CE: R.R.

; ANNSURG-D-17-01636; Total nos of Pages: 13;

ANNSURG-D-17-01636

META-ANALYSIS

Oncological and Survival Outcomes in Watch and Wait Patients

With a Clinical Complete Response After Neoadjuvant
Chemoradiotherapy for Rectal Cancer
A Systematic Review and Pooled Analysis
Mit Dattani, FRCS,  Richard J. Heald, FRCS,  Ghaleb Goussous, FRCS,y Jack Broadhurst, FRCS,z
Guilherme P. São Julião, MD,§ Angelita Habr-Gama, MD,§ Rodrigo Oliva Perez, PhD,§
and Brendan J. Moran, FRCSIz

Objective: The aim of this study was to evaluate the oncological and survival
outcomes of a Watch and Wait policy in rectal cancer after a clinical complete
S urgical resection based on the principles of total mesorectal
excision (TME) is the mainstay of curative treatment for resect-
able rectal cancer,1 combined with neoadjuvant chemoradiotherapy
response (cCR) following neoadjuvant chemoradiotherapy.
(nCRT) in selected cases. However, resectional colorectal surgery
Background: The detection of a cCR after neoadjuvant treatment may
has significant morbidity2 and a 90-day mortality of approximately
facilitate a nonoperative approach in selected patients. However, the long-
4%,3 which is unsurprisingly higher in an increasingly elderly patient
term safety of this strategy remains to be validated.
population with diminished physiological reserve.4 Furthermore, the
Method: This is a systematic review of the literature to determine the
combination of pelvic irradiation followed by surgery is associated
oncological outcomes in Watch and Wait patients. The primary outcome
with long-term functional impairment, which includes genito-uri-
was the cumulative rate of local regrowth, success of salvage surgery, and
nary,5 and even bowel dysfunction6 in those who have a successful
incidence of metastases. We also evaluated survival outcomes. A pooled
restorative procedure. Additionally, sphincter preservation is only
analysis of manually extracted summary statistics from individual studies was
possible in about half of the patients with a low rectal cancer,7 with
carried out using inverse variance weighting.
the remainder having to contend with the psychological morbidity,
Results: Seventeen studies comprising 692 patients were identified; inci-
and in many an impaired quality of life consequent on a permanent
dence of cCR was 22.4% [95% confidence interval (CI),14.3–31.8]. There
stoma.8
were 153 (22.1%) local regrowths, of which 96% (n ¼ 147/153) manifested in
Organ-preserving treatments are therefore an attractive option,
the first 3 years of surveillance. The 3-year cumulative risk of local regrowth
provided equivalent oncological outcomes can be achieved. Transa-
was 21.6% (95% CI, 16.0–27.8). Salvage surgery was performed in 88% of
nal endoscopic excision for rectal cancer has comparable outcomes
patients, of which 121 (93%) had a complete (R0) resection. Fifty-seven
with TME in only a select group of small pT1 tumurs with favorable
metastases (8.2%) were detected, and 35 (60%) were isolated without
histology,9 with high rates of local recurrence reported for lesions
evidence of synchronous regrowths; 3-year incidence was 6.8% (95% CI,
>pT1. Combining chemoradiotherapy with local excision, both in
4.1–10.2). The 3-year overall survival was 93.5% (95% CI, 90.2–96.2).
the neoadjuvant10 and adjuvant setting,11 has failed to reduce local
Conclusion: In rectal cancer patients with a cCR following neoadjuvant
recurrence to acceptable levels, with the added caveat that successful
chemoradiotherapy, a Watch and Wait policy appears feasible and safe.
salvage surgery may be compromised because of a breached TME
Robust surveillance with early detection of regrowths allows a high rate of
plane.12 An alternative approach has been the concept of nonopera-
successful salvage surgery, without an increase in the risk of systemic disease,
tive surveillance, or what is more commonly termed ‘‘Watch and
or adverse survival outcomes.
Wait.’’ This strategy is based on the diagnosis of a clinical complete
Keywords: Clinical complete response, nonoperative management, organ response (cCR) in which there is no evidence of detectable tumor at
preservation, rectal cancer, watch and wait clinical and radiological re-assessment following nCRT.
The concept of Watch and Wait in rectal cancer is derived from
(Ann Surg 2018;xx:xxx–xxx) the observation that following nCRT and interval surgery, an esti-
mated 16% to 24% of rectal cancer specimens have no residual tumor
cells which arguably obviates, albeit in retrospect, the need for
surgery if it was possible to predict a pathological complete response
From the Pelican Cancer Foundation, Basingstoke. Hampshire, UK; yUniversity (pCR).13,14 Habr-Gama and et al15 were the first to demonstrate that
Hospitals Birmingham NHS Foundation Trust, UK; zBasingstoke and North for carefully selected patients exhibiting criteria defined cCR and
Hampshire Hospital. Hampshire, UK; and §Angelita & Joaquim Gama Insti-
tute, São Paulo, SP, Brazil.
enrolled into a Watch and Wait programme, the 5-year disease-free
Sources of funding: M.D. is supported by a grant from the Pelican Cancer and overall survival was >90%, which was superior to that of
Foundation patients who had undergone surgery and were found to have a pCR.
The authors report no conflict of interests. These seminal results have generated considerable interest,
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
and debate, around the concept of Watch and Wait as a treatment
this article on the journal’s Web site (www.annalsofsurgery.com). choice in the multimodality management of rectal cancer. A recent
Reprints: Mit Dattani, FRCS, Pelican Cancer Foundation, The Ark, Dinwoodie review has shown the safety and feasibility of this approach,16 but
Drive, Basingstoke, Hampshire RG24 9NN, UK. several critical questions remain unanswered regarding its routine
E-mail: mit_dattani@hotmail.com.
Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
adoption in clinical practice, including those pertaining to the
ISSN: 0003-4932/16/XXXX-0001 incidence of cCR following nCRT, the cumulative risk and location
DOI: 10.1097/SLA.0000000000002761 of regrowths, the risk of systemic dissemination, and the overall

