Int J Colorectal Dis
DOI 10.1007/s00384-014-1928-5
REVIEW
Advances in the management of colorectal cancer:
from biology to treatment
Shahid Ahmed & Kate Johnson & Osama Ahmed & Nayyer Iqbal
Accepted: 12 June 2014
# Springer-Verlag Berlin Heidelberg 2014
Abstract
Background Colorectal cancer (CRC) is the third most com-
mon malignant neoplasm worldwide and the fourth leading
cause of cancer-related deaths. This article reviews the epide-
miology, risk factors, pathogenesis, and prognosis of CRC
with special emphasis on advances in the management of
CRC over the past decade.
Methods A review of the published English literature was
conducted using the search engines PubMed, Medline,
EMBASE, and Google Scholar. A total of 127 relevant pub-
lications were identified for further review.
Results Most CRC are sporadic and are due to genetic insta-
bility and multiple somatic mutations. Approximately 80 % of
cancers are diagnosed at the early stage and are curable. The
pathologic stage at presentation is the most important predic-
tor of outcome after resection of early stage cancer. Surgery is
the primary treatment modality for localized CRC. Advances
in (neo)adjuvant chemotherapy and radiation have reduced
the disease recurrence and increased survival in high risk
diseases. Although recent advancements in combination che-
motherapy and target agents have increased the survival of
O. Ahmed and K. Johnson made equal contribution to this work
S. Ahmed : N. Iqbal
Saskatchewan Cancer Agency, Regina, SK, Canada
S. Ahmed : K. Johnson : O. Ahmed : N. Iqbal
Department of Medicine, University of Saskatchewan, Saskatoon,
SK, Canada
S. Ahmed
Department of Community Health and Epidemiology, University of
Saskatchewan, Saskatoon, SK, Canada
S. Ahmed (*)
Saskatoon Cancer Center, University of Saskatchewan, 20 Campus
Drive, Saskatoon, SK, Canada S7N 4H4
e-mail: shahid.ahmed@saskcancer.ca
incurable CRC, it is remarkable that only selected patients
with advanced CRC can be cured with multimodality therapy.
Conclusion Over the past decade, there has seen substantial
progress in our understanding of and in the management of
CRC.
Keywords Colorectal cancer . Colon cancer . Rectal cancer .
Management . Advances
Epidemiology
Colorectal cancer (CRC) is the third most common malignant
neoplasm worldwide and the fourth leading cause of cancer-
related deaths globally. In 2008, over 1.2 million new cases
were diagnosed and 608,700 deaths were attributed to CRC
[1, 2]. The incidence of CRC varies about 15-fold in various
geographic regions across the world. It ranges from more than
40 per 100,000 people in the United States, Australia, New
Zealand, and Western Europe to less than 5 per 100,000 in
Africa and some parts of Asia [3]. Of note, migrants from low-
risk to high-risk regions, tend to acquire CRC incidence rates
of the host country [4]. CRC is uncommon before age 40 but
the incidence rises progressively up to 3.7/1,000 per year by
the age of 80. In Western countries, the median age at diag-
nosis is 71 years [3].
Approximately one in three people who develop CRC die
of their disease. Since the 1960s, survival for CRC of all
stages has increased substantially in North America, New
Zealand, Australia, and Western Europe [1–3].
Risk factors and pathogenesis
The risk factors for CRC are both environmental and
inherited. Age is a major risk factor for sporadic CRC. The

