their opinion in real time. The same soft- 34(11):2689–2700
ware will automatically create electronic atten- 5. Blazeby JM, Wilson L, Metcalfe C, Nicklin J, English
dance sheets, MDT records and communications R, Donovan JL (2006) Analysis of clinical decision-
making in multi-disciplinary cancer teams. Ann Oncol
to the GP, patient and other health-care individu- 17(3):457–460
als. The day of the virtual MDT is here. 6. Obias VJ, Reynolds HL (2007) Multidisciplinary
Core members of the MDT are clearly teams in the management of rectal cancer. Clin Colon
specified, but future MDTs may include individu- Rectal Surg 20(3):143–147
7. Lamb BW, Brown KF, Nagpal K, Vincent C, Green
als who are increasingly part of management JS, Sevdalis N (2011) Quality of care management
decisions such as anaesthetists and perhaps even decisions by multidisciplinary cancer teams: a sys-
patient representatives. Currently, many MDTs tematic review. Ann Surg Oncol 18(8):2116–2125, 7
include operative photographs (this in fact makes 8. Wood JJ, Metcalfe C, Paes A, Sylvester P, Durdey P,
Thomas MG et al (2008) An evaluation of treatment
up an important aspect of rectal cancer surgery), decisions at a colorectal cancer multi-disciplinary
but it may be feasible to include photos of patients team. Colorectal Dis 10(8):769–772
so that clinicians may get an idea of whether par- 9. Morris E, Haward RA, Gilthorpe MS, Craigs C,
ticular treatments may be more efficacious or Forman D (2006) The impact of the Calman-Hine
report on the processes and outcomes of care for
possible than others (e.g. laparoscopic vs. open Yorkshire’s colorectal cancer patients. Br J Cancer
surgery). 95(8):979–985
10. Birbeck KF, Macklin CP, Tiffin NJ et al (2002) Rates
of circumferential resection margin involvement vary
Competing Interests All authors declare that they have
between surgeons and predict outcomes in rectal can-
no conflict of interest.
cer surgery. Ann Surg 235:449–457
11. Bujko K, Nowacki MP, Nasierowska-Guttmejer A
et al (2004) Sphincter preservation following preop-
Conclusions
erative radiotherapy for rectal cancer: report of a ran-
Increasingly, in developed countries, cancer domized trial comparing short-term radiotherapy vs.
care is being delivered by multidisciplinary conventionally fractionated radiochemotherapy.
teams. Assessment, training and support both Radiother Oncol 72:15–24
12. Kane B, Luz S, O’Briain DS, McDermott R (2007)
for the team and the chair and modern facili- Multidisciplinary team meetings and their impact on
ties including videoconferencing, in addition workflow in radiology and pathology departments.
to tackling some of the practical barriers to BMC Med 5:15
effective team-working, will require consider- 13. National Cancer Action Team (2008) National Cancer
Peer Review Programme 2004–2007. National report:
able future investment and resources. an overview of the findings from the Second National
Round of Peer Reviews of Cancer Services in England.
National Cancer Action Team, London
14. Department of Health (2007) Cancer reform strategy.
Department of Health, London
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tics of an effective multidisciplinary team (MDT).