Annals of Surgery  Volume XX, Number XX, Month 2018 www.annalsofsurgery.com | 1

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: R.R.; ANNSURG-D-17-01636; Total nos of Pages: 13;
ANNSURG-D-17-01636
Dattani et al
survival of patients.17 The aim of this study was to carry out a
systematic review and a pooled analysis of outcomes following a
Watch and Wait approach, with the specific objectives of evaluating
the actuarial rates of local regrowth, the rate and success of salvage
surgery, the risk of developing metastatic disease whilst on surveil-
lance, and the impact on survival.
METHODS
Search Strategy
A review of the published literature according to the guide-
lines set out in the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) statement was performed.18 A sys-
tematic search of the Medline, EMBASE, and PubMed databases was
conducted using free-text and controlled MeSH terms relevant to
rectal cancer, cCR, and the Watch and Wait approach. Boolean
operators were used to focus the search strategy; details of the search
strategy are provided as a Supplemental Digital Content 1, http://
links.lww.com/SLA/B424. The databases were searched from the
beginning of indexing, with the last search carried out on January 13,
2017.
Study Selection and Inclusion Criteria
Full-text articles in English which reported on the oncological
and survival outcomes of rectal cancer patients with a cCR following
nCRT, and managed in a Watch and Wait surveillance programme,
were eligible for inclusion. Publications reporting on the cohort of
interest as part of a wider rectal cancer study were also eligible,
provided that the relevant outcome data were separately reported for
extraction and analysis. The reference lists of eligible articles were
screened to identify additional studies not captured in the initial
database search. Conference abstracts were excluded because of the
paucity of clinical information relevant to some of the secondary
objectives. In the event of multiple publications originating from the
same group, only the latest study report with the most up-to-date
outcome data was included. Alternatively, for studies with seemingly
distinctive patient groups, for example those treated by a different
nCRT regime or recruited over a different time period or institution,
individual authors were contacted to clarify that these were non-
overlapping studies to avoid duplication bias.
Studies reporting on <10 patients were excluded, as were
cases with recurrent rectal cancer, nonadenocarcinomas, patients
treated exclusively with endoluminal contact or brachytherapy,
and those treated without curative intent. The initial screening
process involved a review of all titles and abstracts to identify
potential eligible studies, which were then subject to a full-text
assessment before final inclusion.
Quality Assessment
The methodology of included studies was independently
assessed by 2 authors according to the Methodological Index for
Non-Randomized Studies (MINORS) tool.19 This is a validated
instrument comprising of 8 items to assess noncomparative studies,
with a maximum achievable score of 16, which reflects a high-
quality study. Additional questions for comparative studies are
available; however, these were not utilized for the purpose of
this study.
Data Extraction
Two independent reviewers extracted and compiled the data of
interest into a predesigned spread sheet. Data were matched for
accuracy and disagreements were resolved jointly, or where neces-
sary, clarification was sought with a third reviewer. In brief, the data
collected included demographic patient data; baseline tumor
2 | www.annalsofsurgery.com
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery  Volume XX, Number XX, Month 2018
characteristics and pretreatment stage; number of rectal cancer
patients undergoing nCRT and the regimen of choice; proportion
of patients achieving a cCR and the method and timing of this
assessment; frequency and modality of assessments in the surveil-
lance protocol; number and location of regrowths, time to detection,
and how regrowths were managed; number and time to occurrence
of distant metastases, and the survival data over the reported
follow-up time.
Outcome Measures and Statistical Analyses
The primary outcome was the cumulative incidence of local
regrowth and metastasis in rectal cancer patients treated under a
Watch and Wait programme. The 3-year non-regrowth-free survival
and overall survival were also evaluated. Local regrowths were
categorized as clinical, endoscopic, or radiological reappearance
of tumor on the luminal surface or within the mesorectal package,
as this represents disease that is still potentially salvageable by TME
surgery. We included all regrowths and did not differentiate between
early and late occurrences; the latter are regrowths detected after 1-
year of surveillance in patients Habr-Gama et al.15 initially defined as
having a ‘‘sustained cCR.’’ Isolated extramesorectal disease was
classified as a non-regrowth pelvic recurrence, as this has a low
potential for curative salvage. Thus, non-regrowth-free survival was
defined as the time after nCRT to death from any cause, or the
detection of metastases or non-regrowth pelvic recurrence. Success-
ful salvage surgery for tumor regrowth was documented and was
defined as a complete tumor resection with no involvement of the
resection margins. Salvage surgery was further stratified into the type
of operation to allow an estimate of sphincter preservation. Other
salvage therapies were reported separately.
The meta-analysis of time-to-event data presents a significant
challenge because of the variable duration of follow-up in individual
studies. We therefore used the method proposed by Parmar et al20 to
manually compute the number of patients at risk at each year of
follow-up, thus adjusting for the effect of censoring. Where insuffi-
cient information was available to perform this calculation, we either
contacted the authors to acquire the additional parameters, or derived
the effective number of patients at risk by extracting summary
statistics from Kaplan-Meier survival curves, as described by Tierney
et al.21 The latter method was also used to verify the number of
observed events within an annual time point, for example, the
number of local regrowths in year 1 of follow-up, wherein this
information was not explicit in the publication, or the author
not contactable.
The resulting cumulative proportions from each study were
first transformed with the Freeman-Tukey method for variance
stabilization,22 and then pooled to calculate a weighted average
using a generic inverse-variance method. An a priori decision to
use a random-effects model (DerSimonian and Laird)23 to perform
this analysis was made, owing to the highly variable effect sizes
reported in the literature with the Watch and Wait approach. A formal
assessment of heterogeneity was carried out using the I2 statistic in
which a value of 75%, or higher, is suggestive of considerable
heterogeneity.24 Funnel plot analysis with visual inspection of
symmetry was performed to detect potential publication bias, as
has been described previously.25 All analyses were performed using
MedCalc statistical software for Windows, version 17.5.5 (MedCalc
Software, Ostend, Belgium).
RESULTS
Study and Patient Characteristics
The database search identified 3098 records, and after an
initial screen of the titles and abstracts for potential inclusion, 103
ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
CE: R.R.; ANNSURG-D-17-01636; Total nos of Pages: 13;
ANNSURG-D-17-01636
Annals of Surgery  Volume XX, Number XX, Month 2018
records were subject to a detailed review of the full-text article. As
shown in Figure 1, there were 17 studies which met the eligibility
criteria and comprised of 692 patients managed in a Watch and Wait
protocol in patients with a cCR.26– 42 The Habr-Gama et al’s series
consisted of 8 publications,15,29–31,43 –46 of which 3 unique studies
with nonoverlapping patient cohorts were identified after confirma-
tion with the authors.29–31
Ten studies were retrospective cohorts, 4 were prospective,
2 comprised of a combination of patient groups, and in 1 study, the
design was not determinable (Table 1).26– 42 The methodological
quality of each included study is available in the Supplemental
Digital Content 2, http://links.lww.com/SLA/B424. The main limi-
tation was retrospective cohorts with relatively small sample sizes;
13 of 17 (76.5%) studies had <50 Watch and Wait patients. However,
the assessment and reporting of endpoints was adequate and over a
reasonable period of follow-up. The median follow-up in individual
studies ranged from 24 to 72 months; 16 of 17 (94%) and 13 of 17
(76%) studies had a median follow-up of over 2 and 3 years,
respectively. Publication bias for the various endpoints is presented
in the Supplemental Digital Content 3, http://links.lww.com/SLA/
B424.
The estimated average age of patients was 63 years with 61%
being male. Tumor height was approximately 3.9 cm above the anal
verge. In the more recent studies, pretreatment staging of the primary
tumor was predominantly by high-resolution pelvic magnetic reso-
nance imaging (MRI), although digital rectal examination (DRE) and
endorectal ultrasound were utilized in the earlier studies.26– 28 The
baseline tumor clinical T (cT) stage and cN status were not explicitly
stated in 4 studies,26,34,39,41 with the clinical T-stage distribution for
the remaining studies being as follows: cT1, 0.8%; cT2, 25.2%; cT3,
68.8%; and cT4, 5.2%. Martens et al40 grouped cT1/2 (n ¼ 22)
tumors together, and for the purpose of this calculation, we incorpo-
rated these into the cT2 category owing to the relatively fewer cT1
tumors in general. For the clinical N-stage, 49.7% of the tumors were
classified as node-positive on pretreatment staging; Seshadri et al28
did not specify this information (n ¼ 14). Patient and tumor
characteristics are shown in Table 1.
Neoadjuvant Treatment and Assessment of Tumor
Response
With the exception of 2 patients treated with 5Gy/5 and
capecitabine/oxaliplatin and subsequently found to have a cCR,40
the standard of neoadjuvant treatment was long-course chemoradio-
therapy. This typically consisted of 50- to 54-Gy dose external beam
radiotherapy, delivered in 1.8-Gy fractions. A smaller dose of 45 Gy
was administered to all patients in the study by Renehan et al,37 and
to some patients in 2 other studies.34,36 All patients received con-
current sensitizing chemotherapy, which was predominantly fluo-
ropyridimine based, either in the form of oral capecitabine, or more
commonly, intravenous fluorouracil and folinic acid. The notable
exception was a tegafur-uracil combination used by Appelt et al.33 In
this study, radiotherapy dose escalation was also used to maximize
regression, with a total dose of 66 Gy to the tumor, which in part was
achieved with a 5-Gy endorectal brachytherapy boost. Habr-Gama
et al29 used a different strategy and administered 3 additional cycles
of consolidation chemotherapy in the interval between completion of
radiotherapy and assessment of response in addition to dose escala-
tion to 54 Gy.
The time to response assessment was reported in 15 studies
and was highly variable, ranging between 3 and 24 weeks. However,
in 10 studies (66.7%), re-assessment took place at a minimum of
8 weeks after the completion of nCRT. The methodology of tumor
assessment was reported in 16 studies, of which 88% (n ¼ 14)
ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Watch and Wait Outcomes in Rectal Cancer
Records idenfied through
database search
(n=3098)
Duplicates removed
(n=767)
Titles and/or Abstracts screened
(n=2331)
Records excluded
(n=2228)
Arcles eligible for full text
review
(n=103)
Arcles idenfied
through reference
checking
(n=4)
Arcles excluded
(n=90)
Arcles included in systemac
review
(n=17)
FIGURE 1. Flow diagram of search strategy.
utilized a combination of DRE, endoluminal assessment, and radio-
logical imaging to detect a cCR; Smith et al27 did not have a
radiological component, and Nakagawa et al26 only used procto-
scopy and biopsies. A negative biopsy to define a cCR was consid-
ered mandatory in only 2 studies,26,33 and use of biopsy was not
standardized in the other studies. The definition of a cCR was also
inconsistent across the studies, but most adopted the clinical and
endoscopic criteria proposed by Habr-Gama et al,47 which only
became available in 2010. In only 1 study was the presence of a
superficial ulcer acceptable to define a cCR,33 provided that biopsies
were benign.
Following the diagnosis of a cCR, 75 of 692 (10.8%) patients
from 5 studies received adjuvant chemotherapy as part of the Watch
and Wait strategy.
Incidence of cCR
In 13 studies, the number of rectal cancer patients undergoing
nCRT was provided (n ¼ 2973) and this was used as a denominator to
calculate the pooled incidence of cCR (Fig. 2), which was estimated
at 22.4% [95% confidence interval (CI), 14.3–31.8]. In 2 multicenter
studies,37,40 the number of patients undergoing nCRT was available
for only part of the study sample (Table 1), and was taken into
account for this calculation.
Oncological Outcomes of Patients With a cCR
Managed in a Watch and Wait Protocol
The surveillance protocol, recurrence outcomes, and salvage
strategy for regrowth are summarized in Table 2. In the majority of
studies, the frequency of assessment in the first year of follow-up was
on a 1- to 3-montly basis, and less frequent in subsequent years.
The mainstay of surveillance was a DRE and endoluminal assess-
ment, apart from Seshadri et al,28 who used the latter selectively in
patients suspected of having a regrowth. In contrast, the method and
frequency of imaging were variable, with pelvic MRI being the
modality of choice.
www.annalsofsurgery.com | 3
 TABLE 1. Study Characteristics
Study Design Baseline
Article Recruitment (No. of Patients Tumor Radiotherapy Chemotherapy Additional Diagnosis Definition Proportion
(Year) Country Period Receiving nCRT) Age, y Characteristics Schedule Regimen Information of cCR of cCR Achieving cCR
z §
Dattani et al