lifetime incidence of CRC in average risk person is about 5 %;
with 90 % of cases occur in people over 50 years of age. The
other important risk factors in colorectal carcinogenesis in-
clude family history of CRC, prior CRC or polyps, inflamma-
tory bowel disease such as ulcerative colitis, obesity, tobacco
and alcohol abuse, high stress, and factors associated
with the Western diet [5–10]. Conversely, there are
several factors that lower the risk of CRC. These factors
include regular physical activity, a variety of dietary
factors, the regular use of aspirin or non-steroidal anti-
inflammatory drugs, and hormone replacement therapy
in postmenopausal women [10]. A meta-analysis of 21
studies demonstrated that people with regular physical
activity have 27 % lower (relative risk [RR], 0.73;
95 % confidence interval [CI], 0.66–0.81) risk of prox-
imal colon cancer [11]. Moreover, there is evidence that
various dietary components such as diet high in fruits
and vegetables, fibers, fish as well as vitamin B6, vitamin
D, calcium, and magnesium supplement have protective effect
on the incidence of CRC [12–17]. Diets rich in red and
processed meats and refined sugar with little fruits, vegetables,
and fiber are thought to increase the risk of CRCs. A meta-
analysis of nine case-control studies demonstrated that each
4 ng/ml (10 nmol/l) increase in pre-diagnosis serum 25-
hydroxyvitamin D concentration was associated with 6 %
reduction in CRC prevalence [18].
Cigarette smoking is a known risk factor and has been
associated with a modest increased risk of CRC, especially
with long duration or high level of exposure [19–26]. There
are more than 60 carcinogens in cigarette smoke including
tobacco specific nitrosamines, polycyclic aromatic hydrocar-
bons and aromatic amines [27]. For both incidence and mor-
tality, the association is stronger for cancer of the rectum than
colon cancer [21, 28]. A meta-analysis of 106 observational
studies estimated that the risk of CRC was higher among
smokers compared with non-smokers (RR 1.18, 95 % CI
1.11–1.25) [19]. The risk of mortality from CRC was also
high in smokers (RR 1.25, 95 % CI 1.14–1.37). The incidence
of CRC appears to be higher in former smokers than in current
smokers [19, 20].
Most CRC arise from adenomas and progress from small to
large polyps, to dysplasia and eventually to cancer [29]. The
transformation of adenoma to carcinoma, on average, takes at
least 10 years. The neoplastic changes likely result from both
inherited and acquired genetic defects. A multistep process
involving specific genetic changes is thought to drive the
transformation of normal colonic epithelium into an
invasive cancer. The risk of CRC increases with adeno-
ma size, number, and type of histology (villous adenomas
has greater risk of malignant transformation than tubular
adenomas) [30, 31].
Most CRCs are sporadic and develop due to multiple so-
matic mutations and genetic instability [29]. Approximately
Int J Colorectal Dis
20 % of CRC are associated with familial clustering [32]. The
two well-recognized inherited syndromes are (1) familial ade-
nomatous polyposis (FAP) and (2) hereditary nonpolyposis
CRC (HNPCC) also known as Lynch syndrome. FAP
results from inheritance of a single copy of a mutated
gene, APC [33, 34]. Lynch syndrome accounts for 2–4 %
of all CRC that results from germline mutation in DNA
mismatch repair (MMR) gene such as MLH-1, MSH2,
MSH6 and PMS2 [33, 35, 36]. There appear to be at least
three different molecular pathways that lead to colorectal
tumorigenesis [37]: the chromosomal instability (CIN) path-
way, the mutator-phenotype/DNA mismatch repair pathway,
and the hypermethylation phenotype hyperplastic/serrated
polyp pathway characterized by a high frequency of methyl-
ation of some CpG islands.
Diagnosis and screening
Screening is effective to reduce CRC-related mortality,
due to the fact that it is a cancer with high prevalence,
has recognized precursors, and early treatment is cura-
tive. A joint analysis of CRC incidence and death rates
in the US population, over a period of 30 years (be-
tween 1975 and 2006), has shown declines in CRC
death rates [38]. Using microsimulation modeling, the
investigators estimated that screening may account for
53 reduction in CRC mortality. Various screening tools
have been employed for early detection of CRC. These
tools can be broadly categorized to stool-based test such
as the fecal occult blood test (FOBT) or endoscopic/
radiographic examination. Their advantages and disad-
vantages are discussed in Table 1. Stool-based DNA
(sDNA) tests are useful to identify specific DNA alter-
ations that correlate with tumorigenesis. Although it is
more sensitive than FOBT for early detection of CRC
and adenomas, currently the large-scale population based
studies are lacking.
Prognostic factors
The College of American Pathologists consensus statement
has summarized the role of various biologic, genetic, molec-
ular, and other tissue-based factors in CRC (Table 2) [39].The
pathologic stage at presentation is the most important predic-
tor of outcome after resection of CRC [40] (Table 3).
According to the SEER (Surveillance, Epidemiology and
End Results) database, involving 119,363 patients with colon
cancer diagnosed between 1991 and 2000, 5-year survival
rates varied from 93 % for stage 1 disease to 44 % for stage
3 colon cancer [40].
Int J Colorectal Dis