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Multidisciplinary cancer teams. Crucial for popula- 16 August 2011
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2. Fennell ML, Das IP, Clauser S, Petrelli N, Sainer A N (2011) Teamwork and team performance in multi-
(2010) The organization of multidisciplinary care teams: disciplinary cancer teams: development and evalua-
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17. Taylor C (2008) Improving the working lives of UK 21. Burton S, Brown G, Daniels IR, Norman AR, Mason
colorectal cancer teams: an evaluation of the Pelican B, Cunningham D (2006) MRI directed multidisci-
team-based training programme (abstract). National plinary team preoperative treatment strategy: the way
Cancer Research Institute Conference. http://www. to eliminate positive circumferential margins? Br J
ncri.org.uk/ncriconference/2008abstracts/abstracts. Cancer 94:351–357
Accessed date: 16 August 2011 22. West NP, Morris EJ, Rotimi O, Cairns A, Finan PJ,
18. Taylor C, Ramirez AJ (2009) Multidisciplinary team Quirke P (2008) Pathology grading of colon cancer
members’ views about MDT working: results from a surgical resection and its association with survival: a
survey commissioned by the National Cancer Action retrospective. Lancet Oncol 9:857–865
Team. National Cancer Action Team, London. (www. 23. Olver IN, Selva-Nayagam S (2006) Evaluation of a
ncin.org.uk/view.aspx?rid=136). Accessed date: 16 telemedicine link between Darwin and Adelaide to
August 2011 facilitate cancer management. Telemed J 6(2):213–218
19. Haward R, Amir Z, Borrill C, Dawson J, Scully J, 24. Warkentin M, Sayeed L, Hightower R (1997) Virtual
West M et al (2003) Breast cancer teams: the impact teams versus face-to-face teams: an exploratory study
of constitution, new cancer workload, and methods of of a web-based conference system. Decis Sci 28(4):
operation on their effectiveness. Br J Cancer 89(1): 975
15–22 25. Picker Institute Europe (2005) Is the NHS getting bet-
20. Catt S, Fallowfield L, Jenkins V, Langridge C, Cox A ter or worse? An in-depth look at the views of nearly
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health of members of 10 oncology multidisciplinary Institute Europe, Oxford
teams in the UK. Br J Cancer 93(10):1092–1097
What Is the Appropriate Timetable
for Tailored Follow-up? 35
Lars Påhlman
tailored follow-up is based upon how to find and should be followed. After surgery for stage II and
cure the distant metastases, taking care of local III disease, several randomised trials have tested
recurrences and screen for metachronous new the hypothesis of no or mediocre follow-up ver-
primaries in the large bowel. sus a more ambiguous follow-up. Data from
meta-analysis of all these trials indicate that fol-
low-up will increase survival but the timing is not
35.2 Who Shall Be Followed? known [1, 2]. There are programmes with follow-
up every third month or every 6 months or yearly.
The rationale for follow-up and surveillance for Only one randomised trial has addressed the tim-
metastatic disease or synchronous tumours ing of the follow-up. That is a Danish-Swedish
depends upon the health of the patient and the trial, COLOFOL, where stage II and III patients
co-morbidity. If the patients do not tolerate liver are randomised to either a follow-up after 1 and
surgery or lung surgery or is too sick to be oper- 3 years (the standard arm) or every 6 months, the
ated for a new primary, there is no real rationale first 2 years and then it is 3 years follow-up [3]. In
to follow the patient. Therefore, this has to be both arms, a final 5 years’ follow-up is required
taken into account before putting patients in the including a colonoscopy. At each scheduled fol-
follow-up programme. low-up, CT scan over the thorax and liver is rec-
The second decision making must be based ommended and also a carcinoembryonic antigen
upon the stage of the disease. Since patients with (CEA) test. If the scanning is negative but the
stage I disease rarely recur, there is no real ratio- CEA is raising, the patient has to be re-investi-
nale to follow those patients for metastatic dis- gated with other methods like PET-CT. In this
ease. However, they should be scheduled for trial, the recruitment has just been finished (Dec.
surveillance due to metachronous colonic cancer 2010) and the end point is overall survival and
or precancer lesions to the same extent as those possibility to offer curative treatment to those
with stage II and III disease (see below). with metastatic disease. In total, 2,500 patients
Subsequently, only patients with stage II and have been randomised.
III disease should be followed for distant metas- In patients with a stage IV tumour, with radi-
tases. Another group that should be followed is of cal resected metastases, it is obvious that such a
course patients who have been curatively treated tumour has a ‘metastatic capacity’, and therefore,
for stage IV disease with a radical resected pri- those patients might be scheduled to a tighter
mary as well as radically resected metastases to follow-up. However, no evidence exists, but most
the liver and/or lung. centres used to follow those patients every
6 months over a 2-year period.