Nakagawa et al Brazil 1993–1997 NS (n ¼ 52) 61 Stage: NS 50.4 Gy/28 5-FU/folinic acid 20 Gy Re-assessment: Complete regression of 19.2% (n ¼ 10)
26
(2002) Tumor height DL: Brachytherapy 3–4 wk after nCRT lesion and negative
3 cm (0–8 cm) to cCR tumors Mode: endoluminal biopsy
assessment with
biopsy
z
Smith et al USA 2006–2010 Retrospective 70 Stage: cT2–3, cN0/þ 50.4 Gy/28 Fluoropyridimine Adjuvant Re-assessment: No palpable or visible N/A
27
(2012) (NS) Tumor height: 6 cm based chemotherapy 4–10 wk after nCRT pathology, other than a
(0.5–12 cm) chemotherapy permissible Mode: DRE and flat scar
endoluminal
assessment  biopsy
§
Seshadri et al India 1991–2008 Retrospective (n ¼ 291) 50 Stage: cT2-3 50 Gy/28 5-FU/mitomycin C Re-assessment: No residual tumor on 11.3% (n ¼ 33)
28

4 | www.annalsofsurgery.com
(2013) Tumor height: 4–6 wk after CRT DRE or endoluminal
3 cm (0–6 cm) Mode: DRE, assessment
endoluminal
assessment (biopsy)
and CT A/P
Habr-Gama et al Brazil 2006–2010 Prospective (n ¼ 70) 60.2 Stage: cT2-4, cN0/þ 54 Gy/30 5-FU/folinic acid Consolidation Re-assessment: 10 Absence of residual 67.1% (n ¼ 47)
29
(2013) Tumor height: 3.6 cm chemotherapy wk after nCRT ulceration, mass or
(1.7 cm) with 3 cycles Mode: DRE, significant rectal wall
CE: R.R.; ANNSURG-D-17-01636; Total nos of Pages: 13;

of 5-FU/folinic endoluminal irregularity.

acid in the assessment, pelvic Radiological evidence
‘waiting period’ MRI/ERUS and/or of cCR
FDG-PET (full-
thickness local
excision for mucosal
abnormalities)
Habr-Gama et al Brazil 1991–2011 Retrospective (n ¼ 183) 58.9 Stage: cT2–4, cN0/ 50.4 Gy/28 or 5-FU/folinic acid Re-assessment: Absence of residual 49.2% (n ¼ 90)
30
(2014) þTumor height: 54 Gy/30 8 wk after nCRT ulceration, mass or
3.3 cm (2.0 cm) Mode: DRE, mucosal irregularity.
endoluminal Absence of extrarectal
ANNSURG-D-17-01636

assessment, CT A/P, disease on imaging.

pelvic MRI, and/or Whitening of mucosa
ERUS and teleangiectasia
acceptable.
Perez et al Brazil 2005–2009 Prospective (n ¼ 99) 60.3 Stage: cT2–4, cN0/þ 54 Gy/30 5-FU/folinic acid Re-assessment: 12 Absence of residual 16.2% (n ¼ 16)
31
(2014) Tumor height: 4.3 cm wk after nCRT ulceration, mass or
(1.1 cm) Mode: DRE, mucosal irregularity.

ß
endoluminal Whitening of mucosa
assessment, CT A/P, and teleangiectasia
pelvic MRI acceptable.
Smith et al USA 2001–2013 Retrospective (NS) 62.3 Stage: cT1–3, cN0/þ NS Fluoropyridimine Re-assessment: Definition of cCR not N/A
32
(2015) Tumor height: 4.1 cm based 7–24 wk after nCRT standardized
chemotherapy Mode: not
standardized, but
included DRE,
endoluminal
assessment (
biopsies), ERUS, and
axial imaging
z §
Appelt et al Denmark 2009–2013 Prospective (n ¼ 51) 67 Stage: cT2–3, cN0/þ 60 Gy/30 to tumor Tegafur-uracil Endorectal Re-assessment: No palpable tumor. 78.4% (n ¼ 40)
33
(2015) Tumor height: þ (UFT) brachytherapy 6 wk after nCRT Small, white scar in
ô
4.8 cm (4.0–5.2 cm) 50 Gy/30 to LNs boost to tumor Mode: DRE, rectal wall, or a
(5 Gy) endoluminal superficial erosion/ulcer
assessment with with benign biopsies.
biopsy, and pelvic MRI not used to assess
MRI tumor response, but
identify extramural
lymph node disease
z
Araujo et al Brazil 2002–2013 Retrospective (NS) 63.6 Stage: NS 45 Gy/25 Fluoropyridimine Adjuvant Re-assessment: NS NS N/A
34
(2015) Tumor height: NS or based chemotherapy Mode: DRE,
50.4 Gy/28 chemotherapy permissible endoluminal
assessment, and
pelvic MRI
Annals of Surgery  Volume XX, Number XX, Month 2018

2018 Wolters Kluwer Health, Inc. All rights reserved.

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 ß
TABLE 1. (Continued)
Study Design Baseline
Article Recruitment (No. of Patients Tumor Radiotherapy Chemotherapy Additional Diagnosis Definition Proportion
(Year) Country Period Receiving nCRT) Age, y Characteristics Schedule Regimen Information of cCR of cCR Achieving cCR
z
Li et al China 2006–2013 Prospective (n ¼ 900) 62 Stage: cT1–4, N0/þ 50 Gy/25 Capecitabine Re-assessment: No palpable or visible 13.6% (n ¼ 122)
35
(2015) Tumor height: 8–10 wk after nCRT lesion other than flat
3.7 cm (0–7 cm) Mode: DRE, scar. No residual tumor
endoluminal on imaging
assessment with
biopsy, pelvic MRI
and ERUS
Lai et al Taiwan 2007–2014 Retrospective (n ¼ 267) 67.6 Stage: cII/III 45 Gy/25 5-FU/folinic acid Re-assessment: Absence of residual 16.5% (n ¼ 44)
36
(2016) Tumor height DL: or 8–12 wk after nCRT mass, ulceration or
3.4 cm 54 Gy/30 Mode: DRE, mucosal irregularity.
endoluminal Whitening of mucosa
assessment, pelvic with telangiectasia.
MRI, ERUS, and CT Absence of extrarectal
pelvis residual disease on
imaging
 z §
Renehan et al U.K. 2011–2013 Retrospective/prospective 66.9 Stage: cT2-4, N0–2 45 Gy/25 Fluoropyridimine Adjuvant Re-assessment: 8 No palpable or visible 12% (n ¼ 31)
37 
(2015) 2005–2015 (n ¼ 259) Tumor height: based chemotherapy wk after nCRT residual mass,
5 cm (4–8 cm) chemotherapy permissible Mode: DRE, ulceration or stenosis
endoluminal within the rectum.
CE: R.R.; ANNSURG-D-17-01636; Total nos of Pages: 13;

assessment, and Normal radiological

pelvic MRI imaging of the
mesorectum and pelvis
§
Loria et al Argentina 2006–2015 Retrospective (NS) 57.7 Stage: cT2–4, cN0/þ 50.4 Gy/28 Fluoropyridimine Adjuvant Re-assessment: Absence of residual N/A
38 jj

2018 Wolters Kluwer Health, Inc. All rights reserved.

(2016) Tumor height: based chemotherapy 9 wk after nCRT mass or ulcer. Flat,
3 cm (0.5–10 cm) chemotherapy permissible Mode: DRE, white scar or
(oxaliplatin) endoluminal telangiectasia
assessment, and acceptable. No
Annals of Surgery  Volume XX, Number XX, Month 2018

pelvic MRI radiological evidence of

residual disease
Vaccaro et al Argentina 2005–2014 Retrospective (n ¼ 204) 71 Stage: NS 50.4 Gy/28 5-FU/folinic acid Re-assessment: Disappearance of lesion 11.3% (n ¼ 23)
39
ANNSURG-D-17-01636