Table 1 The available screening methods and their advantages and disadvantages

Screening methods Advantages Disadvantages

Stool-based test
Guaiac-based fecal occult blood test
(gFOBT)
Immunochemical-based fecal occult blood • Increased sensitivity without loss of
test (iFOBT) or fecal immunochemical
test (FIT)
Endoscopic and Radiologic Examination
Flexible sigmoidoscopy
Double-contrast barium enema
Computed tomographic colonography
Colonoscopy
• Non-invasive and inexpensive
specificity
• High sensitivity and specificity for distal
colon
• Can be performed with minimal bowel
preparation
• Does not require sedation
• Can be performed by non-specialist
• Visualize the entire large bowel
• Relatively safe
• Does not require sedation
• Does not risk bowel perforation
• High sensitivity and specificity
• Not require sedation
• Does not risk bowel perforation
• Highest sensitivity and specificity
• Low sensitivity for polyps
• Relatively low specificity for cancer
• Requires compliance with annual testing and colonoscopy
for positive results
• More expensive than guaiac-based tests
• Requires compliance with annual testing and colonoscopy
for positive results
• Only identify lesions in the distal 60 cm of the bowel
• Abnormal findings in the distal bowel may require
colonoscopy
• Detect one-half of large (>1 cm) polyps
• Abnormalities must be followed by colonoscopy
• Requires aggressive bowel preparation
• Positive findings require colonoscopy follow-up
• Cumulative dose of radiation may increase cancer risk
• Requires conscious sedation and a Vigorous bowel
preparation
• Risk of perforation and bleeding

With respect to rectal cancer following surgery, 5-year disease, while they are 70 % or lower for those with stage II or
survival rates are 80 % and 90 % for patients with stage I III disease.

Table 2 Various prognostic factors in early stage colorectal cancer that affect the outcome following surgery

Category 1 Category IIA Category IIB Category III Category IV

Local tumor extent Tumor grade Histologic type DNA content Tumor size
Regional nodes Circumferential (radial) Mismatch repair deficiency All other molecular markers [tumor Gross tumor
margin and tumor infiltrating suppressor genes (LOH 1p, LOH 8p; configuration
lymphocytes LOH 5q; LOH 17p), oncogenes
(K-ras; c-myc)]
Mesenteric nodules Tumor regression after 18q deletions K-ras and benefit from EGFR-targeted
neoadjuvant therapy treatments
Nodal micrometastases Tumor border Microvessel density
Vascular invasion Perineural invasion Cell surface molecules
Residual tumor Peritumoral fibrosis and inflammatory
response
Serum CEA Focal neuroendocrine differentiation
Proliferative activity

Category I — definitively proven to be of prognostic importance based upon evidence from multiple statistically robust published trials and generally
used in patient management
Category IIA — extensively studied biologically and/or clinically and shown to have prognostic value for outcome and/or predictive value for response
to therapy. These factors are of sufficient importance to be included in the pathology report, but their importance for clinical care is not yet validated in
statistically robust studies
Category IIB — shown to be promising in multiple studies; data insufficient for inclusion in Category I or IIA
Category III — not yet sufficiently studied to determine their prognostic value
Category IV — Well studied and shown to have no prognostic significance
 Int J Colorectal Dis