cancer [4]. Although this is the only trial but a scopic follow-up too often. Data do support that,
rather large one, one can justify that colonoscopy provided a ‘clean colon’ has been performed
surveillance is not indicated more often than in perioperatively, the next colonoscopy can be
5-year periods. Therefore, those who survive the postponed to the 5-year follow-up [4].
disease with no metastatic recurrences should be The liver and lungs should preferably be
scheduled for a colonoscopy 5 years after surgery scanned with the same method as was used in the
and then every fifth year until the age of 75 [5]. preoperative scanning, giving an opportunity to
The reason why there is no use to follow the compare and evaluate the findings. There are no
patients longer is that if the bowel is clean from strong data supporting a specific method, but for
adenomas or cancers at 75 years of age, it takes at the liver, contrast-enhanced ultrasound or CT scan
least 15 years to receive other adenomas and can- is available. For the lungs, CT scan or thoracic
cers in that age group, making the follow-up after plain X-ray has been suggested. For detection of a
75 years not cost effective. local recurrence, both endoscopic evaluation and
an imaging technique could be beneficial. The
MRI is probably better than CT scan since fibrosis
35.5 Local Recurrence is better displayed on MRI. Most patients with a
local recurrence experience pain, and, therefore,
Provided a centre has an optimal performance, not if a patient has pain, he/she should automatically
more than 5% of the patients will recur locally. be scheduled for a follow-up with MRI.
Those who recur are the patients with advanced
disease and with a circumferential resection mar-
gin of less than 1 mm [6]. The problem with local 35.7 Tumour Markers
recurrences is that the majority of them are
difficult to treat after TME surgery and only a Several follow-up programmes include testing
minority is possible to resect. Therefore, it is not with tumour markers. The most common used
cost-effective to have everyone in a follow-up marker is CEA. Several series have shown that a
programme, but only patients who are fit and will rising CEA indicates a recurrence, and this
tolerate major surgery can benefit from such a increase often occurs 6 months before a recur-
programme. Probably, a good history is enough rence becomes clinically detectable [2, 8].
together with the scheduled follow-up for distant Therefore, several programmes have included
metastases. Since a local recurrence is rather rare CEA testing in-between the imaging controls,
today, only those with symptoms should be evalu- although no studies have shown any clear advan-
ated with specific imaging. The timing is not tages with such a policy regarding overall sur-
known, but with the modern treatment including vival or cancer-specific survival.
neoadjuvant radiotherapy or chemoradiotherapy
data support that some of the recurrences will be Conclusion
postponed more than 3 years [7]. Therefore, one The available evidence will not support a
could argue to follow patients at risk more after specific timetable for tailored follow-up.
the period of follow-up for distant metastases Tumour biology is probably more important
(after 3 years) including a follow-up for local than the schedule. If there is a massive spread,
recurrences at 4 years and at the 5-year follow-up it will not matter how often a patient is sched-
when the colonoscopy is done. uled for the follow-up to be done since such a
patient is not curable. Therefore, it is probably
enough to see the patient every 6 months or
35.6 Imaging Technique even less. The COLOFOL trial will answer
that question. Regarding colonoscopy, surveil-
The question is which technique should be used. lance data support that only those who have
Most recurrences do recur outside the bowel, and, survived 5 years should be scheduled for a
therefore, there is no real rationale to do endo- follow-up every fifth year to the age of 75–80.
354 L. Påhlman
Rectal
cancer Treatment
patient
Age, gender (Diffusion)-MRI Tumor staging Gastro-intestinal Biological Proliferation Structure
decision
Medical history (Perfusion)-CT Resection quality Dermatology Growth factors Hypoxia Cellular defense
Social status PET / SPECT Genitor-urinary Tumor load Metabolism
Health status Endoscopy Neuropathy Infalmmation RNA processing
Work history Bone-marrow Metabolism Cycle regulation
Lifestyle Cardiac Angiogenesis
Pain Translation
Fig. 36.1 Treatment decision for rectal cancer patients can be based on various data origins, each complementing each
other in capturing disease characterization and progression
for a typical patient diagnosed with (rectal) can- electronic health record development is most
cer. This increase in decision-making complexity focused on.