(2016) Tumor height: 8–12 wk after nCRT with or without residual

4 cm (2–8 cm) Mode: DRE, scarring, whitish
endoluminal mucosa or
assessment, pelvic telangiectasia
MRI, and CT
Martens et al Netherlands 2004–2014 Retrospective/prospective 62.7 Stage: cT1–4, cN0/þ 50.4 Gy/28 Capecitabine or Adjuvant Re-assessment: No palpable tumor. No 17% (n ¼ 24)
40 y
(2016) (n ¼ 141) Tumor height: NS or capecitabine and chemotherapy 8 and 20 wk after residual tumor on MRI
5 Gy/5 oxaliplatin permissible nCRT (latter for or endoluminal
‘near complete assessment, apart from

response at 8 wk) white scar. Negative
Mode: DRE, biopsies, where
endoluminal performed
assessment
(biopsies) and
pelvic MRI
§
Kusters et al U.K. 2006–2011 Retrospective (n ¼ 94) NS Stage: NS NS NS Re-assessment: NS NS 11.7% (n ¼ 11)
41
(2016) Tumor height: Mode: NS
2 cm (0–7 cm)
z
Creavin et al Ireland 2005–2015 Retrospective (n ¼ 362) 67 Stage: cT1–3, cN0/þ 50–54 Gy/30 5-FU Re-assessment: 6–8 Visible scar only 2.8% (n ¼ 10)
42
(2017) Tumor height: NS wk after CRT
Mode: DRE,
endoluminal
assessment, pelvic
MRI, and CT C/A
18
5-FU indicates fluorouracil; cCR, clinical complete response; CT C/A/P, computed tomography of chest/abdomen/pelvis; DRE, digital rectal examination; ERUS, endorectal ultrasound scan; FDG-PET, FDG positron
emission tomography; MRI, magnetic resonance imaging; nCRT, neoadjuvant chemoradiotherapy; NS, not stated.

Prospective recruitment of 259 patients who had nCRT, with an additional 98 Watch and Wait patients enrolled from a regional cancer network registry between 2005 and 2015.
yThis is a multicenter study comprising 85 Watch and Wait patients, of which 24 patients were enrolled from 1 institution, which reported the nCRT denominator (n ¼ 141).
zData shown are median age; all other numbers are mean.
33 35
§Median (range) tumor height above the anal verge apart from Ref. and where the corresponding numbers in the parentheses are IQR; all other figures are mean (SD) height above the anal verge, apart from ‘‘DL’’ which
indicates ‘‘Dentate line.’’
ôThe combined total radiotherapy dose to the tumor, including the brachytherapy boost is 66Gy.
jjThis is the median time to re-assessment of response (range: 5–19 wk).
Patients with a ‘‘very good response’’ who did not satisfy the criteria for a cCR were offered a second re-assessment 3 months after the initial assessment at 8 wk post-nCRT.

www.annalsofsurgery.com | 5
Watch and Wait Outcomes in Rectal Cancer

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: R.R.; ANNSURG-D-17-01636; Total nos of Pages: 13;
ANNSURG-D-17-01636

Dattani et al Annals of Surgery  Volume XX, Number XX, Month 2018

Study nCRT Weight cCR proporon

denominator (%) (95% CI)

Nakagawa et al.26 52 7.2 19.2 (9.6–32.5)

Seshadri et al.27 291 8.0 11.3 (8.0–15.6)

28
Habr-Gama et al. 70 7.4 67.1 (54.9–78.0)

Habr-Gama et al.29 183 7.9 49.2 (41.8–56.7)

Perez et al.30 99 7.6 16.2 (9.6–25.0)

33
Appelt et al. 51 7.2 78.4 (64.7–88.8)
35
Li et al. 900 8.1 13.6 (11.4–16.0)

Lai et al.36 267 8.0 16.5 (12.2–21.5)

Renehan et al. 37
259 8.0 12.0 (8.3–16.6)
39
Vaccaro et al. 204 7.9 11.3 (7.3–16.4)

Martens et al.40 141 7.8 17.0 (11.2–24.3)

Kusters et al. 41
94 7.6 11.7 (6.0–20.0)
42
Creavin et al. 362 8.0 2.8 (1.3–5.0)

Total 2973 100.0 22.4 (14.3–31.8)

FIGURE 2. Pooled incidence of cCR in rectal
cancer patients after neoadjuvant chemoradio-
Heterogeneity: I2=96.8%; P<0.01 therapy. cCR indicates clinical complete
0% 20% 40% 60% 80% 100%
response; CI, confidence interval; nCRT, neo-
Incidence of cCR
adjuvant chemoradiotherapy.

Tumor regrowth was reported in 153 of 692 (22.1%) patients,
of which 147 of 153 (96.1%) were detected within the first 3 years of
follow-up. The majority of regrowths occurred in the first year (97/
157; 61.8%). The pooled 3-year cumulative rate of local regrowth
was estimated to be 21.6% (95% CI, 16.0–27.8), as shown in
Figure 3. The pooled 1- and 2-year cumulative regrowth rates were
11.7% (95% CI, 6.5–18.2) and 18.2% (95% CI, 12.6–24.5), as
summarized in Figure 4 (See Forest plot, Supplemental Digital
Content 3, http://links.lww.com/SLA/B424). From these figures, it
is clearly evident that the findings of Nakagawa et al26 are an outlier
with a significantly higher rate of regrowths (>85%) when compared
with the other studies. Besides the small sample size, the preliminary
experience of tumor re-assessment without standardization of clini-
cal, endoscopic, and radiological features may have precluded the
selection of true clinical responders. Their study also had the shortest
time interval to tumor re-assessment at 3 to 4 weeks after nCRT,
which may have been insufficient to accurately identify complete
tumor regression. This is somewhat suggested by their reliance on
mucosal biopsies to detect a cCR, which are of suboptimal negative
predictive value in this setting.48 Finally, limited information is
provided about the baseline staging of the patients included, which
has also been shown to predict for early tumor regrowth after an
apparent cCR.49
There were 4 cases of isolated extramesorectal disease, which
were reported as ‘‘regrowths’’ (Table 2). These were reclassified as
nonregrowth pelvic recurrences as per definitions established previ-
ously.16,37 Two cases were of pelvic nodal recurrence,27,29 of which 1
patient had preexisting extensive nodal disease at diagnosis.27 The
other 2 patients had a vaginal30 and a perineal skin recurrence31; all 4
recurrences were detected within 3 years of follow-up.
Systemic metastatic disease was reported in 57 of 692 (8.2%)
patients, and of these, 34 of 57 (59.6%) were isolated metastases
without evidence of synchronous local regrowth. Data pertaining to
the time of diagnosis were not obtainable in 2 studies,26,37 and these
cases (n ¼ 11) were excluded from further analyses. Of the remaining
46 cases, 36 of 46 (78.3%) of the metastases were detected in the first
3 years of surveillance, and 43 (93.5%) within 5 years. The pooled 3-
year cumulative rate of distant metastases was 6.8% (95% CI, 4.1–
10.2), as shown in Figure 5.
Salvage Surgery
The management strategy for local tumor regrowth is sum-
marized in Figure 6, outlining that for the 147 patients who were
offered and accepted treatment, salvage surgery was possible in
88.4% (n ¼ 130/147) of patients, of which 121 of 130 (93.1%) had a
complete R0 resection [79% (n ¼ 121/153) on an intention-to-treat
basis]. The rate of sphincter preservation in surgically salvaged
patients was 45.3% (n ¼ 59/130).
Survival Outcomes
Survival data for all 129 Watch and Wait patients in the study
by Renehan et al37 were not available. We could only extract the
mortality data for the patients from their matched cohort analysis (n
¼ 109). The pooled 3-year all cause mortality rate is shown in
Figure 7, which translates into an overall survival of 93.5% (95% CI,
90.2–96.2). The 3-year non-regrowth-free survival rate, which cor-
responds to alive patients without any distant metastases or extra-
mesorectal recurrence, was 89.2% (95% CI, 85.0–92.8) (see forest
plot, Supplemental Digital Content 3, http://links.lww.com/SLA/
B424).
DISCUSSION
This comprehensive systematic review is the first to document
the sequential annual risk of local regrowth, the incidence of
metastatic disease, and the survival outcomes of patients managed
by a Watch and Wait approach. The oncological safety of this non-
immediate operative management in patients with a cCR is critically

6 | www.annalsofsurgery.com ß 2018 Wolters Kluwer Health, Inc. All rights reserved.