Table 3 TNM staging for colon

and rectal cancer (modified from Primary tumor (T) Five-year overall survival
American Joint Committee on (colon cancer)
Cancer Staging Manual, 7th ed)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
TIS Carcinoma in situ
T1 Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor invades through the muscularis propria into the
subserosa or nonperitonealized pericolic tissues
T4 Tumor directly invades other organs or perforates the
visceral peritoneum.
Regional lymph nodes (N)
Nx Regional nodes cannot be assessed
N0 No regional lymph node metastases
N1 Metastases in 1–3 regional lymph nodes
N2 Metastases in ‡4 regional lymph nodes
Distant metastases (M)
MX Presence of distant metastases cannot be assessed
M0 No distant metastases
M1 Distant metastases
Staging
Stage 0 Tis N0 M0: (carcinoma in situ)
Stage 1 T1 N0 M0, T2 N0 M0 93 %
Stage 2A T3 N0 M0 85 %
Stage 2B T4 N0 M0 72 %
Stage 3 IIIA Any T1–2, N1, M0 83 %
IIIB Any T3–4, N1 M0 64 %
IIIC Any T N2 M0 44 %
Stage 4 Any T, any N, M1 Less than 10 %

Staging and risk assessment
Patients with newly diagnosed CRC require a complete stag-
ing work up to exclude a synchronous lesion or distant me-
tastases. Tumors with distal extension to ≤15 cm (as measured
by rigid sigmoidoscopy) from the anal margin are classified as
rectal, more proximal tumors are classified as colonic cancer
[5, 7]. Typically, the rectum is located below the peritoneal
reflexion. For colon cancer, evidence does not support pre-
operative or neoadjuvant therapy, so staging is primarily
aimed at resectability of the tumor and to eliminate metastatic
disease. Staging workup for CRC includes total colonoscopy,
complete blood count, chemistry profile, carcinoembryonic
antigen (CEA) level, and baseline computed tomography
(CT) scan of chest, abdomen, and pelvis. For rectal cancer a
rigid endoscopic examination is usually performed to deter-
mine tumor location and distance from the anal verge. In
addition, endorectal ultrasound or magnetic resonance imag-
ing (MRI) is recommended for preoperative assessment of
tumor depth, lymph node status, and status of the circumfer-
ential resection margin (CRM) [41]. However, contrary to
MRI examination which is helpful for both anterior and pos-
terior rectal cancers, endorectal ultrasound is only useful for
anterior tumor to determine CRM.
Surgical management of localized colorectal cancer
Management of localized colon cancer is different from the
rectal cancer (Fig. 1). The goal of surgery is a wide resection
of the involved segment of bowel together with the removal of
its lymphatic drainage. The recommended technique is a
mesocolic excision, i.e., the removal of all lymphatic tissue
up to the central vessels. For staging (to differentiate stage II
from stage III) and therapeutic purpose (to eradicate potential
lymph node metastases), it is recommended to remove at least
12 lymph nodes [42]. Several randomized trials and meta-
analyses have demonstrated comparable recurrence rate and
survival with laparoscopic surgery compared with open
colectomy [43–45]. Therefore, laparoscopic-assisted
colectomy is preferred over open colectomy for patients with
nonobstructed, nonperforated, non-locally advanced colon
Int J Colorectal Dis

Fig. 1 Framework of Surgery

management of colorectal cancer. Stage 1
Patients with stage 1 disease are
treated with surgery alone. Surgery +/-
Patients with stage 2 (high risk Newly diagnosed CRC Stage 2 (neo)adjuvant
disease) and stage 3 colon cancer chemotherapy/RT*
are treated with surgery followed
by adjuvant chemotherapy Stage 4 Stage 3 Surgery &
(neo)adjuvant
whereas patients with stage 2 and
chemotherapy/RT*
stage 3 rectal cancer are treated
with neoadjuvant chemoradiation Poor performance status Good performance status
therapy followed by surgery with
or without adjuvant Unresectable PotenƟally resectable
SupporƟve care
chemotherapy. Patients with stage metastases metastases
4 CRC are primarily treated with
chemotherapy although a selected
group of patients can be cured chemotherapy & Surgery of primary
Median overall biologics +/- surgery of
with metastasectomy Survival tumor & metastases &
primary tumor adjuvant chemotherapy
6 months
+/- biologics
Median overall
Survival Median overall
18-24 months Survival
•Stage 2 and 3 rectal cancer neoaadjuvant chemotherapy and radiation 50-60 months
•Stage 2 and 3 colon cancer adjuvant chenotherapy