requires decision support systems (DSS) and From medical literature of the last two decades
computational support on different levels and (Fig. 36.2), a steep increase is seen of the number
steps in the treatment process [5]. of publications related to clinical decision mak-
The development of a rapid learning health- ing, database infrastructure (represented by ontol-
care system may be very effective to achieve this ogy), and data sharing. While clinical decision
support [1]. In such a system, data is routinely making was important before 1990, research
generated through patient care and clinical involving data ontology and data sharing
research and fed into an ever-growing databank increased only after 2000, in parallel with an
or set of coordinated databases. High-quality data increase of Internet availability and computa-
should be available in real time, simultaneously tional power. Cancer-related publications show a
used to improve clinical care, yield quality mea- proportional trend, except that the number of data
sures, and focus on research. This system intends ontology and data sharing publications stagnates
to improve collaborative care, patient safety, and the last couple of years.
health-care quality and efficiency and supports
medical and clinical research, training, and pub-
lic health. It would also expand the pace and 36.2 Electronic Health Record
magnitude of evidence generation. The steps to
be taken within the rapid learning health-care Currently, electronic health records (EHR) are
system are: the main focus of investments made to transform
1. Collecting data in standardized manner health care. Paper-based records are still the pre-
2. Analyzing captured data ferred method of recording patient information
3. Generating evidence through retrospective for most hospitals and practices in the Western
analyses and prospective studies countries. Medical professionals experience in
4. Implementing new insights in clinical care general that it is easier to record data in paper
5. Evaluating outcomes of changes in care records than in electronic records. Handwritten
6. Generating new hypotheses for investigation paper medical records however can be associated
Many aspects are involved in the develop- with poor legibility, which can contribute to med-
ment of these systems, like setting up and link- ical errors. Standardization in form design, abbre-
ing registries and databases, implementing an viations, and penmanship were improved to
information technology infrastructure, and improve reliability of paper medical records. But
developing applications and interfaces for the shift toward digital records is currently inevi-
patient-centered clinical decision support and table in the ongoing globalization of health care.
policy issues and implications. Each of these Paper records require significant amount of stor-
aspects will be discussed in this chapter. Some age space, and it is very time consuming and
investments have already been made, of which complicated to collate them to a single location to
36 How Should Data Be Shared and Rapid Learning Health Care Promoted? 357
500
80
300
400
60
300 200
40
200
100
100 20
0 0 0
1990 1995 2000 2005 2010 1990 1995 2000 2005 2010 1990 1995 2000 2005 2010
Year of publication Year of publication Year of publication
Fig. 36.2 Number of publications over the last two decades related to clinical decision making, data ontology, and data
sharing. Overall and cancer-related publications are reported
be reviewed by a health-care provider. Related records is the first and most crucial requisite to
copying, faxing, and transporting costs are achieve this. It becomes however more challeng-
required for multiple institutional evaluations. ing when data is shared among institutes on a
EHRs on the other hand have increased porta- regional, national, and international level. Data
bility and accessibility and can be instantly updated warehouses and connected medical software have
(within certain legal limitations). Furthermore, it to “understand” what the exchanged data means in
is possible to exchange records between different order to process it. These machine-machine inter-
EHR systems, and data can be used anonymously actions seem straightforward to humans because
for statistical reporting for quality improvement, our brain is continuously and unconsciously pro-
resource management, and public health commu- cessing information in such a manner, but they are
nicable disease surveillance. However, the down- not. What may give insight is the process of
side of the improved accessibility of electronic knowledge generation in decision making
records is that unauthorized persons may be able (Fig. 36.3). This process describes the conversion
to access sensitive medical data. This concern of data to information by putting it in context, gen-
about security is the main reason why resistance is erating knowledge by making sense of the infor-
shown to their widespread adoption. mation, and comparing all the knowledge in the
In current developed EHRs, the quality of data field to find the best path to take in the decision.