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 ß
TABLE 2. Outcomes of Watch and Wait patients Managed in a Surveillance Protocol
Number of Surveillance Follow-up Number of Regrowths Salvage
 y
Article (Year) W þ W Patients Protocol Time, mo Relapse Data Within Mesorectum Surgery
26 st
Nakagawa et al (2002) 10 1 year: 32 (1–64) Regrowths: 8 Not known 75% (n ¼ 6)
 3 monthly: endoluminal assessment, serum CEA and Metastases: 4
Ca19.9, CXR, USS or CT A/P and colonoscopy
nd
2 year:
 3 monthly: endoluminal assessment, serum CEA and
Ca19.9, CXR, USS or CT A/P and colonoscopy
27 st
Smith at al (2012) 32 1 year: 28 (9–70) Regrowths: 6 5/6 100% (n ¼ 6)
 3 monthly: physical examination and endoluminal Metastases: 3
assessment
nd
2 year:
 4 to 6 monthly: physical examination and endoluminal
assessment
 Diagnostic imaging not standardized—MRI and ERUS not
used routinely
28 st
Seshadri et al (2013) 23 1 year: 72 (12–180) Regrowths: 7 7/7 71.4% (n ¼ 5)
 Monthly: DRE and serum CEA Metastases: 3
 Annual CT/USS abdomen
 Endoscopy for suspected recurrence
nd
2 year:
CE: R.R.; ANNSURG-D-17-01636; Total nos of Pages: 13;

 Monthly: DRE and serum CEA

 Annual CT/USS abdomen
 Endoscopy for suspected recurrence
29 st
Habr-Gama et al (2013) 47 1 year: 46 (12–91) Regrowths: 12 11/12 91.7% (n ¼ 11)

2018 Wolters Kluwer Health, Inc. All rights reserved.

 2 monthly: DRE, endoluminal assessment, serum CEA, Metastases: 8
pelvic  MRI and/or CT-PET
 6 monthly: pelvic MRI or CT-PET
Annals of Surgery  Volume XX, Number XX, Month 2018

 (full thickness local excision for mucosal abnormalities)

nd
2 year:
 3 to 4 monthly: DRE, endoluminal assessment, serum
CEA, pelvic MRI and/or CT-PET
ANNSURG-D-17-01636

 6 monthly: pelvic MRI or CT-PET

30 st
Habr-Gama et al (2014) 90 1 year: 60 (12–233) Regrowths: 28 27/28 89.3% (n ¼ 25)
 1-2 monthly: DRE, endoluminal assessment Metastases: 13 1 patient had salvage
 2-3 monthly: serum CEA brachytherapy
 6 monthly: CT C/A/P and pelvic MRI and/or ERUS
nd
2 year:
 3 monthly: DRE, endoluminal assessment, serum CEA
 Annual: CT C/A/P and pelvic MRI and/or ERUS
31 st
Perez et al (2014) 16 1 year: 64 (7–90) Regrowths: 2 1/2 50% (n ¼ 1)
 Monthly: DRE, endoluminal assessment Metastases: 0
 6 monthly: radiologic studies
nd
2 year:
 3 monthly: DRE, endoluminal assessment
 6 monthly: radiologic studies
32 st
Smith et al (2015) 18 1 year: 63 (9–161) Regrowths: 1 1/1 100% (n ¼ 1)
 3 monthly: endoluminal assessment and serum CEA Metastases: 1
nd
2 year:
 6 monthly: endoluminal assessment and serum CEA
 PET-CT or CT C/A/P at 6 months and annually thereafter.
33 st
Appelt et al (2015) 40 1 year: 24 (8–49) Regrowths: 9 9/9 100% (n ¼ 9)
 2 monthly: clinical examination and endoluminal Metastases: 3
assessment
 4 montly PET-CT
nd
2 year:
 3 monthly: clinical examination and endoluminal
assessment
 6 monthly: PET-CT
34 st
Araujo et al (2015) 42 1 year: 48 (15–114) Regrowths: 8 8/8 50% (n ¼ 4)
 3 monthly: physical examination, endoluminal assessment Metastases: 7
and serum CEA
nd
2 year:
 3 monthly: physical examination, endoluminal assessment
and serum CEA
 Radiological assessment not specified

www.annalsofsurgery.com | 7
Watch and Wait Outcomes in Rectal Cancer

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 TABLE 2. (Continued)
Number of Surveillance Follow-up Number of Regrowths Salvage
 y
Article (Year) W þ W Patients Protocol Time, mo Relapse Data Within Mesorectum Surgery
35 st
Li et al (2015) 30 1 year: 58 (19–108) Regrowths: 2 2/2 100% (n ¼ 2)
Dattani et al

 Monthly: DRE and serum CEA Metastases: 1

 3 monthly: endoluminal assessment with biopsy and ERUS
nd
2 year:
 6 monthly assessments—not specified
 6 monthly: pelvic MRI, CT A/P and CXR
36 st
Lai et al (2015) 18 1 year: 46 (14–80) Regrowths: 2 2/2 100% (n ¼ 2)
 3 monthly: clinical examination, endoluminal assessment, Metastases: 0
serum CEA
nd
2 year:
 3 monthly: clinical examination, endoluminal assessment,
serum CEA

8 | www.annalsofsurgery.com
 Pelvic MRI, ERUS, CT A/P and CXR 6 months after
nCRT and annually thereafter
37 st nd
Renehan et al (2015) 129 1 and 2 year: 33 (19–43) Regrowths: 44 44/44 72.7% (n ¼ 32)
 DRE and endoluminal assessment Metastases: 7 5 patients had salvage
 4 to 6 monthly: pelvic MRI contact radiotherapy
 6 monthly: serum CEA
At least 2 CT C/A/P in first 3 years
38 st
Loria et al (2016) 68 1 year: 38 (7–134) Regrowths: 9 9/9 100% (n ¼ 9)
CE: R.R.; ANNSURG-D-17-01636; Total nos of Pages: 13;

 3 monthly: endoluminal assessment, and pelvic MRI Metastases: 2

 6 monthly: CT C/A/P
nd
 2 year:
 3 monthly: endoluminal assessment, and pelvic MRI
6 monthly: CT C/A/P
39 st
Vaccaro et al (2016) 23 1 year: 46 (10–119) Regrowths: 4 4/4 100% (n ¼ 4)
 Monthly: DRE and endoluminal assessment Metastases: 1
nd
2 year:
 2 monthly: DRE and endoluminal assessment
 3 to 6 monthly: pelvic MRI and CT C/A/P
PET/CT included recently.
ANNSURG-D-17-01636

40 st
Martens et al (2016) 85 1 year: 41 (12–120) Regrowths: 12 12/12 91.7% (n ¼ 11)
 3 monthly: DRE, endoluminal assessment, serum CEA and Metastases: 3
pelvic MRI
 6 monthly: CT C/A/P
nd
2 year:
 3 monthly: serum CEA
 6 monthly: DRE, endoluminal assessment and pelvic MRI
CT C/A/P

ß
41
Kusters et al (2016) 11 NS 45 (17–68) Regrowths: 2 2/2 100% (n ¼ 2)
Metastases: 0
42 st
Creavin et al (2017) 10 1 year: 42 (13–74) Regrowths: 1 1/1 100% (n ¼ 1)
 3 to 6 monthly: endoluminal assessment and pelvic MRI Metastases: 1
 6 monthly: CT C/A/P
nd
2 year:
 3 to 6 monthly: endoluminal assessment and pelvic MRI
 6 monthly: CT C/A/P

5-FU indicates 5-fluorouracil; CEA, carcinoembryonic antigen; CT C/A/P, computed tomography of chest/abdomen/pelvis; CXR, chest x-ray; DRE, digital rectal examination; ERUS, endorectal ultrasound scan; FDG-PET,
18
FDG positron emission tomography; MRI, magnetic resonance imaging; NS, not stated; WþW, Watch and Wait.
 37
Data are median (range) apart from Ref. wherein numbers in parentheses are interquartile range.
yDescription of extramesorectal disease, where present, provided in the main text.
Annals of Surgery  Volume XX, Number XX, Month 2018

2018 Wolters Kluwer Health, Inc. All rights reserved.

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: R.R.; ANNSURG-D-17-01636; Total nos of Pages: 13;
ANNSURG-D-17-01636

Annals of Surgery  Volume XX, Number XX, Month 2018 Watch and Wait Outcomes in Rectal Cancer

Study Effecve Weight Regrowth rate

number of (%) (95% CI)
paents

Nakagawa et al.26 7 3.1 86.4 (44.0–99.7)

Smith et al.27 26 6.0 16.9 (5.3–36.3)

28
Seshadri et al. 21 5.5 32.0 (13.9–55.1)
29
Habr-Gama et al. 42 7.0 28.4 (15.6–44.4)

Habr-Gama et al.30 86 8.2 24.8 (16.1–35.2)

31
Perez et al. 13 4.4 6.4 (0.1–28.7)
32
Smith et al. 16 4.9 5.7 (0.1–28.7)

Appelt et al. 33
29 6.2 25.9 (11.6–45.3)

Araujo et al.34 39 6.8 20.3 (9.2–36.1)

35
Li et al. 28 6.1 7.0 (0.9–23.0)
36
Lai et al. 16 4.8 12.4 (1.5–38.0)

Renehan et al.37 115 8.6 38.0 (29.1–47.5)

38
Loria et al. 61 7.7 13.0 (5.8–23.9)
39
Vaccaro et al. 21 5.4 17.7 (4.7–40.3)

Martens et al.40 78 8.1 15.2 (8.1–25.1)

Kusters et al.41 9 3.7 20.2 (2.5–56.0)

42
Creavin et al. 8 3.5 10.5 (0.2–48.1)

Total 615 100.0 21.6 (16.0–27.8)