cancers who have not had prior extensive abdominal surgery.
However, laparoscopic approach should be carried out by
technically experienced surgeons.
There are three major curative surgical resection options for
rectal cancer: local excision, sphincter-preserving procedures,
and abdominal perineal resection (APR). Following criteria
are required for consideration for transanal or transsphincteric
local excision: Superficial T1 cancers (limited to submucosa),
no radiographic evidence of metastatic disease to regional
nodes (N0), tumor less than 3 cm in diameter, tumor located
in middle to distal rectum, low risk of developing positive
regional lymph nodes (well differentiated, no vascular and/or
neural invasion) and compliance with aggressive postopera-
tive surveillance [46, 47].
APR is the standard option for all invasive rectal cancers
beyond the submucosa if negative distal margin of resection
cannot be achieved. In all other cases sphincter-sparing pro-
cedure such as low anterior resection or very low anterior
resection is recommended. In recent years, intersphincteric
resection has been proposed as an alternative to APR to offer
sphincter preservation in patients with very low rectal lesions.
Total mesorectal excision (TME) or en bloc removal of
mesorectum (the perirectal areolar tissue involving the lateral
and circumferential margins), is the standard surgical ap-
proach when performing an APR or sphincter-sparing proce-
dure. The local recurrence rate following inclusion of a TME
with an APR or sphincter-sparing procedure ranges from 4 %
to 7 % [48, 49]. A randomized trial involving patients with
mid to low rectal cancer who received preoperative chemora-
diation therapy and were assigned to laparoscopic versus open
surgery demonstrated no significant differences between the
two groups with respect to involvement of the CRM, number
of lymph nodes retrieved, and perioperative morbidity. The
time to return of bowel function, time to resume a normal diet,
and time to defecation were significantly better in the group
treated with laparoscopic-assisted surgery [50]. A 5-year
follow-up of CLASSIC trial that compared two surgical ap-
proaches did not reveal a significance difference in the rates of
local recurrence, disease free survival and overall survival
[51]. Hence, laproscopic resection appears to have long-term
outcomes similar or better than open surgery [52]. Several
large randomized trials are ongoing to confirm clinical equiv-
alence of laproscopic resection to open surgery in rectal
cancer.
Adjuvant and neoadjuvant therapy
Colon cancer
Patients with stage 1 colon cancer have high cure rate with
surgery alone and do not require adjuvant therapy (Fig. 1). On
the other hand, patients with node positive colon cancer
following surgery are at high risk of recurrence. Adjuvant
chemotherapy for patients with high-risk stage II and III colon
cancer has substantially evolved over the past 2 decades. The
patients with stage II are considered to be at high risk of
recurrence if pathology demonstrates at least one of the fol-
lowing characteristics: lymph nodes sampling <12; poorly
differentiated tumor (except in MSI-high cancers); vascular
or lymphatic or perineural invasion; tumor presentation with
obstruction or tumor perforation and pT4 stage [5, 6, 53].