is still a concern. For example, issues related to For example, if for a rectal cancer patient
data accuracy, completeness, and comparability cT = 3 is measured (data), one has to know that cT
must be addressed before routine EHR-based means clinical tumor stage, which is part of the
quality of care measurement can be done with TNM classification system, and is measured by
confidence [2]. It is expected that if system capac- imaging and has a value range of 0–4 (informa-
ity grows, users become more comfortable with tion). Subsequently, a physician knows that this
new health IT systems, and if continuous quality information means that the patient has an
improvement principles are applied to the EHR- extended tumor without invasion of any sur-
based data collection-storage-retrieval process, rounding organs but has poorer outcome than
the quality of data in EHRs will improve. lower staged tumors (knowledge). From litera-
ture, it is known that this kind of patients have the
best outcome when receiving long-course chemo-
36.3 Data Sharing radiotherapy (options), thus the patient will
receive this treatment (action).
Standardization of data definition and handling Machines however are only able to deal with
within hospitals and institutes is very important. data and generate information by using terminol-
As stated, proper development of electronic health ogies, definitions, and ontologies. An ontology is
358 R. van Stiphout et al.
OPTIONS Execution
lteration ACTIONS
difference in outcome. In model development, • Binary outcome: two outcome labels, like for
this is not common since there is usually a example treatment response or no response.
restricted amount of suited data available. It is Methods: logistic regression, support vector
more important to increase the ratio between machines.
patients and features to avoid overfitting. This • Ordinal outcome: three or more outcome val-
occurs when a statistical model describes random ues, like for example toxicity grading.
error or noise instead of the underlying relation- Methods: Naïve Bayes, k-means clustering,
ship because the model is too complex. There are Bayesian nets, decision trees. These methods
no strict guidelines for this ratio because of the can also be applied in binary outcome
high variety in data heterogeneity, but as a rule of prediction.
thumb, 5–10 patients per feature are minimally • Time-to-event: follow-up outcomes like local
required. If increasing the number of patients is recurrence status or overall survival with cor-
not possible, reducing the number of features is responding time-to-event. Methods: Cox pro-
necessary. The best method for feature reduction portional hazards (PH) model, Fine and Gray
is selection based on knowledge from literature model (competing risks).
and medical expertise.
The quality of the data may also affect the 36.4.1.3 Performance Evaluation
accuracy of the models. After collection, one may Evaluation of the performance of the model is
be able to deal with wrongly entered data or miss- essential when selecting important features and
ing data. Typos in data are usually found with comparing classification methods. When a pre-
outlier detection, either without prior knowledge diction model is developed, reporting the accu-
or with prelabeled data (normal or abnormal). racy of the model is required for the acceptance
Usually, normal value ranges of prognostic fac- of the model in the target community. In the
tors are known from literature. There are many simplest case of two outcomes, performance is
methods to deal with missing data, but they usually given as sensitivity, i.e., proportion of
mainly involve: actual positive labels which are correctly
• Imputation: missing values are substituted by identified as such, and specificity, i.e., the pro-
the most likely value, calculated by, for exam- portion of negatives which are correctly
ple, the mean or expected maximization identified. When however the discrimination
algorithm. threshold for the classifier is varied, a spectrum
• Partial deletion: patients with too many miss- of sensitivities and specificities is generated.
ing data will be excluded from the analysis. The receiver operating characteristic (ROC)
• Full analysis: the classification method is able curve is the plot of sensitivity vs. 1-specificity.
to deal with missing values. Assumptions and The ROC curve allows selection of the optimal
distortions in the data can be avoided. models because there is always a trade-off
between sensitivity and specificity, and one
36.4.1.2 Model Types might be more important than the other for
In traditional statistics, there is a subset of meth- specific outcomes (Fig. 36.4). A more robust
ods which are used most frequently for cancer- measure for performance is the area-under-the-
related studies. In general, alternative methods curve (AUC) of the ROC curve. A value of 1
are not easily accepted in the medical commu- corresponds to perfect prediction, while an AUC
nity, as for example, methods from machine of 0.5 means random prediction. For time-to-
learning. The method of choice to predict out- event–related data, an equivalent of the AUC,
come is dependent on the type of input and out- the c-statistic, has to be used to deal with cen-
put data. Exploratory modeling studies are sored data.