2
Heterogeneity: I =66.5%; P<0.01
0% 20% 40% 60% 80% 100%
FIGURE 3. Pooled 3-year incidence of local
regrowth in Watch and Wait patients. Regrowth rate

dependent on the risk of tumor regrowth, its timely detection and

successful salvage, and the possible risk of systemic dissemination,
which might stem from not having an operation at the outset. Data 147
(96.1%)
from this pooled analysis demonstrate that the 3-year cumulative risk
of local regrowth is 21.6%, with 88% of these undergoing operative 50

salvage. The majority (61.8%) present in the 1st year of surveillance, 45

96 34 17
with diminishing frequency thereafter, such that only 6 of 157 (3.8%) 40 (65.3%) (23.1%) (11.6%)
regrowths were detected beyond 3 years. These data suggest that
surveillance protocols should include close follow-up during the first 35

1 to 2 years of observation, with less frequent assessments at 3 years

Regrowth rate (%)

30
and beyond. 25
Most local regrowths were detected endoluminally, and only
20
4 of 149 (2.7%) were located exclusively outside the mesorectal
envelope, in what is termed a non-regrowth pelvic recurrence. This 15
suggests that delayed surgery would be technically feasible in the 10
vast majority of patients with regrowths, with the main preclusions
5
being extensive systemic disease, prohibitive comorbidity, and
patient refusal or surgeon preference. We would therefore advocate 0
1yr 2yr 3yr
that the most clinically relevant endpoint following the detection of a Year of follow-up
regrowth—irrespective of its location within the mesorectal enve-
lope—is successful salvage surgery, which should ideally be no more FIGURE 4. Cumulative risk of local regrowths in Watch and
extensive than was originally required to achieve a curative resection. Wait patients. The boxes at the top of the chart represent the
Although we lack data pertaining to the initially planned operation, proportion of regrowths detected annually in the first 3 years of
sphincter preservation was possible in 45% of the salvaged surveillance (Vertical lines in the box plots represent 95% CI).

ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.annalsofsurgery.com | 9

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: R.R.; ANNSURG-D-17-01636; Total nos of Pages: 13;
ANNSURG-D-17-01636

Dattani et al Annals of Surgery  Volume XX, Number XX, Month 2018

Study Effecve Weight Metastases rate

number of (%) (95% CI)
paents

Smith et al.27 26 6.5 11.2 (2.4–29.4)

28
Seshadri et al. 21 5.7 4.3 (0.1–22.6)
29
Habr-Gama et al. 42 8.3 18.9 (8.5–33.9)

Habr-Gama et al.30 86 11.3 10.1 (4.7–18.5)

Perez et al.31 13 4.2 0.0 (0.0–23.5)

32
Smith et al. 16 4.8 6.0 (0.2–29.0)

Appelt et al.33 29 6.9 10.2 (2.2–27.0)

Araujo et al.34 39 8.1 15.2 (5.8–30.2)

35
Li et al. 28 6.8 0.0 (00–12.1)
36
Lai et al. 16 4.7 0.0 (0.0–20.4)

Loria et al.38 61 10.0 3.1 (0.4–11.0)

39
Vaccaro et al. 21 5.6 2.4 (0.1–23.5)
40
Martens et al. 78 10.9 3.8 (0.2–8.7)

Kusters et al.41 9 3.3 0.0 (0.0–31.1)

Creavin et al.42 8 3.0 0.0 (0.0–34.3)

Total 493 100.0 6.8 (4.1–10.2)

Heterogeneity: I2=42.3%; P=0.04

0% 10% 20% 30%
FIGURE 5. Pooled 3-year incidence of metas-
Metastases rate
tases in Watch and Wait patients.

regrowths, which is comparable to the 49% achieved in low rectal resection clear margins reported for optimally MRI-staged low rectal
cancers of similar heights in the MERCURY II study.7 cancers.7 These findings provide supporting evidence for the opera-
In addition, the results demonstrate for the first time in a large tive safety of deferring surgery in rectal tumors exhibiting a cCR until
series of patients that a complete resection with no involved margins a regrowth is detected, although we acknowledge the absence of
(R0) was possible in 93% of the surgically salvaged regrowths, which postoperative morbidity in drawing definitive conclusions. We can
again, is comparable to the 91% pathological circumferential however extrapolate from a phase II study by Garcia-Aguilar et al,
wherein deferral of surgery at approximately 20 weeks post-nCRT
produced a similar incidence of major complications and technical
n= 153 difficulty compared with conventional surgery at 6 to 8 weeks after
nCRT.50 This was despite an increase in surgeon reported pelvic
n=6 (3.9%)
fibrosis in the delayed resection group. In contrast, the GRECCAR-6
Refused surgery study randomized patients to surgery at either 7 or 11 weeks, and
reported higher postoperative morbidity and inferior quality of TME
specimens after a longer interval post-nCRT.51
Surgery No surgery The other major oncological anxiety in adopting a Watch and
n=130 (88.4%) n=17 (11.6%)
Wait policy following a cCR is the possibility of metastases conse-
quent on waiting.52 This study reports a 3-year cumulative risk of
metastases in patients with a cCR of 6.8%, which is slightly better
Type of surgery: Clinical reason: than the 8.7% reported in a meta-analysis of >1000 operated patients
• APE: 71 (54.6%) • Metastases: 8 (47.1%)* with a pCR, at a median follow-up of >5 years.14 In the latter study,
• LAR: 39 (30.0%)
• LE: 17 (13.1%) • Co-morbidity: 3 (17.6%) >60% of the pCR patients received adjuvant systemic chemotherapy,
• Other: 3 (2.3%)† as opposed to 11% of the Watch and Wait patients in this series. The
• Contact/brachytherapy: 6 (35.3%)
R0 resecon#:
role of adjuvant chemotherapy to sustain a cCR or to mitigate the
• 93.1% (n=121) risks of distant metastases is therefore of questionable merit, and
deserves further investigation. Moreover, 60% of the metastases in
APE=Abdominoperineal excision; LAR=Low anterior resecon; LE=Local excision. †Hartmann’s procedure (n=2) this overview occurred in the absence of an associated regrowth,
and Sub-total colectomy (n=1). #Complete resecon with no pathological margin involvement. *One paent
with lung metastases also had brachytherapy for a tumor regrowth.
suggesting that many isolated distant recurrences are a delayed
manifestation of preexisting micrometastases, which remain clini-
FIGURE 6. Management and outcomes of salvage treatment cally undiagnosed, and would probably have occurred despite rectal
for regrowths. resection.

10 | www.annalsofsurgery.com ß 2018 Wolters Kluwer Health, Inc. All rights reserved.

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: R.R.; ANNSURG-D-17-01636; Total nos of Pages: 13;
ANNSURG-D-17-01636

Annals of Surgery  Volume XX, Number XX, Month 2018 Watch and Wait Outcomes in Rectal Cancer

Study Effecve Weight Mortality rate

number of (%) (95% CI)
paents
26
Nakagawa et al. 7 2.6 27.2 (3.5–68.9)
27
Smith et al. 26 5.9 3.7 (0.1–19.1)

Seshadri et al.28 21 5.3 13.7 (2.9–35.0)

Habr-Gama et al.29 42 7.2 14.2 (5.4–28.4)

30
Habr-Gama et al. 86 9.2 15.0 (8.2–24.3)
31
Perez et al. 13 4.0 14.5 (1.8–43.3)

Smith et al. 32
16 0.0 0.0 (0.0–19.7)
33
Appelt et al. 29 6.1 0.0 (0.0–11.8)
34
Araujo et al. 39 7.0 5.1 (0.6–17.2)

Li et al. 35
28 6.1 0.0 (0.0–12.1)

Lai et al.36 16 4.4 0.0 (0.0–20.4)

37
Renehan et al. 85 9.1 4.0 (1.0–10.6)
38
Loria et al. 61 8.3 1.6 (0.0–8.7)

Vaccaro et al.39 21 5.2 4.8 (0.1–23.8)

40
Martens et al. 78 8.9 3.8 (0.8–10.7)
41
Kusters et al. 9 3.2 20.2 (2.5–56.0)

Creavin et al.42 8 3.0 0.0 (0.0–34.3)

Total 585 100.0 6.5 (3.8–9.9)

Heterogeneity: I2=52.9%; P=0.01

0% 10% 20% 30% 40% 50% 60% 70%
FIGURE 7. Pooled 3-year incidence of mortal-
All cause mortality
ity from any cause in Watch and Wait patients.