Conversely, patients with stage II MSI-high have good prog-
nosis and may not benefit from adjuvant 5-fluorouracil (5-FU)
[5].
Moertel et al. [54] first demonstrated benefit of adjuvant
chemotherapy in high risk colon cancer. One year of 5-FU/
levamisole chemotherapy versus levamisole alone or no treat-
ment was associated with 40 % reduction in risk of recurrence
and 33 % reduction in overall death rate [54]. Subsequent
trials revealed that 5-FU/leucovorin (LV) provided a superior
outcome, with 6 months of treatment being adequate to
achieve similar survival benefit [55, 56]. For more than a
decade, 5-FU/LV using various infusional protocol remained
standard adjuvant therapy [55–57]. Later, the X-ACT trial
demonstrated non-inferiority of oral capecitabine with a better
toxicity profile compared with bolus 5-FU/LV in patients with
stage III colon cancer [58]. However, the major breakthrough
in the management of high risk colon cancer was noted after
the introduction of oxaliplatin based chemotherapy. Three
phase III randomized controlled trials using various combina-
tion of infusional 5-FU or oral capecitabine and oxaliplatin
(FOLFOX or FLOX or XELOX) demonstrated improvements
in survival in patients with node positive colon cancer com-
pared with 5-FU/LV [59–61]. In the landmark MOSAIC trial,
at a median follow-up period of 82 months, 5-year DFS was
73 % with FOLFOX compared with 67 % with infusional 5-
FU (hazard ratio [HR], 0.80). In addition, 6-year overall
survival rates were also significantly higher in those with stage
III (73 vs. 69 %, HR 0.80, p=0.023), but not with stage II
disease [59]. However, oxaliplatin based therapy demonstrat-
ed greater toxicities compared with 5-FU/LV or capecitabine.
Despite efficacy in advanced CRC several randomized
trials failed to demonstrate survival benefit of irinotecan-
based adjuvant therapy or biologic agent bevacizumab or
cetuximab in patients with stages II and III colon cancer
[62–65].
With increasing toxicities associated with oxaliplatin-based
adjuvant therapy several randomized trials are in process of
accruing patients to determine noninferiority of 3 versus
6 months of a fluoropyrimidine/oxaliplatin combination ther-
apy. In addition, efforts are underway to improve prognosti-
cation in stage III colon cancer beyond that achieved by the
TNM staging system by using molecular and clinical prog-
nostic factors [66, 67].
Rectal cancer
Due to close proximity of rectum to the pelvic structure and
absence of serosa surrounding the rectum, rectal cancers are at
high risk of local recurrence. Hence, (neo)adjuvant radiation
therapy is a standard component of multidisciplinary care for
rectal cancer. The use of radiotherapy even in the setting of
a high-quality TME appears to improve local control rates
[68, 69].
Int J Colorectal Dis
Patients with resected stage I rectal cancer have an excel-
lent prognosis with surgery alone and do not need adjuvant
therapy (Fig. 1). For patients with resected stage II or III rectal
cancer, data from the early randomized GITSG and NCCTG
trials demonstrate better local control and survival benefit of
postoperative combined modality therapy over surgery alone
[70, 71]. Adjuvant 5-FU-based chemoradiation resulted in
10–12 % reduction in local failure and 10-15 % improvement
in survival [71, 72]. Subsequent studies demonstrated better
local control following neoadjuvant short course, high-dose
radiation, delivered as daily 5 Gy for 5 days (5×5), compared
with no treatment or selective post-operative chemoradiation
therapy [68, 69].
Several randomized trials were performed to deter-
mine the optimal sequence of surgery and chemoradio-
therapy and compared preoperative concurrent chemora-
diation with postoperative 5-FU-based chemoradiothera-
py [73–75]. In a landmark trial, the German Rectal
Study demonstrated comparable 5-year survival of
76 % with neoadjuvant chemoradiation versus 74 %
with postoperative chemoradiation treatment. However,
the 5-year cumulative incidence of local relapse was
only 6 % in patients who were assigned to preoperative
chemoradiotherapy compared with 13 % in the postoperative-
treatment group (p=0.006), with the corresponding rates of
long-term toxic effects were 14 % and 24 %, respec-
tively (p=0.01) [74]. This phase III randomized trial has
established neoadjuvant infusional 5-FU with conven-
tionally fractionated radiotherapy (5,040 cGy) the new
“standard of care” for T3/4 or node-positive rectal can-
cer. Nonetheless, short course radiation therapy has been
adopted in many institutions, outside the North America, as
the alternate preoperative approach for operable rectal cancer.
Addition of oxaliplatin to 5-FU based preoperative che-
moradiation failed to demonstrate superior outcomes
[76–78]. Retrospective data has shown that patients with
intermediate-risk rectal cancer — defined as T1 to T2N1 or
T3N0 — had only approximately 6 % to 8 % risk of local
recurrence and may not derive any benefit from adjuvant
radiation [79]. Trials are ongoing to asses if preoperative
FOLFOX is equivalent to standard preoperative chemoradia-
tion treatment.
Surveillance
Following curative resection a more intense follow-up is
recommended in patients with high risk disease who, on
recurrence, are candidate of curative surgery or systemic
therapy. The follow-up includes periodic physical examina-
tion, annual CT scan of the chest and abdomen (pelvic CT
scan for rectal cancer) for 3 years, colonoscopy at 3 years and
then every 5 years; and CEA every 3 months for at least
3 years after the diagnosis [5–7, 80].
Int J Colorectal Dis
Metastatic colorectal cancer