required to find the optimal model for the avail- It is very important to calculate the performance
able data. When distinguishing outcome types, of the model on new data, which was not used in
the following examples can be considered: the training process to guarantee robustness of the
36 How Should Data Be Shared and Rapid Learning Health Care Promoted? 361
Predicted outcome 1
positive negative
0.9
positive
(TP) (FN)
0.7
0.6
Sensitivity
negative
0.5
False positive True negative
(FP) (TP)
0.4
0.3
TP 0.2
Sensitivity = TP + FN Random performance (AUC = 0.50)
0.1 Moderate performance (AUC = 0.70)
TN Good performance (AUC = 0.85)
Specificity = TN + FP 0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
1-specificity
Fig. 36.4 Explanation of the confusion matrix (left) definitions in the confusion matrix. By using different
showing the definitions of patient numbers when compar- thresholds in the model, a range of sensitivities and
ing predicted with actual outcomes (positive vs. negative). specificities result in the ROC curve (right)
Sensitivity and specificity are calculated using the
model. There are several options available to do biased accuracy because the validation set is
this validation step: independent.
• Random and temporal split: the data is split
into two sets, one for training and one for vali-
dation. Usually, 70–90% of the data is used for 36.4.2 Current Models
training and 10–30% for validation. This split
can be done randomly or based on patient’s For rectal cancer, not many multivariable models
intake date (temporal). are available in literature. An example of a pre-
• Cross-validation: involves partitioning the diction model for follow-up outcome for locally
data into complementary subsets, train the advanced rectal cancer was recently published
model on one subset and validating the analy- [8]. In this study, four European trials (N = 2,242)
sis on the other subset. To reduce variability, were used to train a Cox PH model to predict
multiple rounds of cross-validation are per- local recurrences, distant metastases, and overall
formed using different partitions, and the vali- survival based on clinical and pathological fea-
dation results are averaged over the rounds. tures. The model was externally validation by
Usually five- or ten-fold cross-validation is another European trial (N = 553). The prediction
performed. Leave-one-out (LOO) cross-vali- models were converted to nomograms for easy
dation is the extreme case in which each round and visual interpretation [4]. The prediction
one patient is the validation dataset. This LOO model performed well on the external dataset
method is typically used when dealing with with c-statistics around 0.7. Other examples of
small amounts of data. successful multivariable models have been pub-
• External validation: comparable data from lished [3, 9]. The upcoming trend of public shared
another institute or another trial is used for data also results in published models based on
validation. This method provides least public repositories [7] (Fig. 36.5).
362 R. van Stiphout et al.
Score
−10 −8 −6 −4 −2 0 2 4 6 8 10
pT-stage
0 1 2 3 4
pN-stage
0 1 2
cT
1+2 3 4
Age [years]
25 35 45 55 65 75 85
Adjuvant chemo
Yes No
Surgery procedure
LAR APR
Radiotherapy dose [Gy]
>45 45 <45
Sex
Female Male
Sum of scores
−20 −10 0 10 20 30
Low Medium High
Probability of death
5 10 20 30 40 50 60 70 80 90 95
within 5 years [%]
0.7 0.7
0.67
0.6 0.6 0.62
0.59 0.57
0.5 0.5
0.4 0.4
0.4
0.3 0.3
0.2 0.2
Low risk: N = 261 Low risk: N = 50
0.1 Medium risk: N = 669 0.1 Medium risk: N = 160
High risk: N = 1312 High risk: N = 343
0 0
0 20 40 60 80 100 120 0 20 40 60 80 100 120
Time from randomization [months] Time from randomization [months]
Fig. 36.5 Example of a prediction model for rectal can- bility for death within 5 years (bottom scale). The Kaplan-
cer: nomogram to predict overall survival for locally Meier curves show for both the training and the validation
advanced rectal cancer. In the nomogram, the predictor datasets what the overall survival is for the three risk
values for a single patient correspond to a score (upper groups provided by the nomogram
scale). The sum of all the scores corresponds to a proba-
Memorial Sloan-Kettering Cancer Center has pre- decision making and care delivery will be
diction tools for different cancer types (http:// increased. Patients are already using the Internet
www.mskcc.org/mskcc/html/5794.cfm). to obtain information about the cancer and treat-
ments, investigate providers and institutions,
and network with other patients. Social net-
36.5 Toward Rapid Learning Health- works can accelerate patient’s access to relevant
Care System information, disseminate clinical trial informa-
tion, expedite recruitment to trials, and thus fos-
As already described in the previous sections, ter research opportunities and data collection
developing a rapid learning health-care system from within patient communities.