Overall, the relatively low incidence of metastases in the
Watch and Wait group supports the hypothesis that patients with a
cCR have biologically indolent tumors compared with ypTNM stage
II and III low rectal cancers, which have a metastatic rate of >35%.53
The favorable prognosis of cCR tumors is reflected in our findings of
a non-regrowth-free survival of 89.2% at 3 years. The results also
demonstrate that the 3-year overall survival in patients managed in a
Watch and Wait protocol is 93.5%, which is in fact marginally
superior than the 90.1% reported in a pooled analysis of individual
patient data from 465 patients with a pCR. The biologically favorable
profile of cCR tumors, relatively low nonsalvageable regrowth and
metastatic rate, coupled with the omission of surgical mortality in
this group translates to the excellent long-term prognosis as evi-
denced by the good survival rate. This is notwithstanding the
functional benefits of avoiding surgery,33,40 although there is still
a paucity of comparative data in this regard. The implications of these
findings are highly relevant in offering Watch and Wait as a man-
agement option for rectal cancer, given that some patients are willing
to trade life expectancy for improvements in quality of life when
making decisions about treatment.54
The main limitation of this study is the heterogeneity of
included patients, which is inherent in several such meta-analyses.
One of the major criticisms of the concept of Watch and Wait has
been the variation in the radiological staging modality, baseline
tumor stage, indications for administering nCRT, and the schedules
and regimens used.55 Although MRI staging of rectal cancer
is becoming standard practice internationally, its quality varies
considerably, as does the use, volume, and dose of neoadjuvant
radiotherapy worldwide.56 – 58 It is therefore difficult to envisage a
uniform dataset of a large number of cCR patients who are compa-
rable at baseline. Despite these limitations, we have deliberately
pooled the incidence of cCR following nCRT to provide an estimate
of 22.3%, which may be a useful ballpark figure in counseling
patients undergoing neoadjuvant treatment. The definition of a cCR
has a major influence on this estimate, and the lack of a uniform set
of defining criteria is a recognized limitation of a Watch and Wait
policy. Studies adopting highly selective cCR criteria may have
ultimately resulted in lower regrowth rates, contributing in part to
the observed variation in regrowths seen across the studies. Variable
follow-up protocols may also influence oncological outcomes, with
the slightly more intensive surveillance programmes possibly
detecting regrowths at an earlier stage, and thus positively affecting
salvage and survival rates. However, most recent studies have
adopted the clinical criteria proposed by Habr-Gama et al,47 with
the exception of a Danish study in which the presence of an ulcer was
permissible.33
The current results vary slightly from a similar recent review
by Dossa et al,16 and this may be because of differences in the
inclusion criteria of studies, definition of regrowths, and methodol-
ogy used. One of the main strengths in the present study is the meta-
analyses of manually extracted summary statistics from individual
studies, which accounts for the effect of censoring. Additional
corroborative data were obtained by contacting individual study
authors and was achieved in all but 2 publications.26,37 We hypothe-
size that these results are a true and representative outcome of what
would be expected from an individual patient data analysis.

ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.annalsofsurgery.com | 11

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: R.R.; ANNSURG-D-17-01636; Total nos of Pages: 13;
ANNSURG-D-17-01636
Dattani et al
In the current era of multimodality treatment, the concept of a
cCR to facilitate nonoperative management marks a turning point in
the management of selected patients with rectal cancer. We have
demonstrated the safety, feasibility, and effectiveness of this
approach in a large series of patients. Although it is tempting to
liberalize the use of nCRT to maximize the proportion of complete
responders, patients, and rectal cancer specialists have to be mindful
of the toxicity and mortality associated with nCRT,59 taking into
account that by far the majority of patients treated by current nCRT
do not achieve a complete response. Future efforts should therefore
focus on the optimal ways to select, induce, define, and sustain
patients with rectal cancer who might obtain, or have a cCR
following neoadjuvant therapy.
ACKNOWLEDGMENTS
The authors thank the following authors of the principal
studies included in this review. They have kindly provided supple-
mentary data that has enabled us to carry out the analysis in this
study, or clarified information that was not apparent in the publica-
tion. Dr AS Ramakrishnan (Cancer Institute, WIA. Chennai, India);
Dr. EC Paulson (Philadelphia VA Medical Centre, Hospital of the
University of Pennsylvania. Philadelphia, USA); Prof. A Jakobsen
(Vejle Hospital. Vejle, Denmark); Dr. ROC Araujo (National Institute
of Cancer – INCA. Rio de Janeiro, Brazil); Dr. J Li (Affiliated
Hospital/Clinical Medical College of Chengdu University. Chengdu,
People’s Republic of China); Dr. C-L Lai (Tri-Service General
Hospital, National Defense Medical Center. Taipei, Taiwan); Dr.
FS Loria (Instituto Alexander Fleming. Buenos Aires, Argentina);
Dr. CA Vaccaro and Dr. GL Rossi (Hospital Italiano de Buenos Aires.
Buenos Aires, Argentina); Prof. GL Beets (Netherlands Cancer
Institute. Amsterdam, The Netherlands); Dr. M Kusters and Mr. C
Cunningham (Catharina Hospital, Eindhoven, The Netherlands and
Oxford University Hospitals NHS Foundation Trust. Oxford, UK);
Dr. B Creavin and Prof. DC Winter (St Vincent’s University Hospital.
Dublin, Ireland).
REFERENCES
1. Heald RJ, Ryall RD. Recurrence and survival after total mesorectal excision
for rectal cancer. Lancet (London England). 1986;1:1479–1482.
2. Fleshman J, Branda M, Sargent DJ, et al. Effect of laparoscopic-assisted
resection vs open resection of stage II or III rectal cancer on pathologic
outcomes: the ACOSOG Z6051 randomized clinical trial. JAMA. 2015;
314:1346–1355.
3. Partnership HQI. National Bowel Cancer Audit London: NHS Digital; 2016
[2:[Available at: http://content.digital.nhs.uk/bowel.
4. Manceau G, Karoui M, Werner A, et al. Comparative outcomes of rectal
cancer surgery between elderly and non-elderly patients: a systematic review.
Lancet Oncol. 2012;13:e525–e536.
5. Lange MM, van de Velde CJ. Urinary and sexual dysfunction after rectal
cancer treatment. Nat Rev Urol. 2011;8:51–57.
6. Battersby NJ, Juul T, Christensen P, et al. Predicting the risk of bowel-related
quality-of-life impairment after restorative resection for rectal cancer: a
multicenter cross-sectional study. Dis Colon Rectum. 2016;59:270–280.
7. Battersby NJ, How P, Moran B, et al. Prospective validation of a low rectal
cancer magnetic resonance imaging staging system and development of a local
recurrence risk stratification model: the MERCURY II study. Ann Surg.
2016;263:751–760.
8. Vonk-Klaassen SM, de Vocht HM, den Ouden ME, et al. Ostomy-related
problems and their impact on quality of life of colorectal cancer ostomates: a
systematic review. Qual Life Res. 2016;25:125–133.
9. Bach SP, Hill J, Monson JRT, et al. A predictive model for local recurrence
after transanal endoscopic microsurgery for rectal cancer. Br J Surg. 2009;
96:280–290.
10. Hallam S, Messenger DE, Thomas MG. A Systematic review of local excision
after neoadjuvant therapy for rectal cancer: are ypT0 tumors the limit? Dis
Colon Rectum. 2016;59:984–997.
12 | www.annalsofsurgery.com
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery  Volume XX, Number XX, Month 2018
11. Borstlap WA, Coeymans TJ, Tanis PJ, et al. Meta-analysis of oncological
outcomes after local excision of pT1-2 rectal cancer requiring adjuvant
(chemo)radiotherapy or completion surgery. Br J Surg. 2016;103:1105–1116.
12. Perez RO, Habr-Gama A, Sao Juliao GP, et al. Transanal endoscopic micro-
surgery (TEM) following neoadjuvant chemoradiation for rectal cancer: out-
comes of salvage resection for local recurrence. Ann Surg Oncol. 2016;
23:1143–1148.
13. Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patients with a
pathological complete response after chemoradiation for rectal cancer: a
pooled analysis of individual patient data. Lancet Oncol. 2010;11:835–844.
14. Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis
of outcomes following pathological complete response to neoadjuvant chemo-
radiotherapy for rectal cancer. Br J Surg. 2012;99:918–928.
15. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative
treatment for stage 0 distal rectal cancer following chemoradiation therapy:
long-term results. Ann Surg. 2004;240:711–718.
16. Dossa F, Chesney TR, Acuna SA, et al. A watch-and-wait approach for locally
advanced rectal cancer after a clinical complete response following neo-
adjuvant chemoradiation: a systematic review and meta-analysis. Lancet
Gastroenterol Hepatol. 2017;2:501–513.
17. Glynne-Jones R, Wallace M, Livingstone JIL, et al. Complete clinical
response after preoperative chemoradiation in rectal cancer: is a ‘‘Wait and
See’’ policy justified? Dis Colon Rectum. 2008;51:10–20.
18. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic
reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.
19. Slim K, Nini E, Forestier D, et al. Methodological index for non-randomized
studies (minors): development and validation of a new instrument. ANZ J Surg.
2003;73:712–716.
20. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform
meta-analyses of the published literature for survival endpoints. Stat Med.
1998;17:2815–2834.
21. Tierney JF, Stewart LA, Ghersi D, et al. Practical methods for incorporating
summary time-to-event data into meta-analysis. Trials. 2007;8:16.
22. Freeman MF, Tukey JW. Transformations related to the angular and the square
root. The Annals of Mathematical Statistics. 1950;21:607–611.
23. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials.
1986;7:177–188.
24. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic
Reviews of Interventions. Version 5.1.0 [updated March 2011]., The
Cochrane Collaboration; 2011. Available from www.handbook.cochrane.org.
Accessed July 2017.
25. Sterne JAC, Sutton AJ, Ioannidis JPA, et al. Recommendations for examining
and interpreting funnel plot asymmetry in meta-analyses of randomised
controlled trials. BMJ. 2011;343:d4002.
26. Nakagawa WT, Rossi BM, de OFF, et al. Chemoradiation instead of surgery to
treat mid and low rectal tumors: is it safe? Ann Surg Oncol. 2002;9:568–573.
27. Smith JD, Ruby JA, Goodman KA, et al. Nonoperative management of rectal
cancer with complete clinical response after neoadjuvant therapy. Ann Surg.
2012;256:965–972.
28. Ayloor Seshadri R, Kondaveeti SS, Jayanand SB, et al. Complete clinical
response to neoadjuvant chemoradiation in rectal cancers: can surgery be
avoided? Hepatogastroenterology. 2013;60:410–414.
29. Habr-Gama A, Sabbaga J, Gama-Rodrigues J, et al. Watch and wait approach
following extended neoadjuvant chemoradiation for distal rectal cancer: are
we getting closer to anal cancer management? Dis Colon Rectum. 2013;
56:1109–1117.
30. Habr-Gama A, Gama-Rodrigues J, Sao Juliao GP, et al. Local recurrence after
complete clinical response and watch and wait in rectal cancer after neo-
adjuvant chemoradiation: impact of salvage therapy on local disease control.
Int J Radiat Oncol Biol Phys. 2014;88:822–828.
31. Perez RO, Habr-Gama A, Sao Juliao GP, et al. Predicting complete response to
neoadjuvant CRT for distal rectal cancer using sequential PET/CT imaging.
Tech Coloproctol. 2014;18:699–708.
32. Smith RK, Fry RD, Mahmoud NN, et al. Surveillance after neoadjuvant
therapy in advanced rectal cancer with complete clinical response can have
comparable outcomes to total mesorectal excision. Int J Colorectal Disease.
2015;30:769–774.
33. Appelt AL, Pløen J, Harling H, et al. High-dose chemoradiotherapy and
watchful waiting for distal rectal cancer: a prospective observational study.
Lancet Oncol. 2015;16:919–927.
34. Araujo RO, Valadao M, Borges D, et al. Nonoperative management of rectal
cancer after chemoradiation opposed to resection after complete clinical
response. A comparative study. Eur J Surg Oncol. 2015;41:1456–1463.
ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
CE: R.R.; ANNSURG-D-17-01636; Total nos of Pages: 13;
ANNSURG-D-17-01636
Annals of Surgery  Volume XX, Number XX, Month 2018
35. Li J, Li L, Yang L, et al. Wait-and-see treatment strategies for rectal cancer
patients with clinical complete response after neoadjuvant chemoradiotherapy: a
systematic review and meta-analysis. Oncotarget. 2016;7:44857–44870.
36. Lai CL, Lai MJ, Wu CC, et al. Rectal cancer with complete clinical response
after neoadjuvant chemoradiotherapy, surgery, or ‘‘watch and wait’’. Int J
Colorectal Dis. 2016;31:413–419.
37. Renehan AG, Malcomson L, Emsley R, et al. Watch-and-wait approach versus
surgical resection after chemoradiotherapy for patients with rectal cancer (the
OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol.
2016;17:174–183.
38. Sanchez Loria F, Iseas S, O’Connor JM, et al. Non-surgical management of
rectal cancer. Series of 68 cases, long follow up in two leading centres in
Argentina. Dig Liver Dis. 2016;48:1372–1377.
39. Vaccaro CA, Yazyi FJ, Ojra Quintana G, et al. Locally advanced rectal cancer:
preliminary results of rectal preservation after neoadjuvant chemoradiother-
apy. Cir Esp. 2016;94:274–279.
40. Martens MH, Maas M, Heijnen LA, et al. Long-term outcome of an organ
preservation program after neoadjuvant treatment for rectal cancer. J Natl
Cancer Inst. 2016;108:pii: djw171.
41. Kusters M, Slater A, Betts M, et al. The treatment of all MRI-defined low
rectal cancers in a single expert centre over a 5-year period: is there room for
improvement? Colorectal Dis. 2016;18:O397–O404.
42. Creavin B, Ryan E, Martin ST, et al. Organ preservation with local excision or
active surveillance following chemoradiotherapy for rectal cancer. Br J
Cancer. 2017;116:169–174.
43. Habr-Gama A, Perez RO, Nadalin W, et al. Long-term results of preoperative
chemoradiation for distal rectal cancer correlation between final stage and
survival. J Gastrointest Surg. 2005;9:90–99. discussion 9-101.
44. Habr-Gama A, Perez RO, Proscurshim I, et al. Patterns of failure and survival
for nonoperative treatment of stage c0 distal rectal cancer following neo-
adjuvant chemoradiation therapy. J Gastrointest Surg. 2006;10:1319–1328.
discussion 28–9.
45. Habr-Gama A, Perez RO, Sabbaga J, et al. Increasing the rates of complete
response to neoadjuvant chemoradiotherapy for distal rectal cancer: results of
a prospective study using additional chemotherapy during the resting period.
Dis Colon Rectum. 2009;52:1927–1934.
46. Perez RO, Habr-Gama A, Gama-Rodrigues J, et al. Accuracy of positron
emission tomography/computed tomography and clinical assessment in the
detection of complete rectal tumor regression after neoadjuvant chemoradia-
tion: long-term results of a prospective trial (National Clinical Trial
00254683). Cancer. 2012;118:3501–3511.
ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Watch and Wait Outcomes in Rectal Cancer
47. Habr-Gama A, Perez RO, Wynn G, et al. Complete clinical response after
neoadjuvant chemoradiation therapy for distal rectal cancer: characterization
of clinical and endoscopic findings for standardization. Dis Colon Rectum.
2010;53:1692–1698.
48. Perez RO, Habr-Gama A, Pereira GV, et al. Role of biopsies in patients with
residual rectal cancer following neoadjuvant chemoradiation after downsiz-
ing: can they rule out persisting cancer? Colorectal Dis. 2012;14:714–720.
49. Habr-Gama A, Sao Juliao GP, Gama-Rodrigues J, et al. Baseline T classifica-
tion predicts early tumor regrowth after nonoperative management in distal
rectal cancer after extended neoadjuvant chemoradiation and initial complete
clinical response. Dis Colon Rectum. 2017;60:586–594.
50. Garcia-Aguilar J, Chow OS, Smith DD, et al. Effect of adding mFOLFOX6
after neoadjuvant chemoradiation in locally advanced rectal cancer: a multi-
centre, phase 2 trial. Lancet Oncol. 2015;16:957–966.
51. Lefevre JH, Mineur L, Kotti S, et al. Effect of interval (7 or 11 weeks) between
neoadjuvant radiochemotherapy and surgery on complete pathologic response
in rectal cancer: a multicenter, randomized, controlled trial (GRECCAR-6).
J Clin Oncol. 2016;34:3773–3780.
52. Smith JJ, Garcia-Aguilar J. Advances and challenges in treatment of locally
advanced rectal cancer. J Clin Oncol. 2015;33:1797–1808.
53. Breugom AJ, Swets M, Bosset J-F, et al. Adjuvant chemotherapy after
preoperative (chemo)radiotherapy and surgery for patients with rectal cancer:
a systematic review and meta-analysis of individual patient data. Lancet
Oncol. 2015;16:200–207.
54. Solomon MJ, Pager CK, Keshava A, et al. What do patients want? Patient
preferences and surrogate decision making in the treatment of colorectal
cancer. Dis Colon Rectum. 2003;46:1351–1357.
55. Glynne-Jones R, Hughes R. Critical appraisal of the ‘wait and see’ approach in
rectal cancer for clinical complete responders after chemoradiation. Br J Surg.
2012;99:897–909.
56. Fitzgerald TL, Zervos E, Wong JH. Patterns of pelvic radiotherapy in patients
with stage II/III rectal cancer. J Cancer Epidemiol. 2013;2013:408460.
57. Morris EJ, Finan PJ, Spencer K, et al. Wide variation in the use of radiotherapy
in the management of surgically treated rectal cancer across the english
national health service. Clin Oncol (R Coll Radiol). 2016;28:522–531.
58. van Leersum NJ, Snijders HS, Wouters MW, et al. Evaluating national practice
of preoperative radiotherapy for rectal cancer based on clinical auditing. Eur J
Surg Oncol. 2013;39:1000–1006.
59. Verseveld M, de Graaf EJ, Verhoef C, et al. Chemoradiation therapy for rectal
cancer in the distal rectum followed by organ-sparing transanal endoscopic
microsurgery (CARTS study). Br J Surg. 2015;102:853–860.
www.annalsofsurgery.com | 13