One in five patients with CRC presents with stage 4 disease
but less than one-quarter of these patients are considered
suitable for radical resection [81, 82].
For most patients with metastatic CRC systemic chemo-
therapy is the primary treatment. The last decade has seen
remarkable improvements in survival of patients with ad-
vanced CRC, primarily attributed to the availability of several
novel agents and increased use of hepatic resection in selected
patients [5–7, 83]. In the following section, we review the
recent advances in treatment options for patients with stage 4
CRC.
Surgical management of stage 4 CRC
The role of surgery in stage 4 CRC has evolved over the past
decade. Surgery can be performed with a curative intention by
removing the metastatic lesions and primary tumor or it can be
contemplated for palliation of symptoms by removing the
primary tumor.
The optimal surgical management of patients with ad-
vanced CRC that is not amenable to curative resection is not
known. Surgical removal of the primary tumor in advanced
CRC by preventing local tumor complications and reducing
the tumor bulk may improve outcome. Overall the quality
evidence available regarding survival benefit of resection of
primary tumor, in patients with stage 4 CRC and otherwise
unresectable metastatic lesions is low [84–86]. While some
have advocated for surgery [84, 85], others have failed to
demonstrate survival benefit with resection of primary tumor
in patients with stage 4 CRC [86, 87]. A recent meta-analysis
of 15 observational studies revealed 31 % reduction in mor-
tality (HR 0.69, 95 % CI 0.61–0.79) with surgical resection of
the primary tumor, with an absolute difference in median
survival of about 4 months [88]. However, due to presence
of different biases the reported benefit may reflect selection of
younger and healthier patients with good performance status.
Recently a large population based cohort study demonstrated
that primary tumor resection improves survival of patients,
independent of other prognostic variables such as age, perfor-
mance status, co-morbid illness and chemotherapy [89].
Randomized trials are in progress to confirm survival benefit
of surgical resection of primary tumor.
In contrast, surgical resection is the only potentially cura-
tive option for selected patients with limited liver or lung
metastases. Although randomized trials have not been con-
ducted, long term survival of about 30–50 % patients follow-
ing metastasectomy, reported in retrospective studies, have led
to the acceptance of aggressive surgical resection in such
patients. Approximately 50–60 % of patients with CRC de-
velop metastases [90]. The liver is the dominant metastatic site
for patients with CRC. Approximately 80–90 % patients with
stage 4 CRC and liver metastases developed unresectable liver
disease. The criteria for defining which patients are suited for
surgical therapy have evolved. In surgical case series, 5-year
survival rates after resection range from 24 % to 58 %, aver-
aging 40 % and surgical mortality rates are generally less than
5 % [91–95] With the availability of novel chemotherapy and
targeted agents, about 10–20 % patients with initially
unresectable or borderline resectable metastatic liver disease
can have significant response to such treatment and able to
undergo resection of the metastases. Subgroups with ad-
vanced age, comorbid disease, and synchronous hepatic and
colon resection may have higher procedure-related mortality
and worse long-term outcomes. In selected patients with re-
currence, second metastasectomies have shown better survival
and low operative mortality [83, 96].
Comparable to liver metastasectomy, patients who
underwent pulmonary metastasectomy along with removal
of the primary tumor had 5- and 10-year survival rates of
about 35–55 % and 20–30 %, respectively [97–99].
Prognostic factors following lung metastasectomy that are
associated with a better survival include limited number of
metastatic nodules, a normal CEA level, absence of lymph
node involvement, metachronous rather than synchronous
presentation, and a longer duration between cancer onset and
the development of lung metastases [97, 98]. Of note, pres-
ence of both liver and lung metastases is not a contraindication
to pulmonary metastasectomy, as long as a complete resection
of all metastatic sites can be accomplished. Nevertheless,
patients with synchronous liver and lung metastases have less
favorable outcomes compared with patients with isolated in-
trathoracic metastases [100].
Systemic therapy is an important component of multidisci-
plinary management of patients who undergo metastasectomy.
Randomized phase III trials have shown superior recurrence
free survival in patients with surgically resectable disease who
were treated with peri-operative chemotherapy [101, 102].
Hence, peri-operative or post-resection adjuvant chemothera-
py is recommended for a period of 6 months to reduce the risk
of recurrence. Furthermore, the development of novel
techniques in hepatic and thoracic surgery as well as ad-
vances in peri-operative care has also contributed to the im-
provement of patients’ prognosis. Unlike liver and pulmonary
metastasectomy, the role of aggressive surgical approaches in
combination with hyperthermic intraperitoneal chemo-
therapy in the setting of peritoneal carcinomatosis remains
controversial.
Systemic therapy in metastatic CRC
The optimal treatment strategy for patients with unresectable
advanced CRC is rapidly evolving. For many years, 5-FU was
the only active agent available in the management of patients
with metastatic CRC with the median overall survival of