requires transformation of IT infrastructure, stan- Some critical hurdles might be encountered
dardization of electronic health records, and seman- while implementing the system. Adding new data
tic interoperability between data sharing systems. collection tasks to the already packed clinicians’
Furthermore, development of accurate prediction schedules may be unrealistic and/or may result in
models and proper knowledge dissemination are poor quality of data. The shift of perspective from
essential for computational clinical decision sup- current care to efforts for future care may be the
port. Linking data systems to regional and national hardest part.
registry-based administrative data also allows for In summary, while research and new discov-
immediate case acquisition and real-time tracking ery are important, the focus needs to be on design-
of care. Technical changes are however not ing new national data policies and HIT systems,
sufficient for a successful implementation of the ensure data interoperability, creating a culture of
system. First of all, several cultural changes should sharing with simultaneous respect for patient pri-
be induced: vacy, and developing methods to make sense of
• Commitment from all levels within and across information and present it to its end users. This
organizations should ultimately lead to the concept of “rapid
• Community participation for infrastructure learning health care.”
development
• Persuade stakeholders to open up information
silos
References
• Federal coordination of intellectual capital
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Nomograms for predicting local recurrence, distant
Index
R
N Radiotherapy treatment technique
Nodal metastases, 45, 73–75, 157, 166, 298, 314 benefits of IMRT, 132
Nodal staging, 36, 73–75, 157, 160, 322 correcting shape variation, 141–142
IGRT, 129–145
patient orientation and belly board use, 136
P planning target volume margins, 139–141
Pathology possibility of dose escalation, 143–145
APR grading, 311–312 prerequisites for IMRT, 132–134
circumferential resection margin involvement, to reduce irradiated small bowel volume, 134–138
310–311 reduction of CTV, 136–138
correct procedure for handling the specimen, set-up errors, 133, 138, 141, 142
305–316 target volume shape variation, 138–139
direct tumour spread and pT stage, 309–310 Rapid learning health, 355–363
histological typing and grading, 309 Rectal function, 5–6
key features in the pathology report, 308–316
local peritoneal involvement, 312
lymph node metastases and pN stage, 314–315 S
mesorectal grade, 309, 311, 312 Surgery
prognostic value of (y)pN, 319–325 APR grading, 311–312
prognostic value of (y)pT, 319–325 diverting stoma, 257–259
prognostic value of TRG, 333–337 extended resections, 275–287
specimen after neoadjuvant radiotherapy, 315–316 extralevator abdominoperineal excision,
vascular invasion, 308–315, 323, 324, 328 261–271, 312
Pathophysiology, 6–7 laparoscopic, 30, 186, 240, 241, 245, 249–255,
Positron emission tomography-computed tomography 267, 293, 298, 349
(PET-CT) nerve-sparing surgery, 233–245
early response evaluation FDG PET-CT, 89 quality of surgery, 177, 229–231, 261, 262, 265,
presurgical FDG PET-CT, 89–91 269, 270, 306, 316, 329, 330
pretreatment FDG PET-CT, 89 surgical procedure avoidance, 291–300
Prediction applications, 359–363
Preoperative long-course chemoradiotherapy
acute and late toxicity of SCPRT and CRT, 111 T
adjuvant chemotherapy, 106, 108 Treatment strategy
biologic targeted agents, 114 cM1, non-synchronous, 15
clinical trials, 109, 113, 114 cM1, resectable synchronous metastases, 14
combined EGFR and VEGF, 188 cM1, unresectable synchronous metastases, 14
Index 367