approximately 10–12 months [103]. Access to several novel
agents has resulted in significant improvement in median
overall survival to approximately 24 months [104–112].
Three major phase III trials demonstrated a survival benefit
of irinotecan when it was combined with 5-FU/LV compared
to bolus or infusional 5-FU/LV alone in chemotherapy naïve
patients [105, 113, 114]. Median survival varied from 17.4 to
20.1 months with irinotecan in combination with infusional 5-
FU (FOLFIRI) compared with 14.1–16.9 months with
infusional 5-FU alone. Likewise, at least three randomized
trials have shown superiority of oxaliplatin plus infusional 5-
FU/LV (FOLFOX) compared with 5-FU/LV alone as first-line
therapy for advanced CRC [104, 115, 116]. The combination
of capecitabine plus oxaliplatin (CAPOX) is alternative regi-
men to FOLFOX [117]. FOLFOX or FOLFIRI is considered
to be acceptable first-line chemotherapy for patients with
advanced CRC. In randomized controlled trials both have
demonstrated comparable efficacy with median overall sur-
vival of about 20 months [106, 118].
Studies have also evaluated efficacy of all three active
drugs (infusional 5-FU, irinotecan, and oxaliplatin) combina-
tion (FOLFOXIRI) compared with FOLFIRI as first-line ther-
apy and have reported conflicting results [119, 120]. It is an
option in selected patients with good performance status when
high response is desirable. Several targeted therapies have
shown efficacy in the first line setting as well as following
progression in advanced CRC. For instance, in a key phase II
randomized trial involving 813 patients, bevacizumab, a hu-
manized monoclonal antibody directed against VEGF-A, in
combination with irinotecan containing regimen (IFL) was
associated with a median overall survival of 20.3 months
compared with 15.6 months with IFL alone [107]. The effica-
cy of bevacizumab was subsequently confirmed in several
phase 3 trials; however, the magnitude of benefit may differ
based on the chemotherapy regimen with which bevacizumab
is partnered [121]. There are no validated predictive molecular
markers available for bevacizumab.
The efficacy of the anti-EGFR antibodies cetuximab and
panitumumab alone or in combination with cytotoxic agents
has been demonstrated in both chemotherapy-refractory and
untreated advanced CRC [108, 109, 122–124]. Unlike
bevacizumab both cetuximab and panitumumab are active as
single agent in chemorefractory advanced CRC. However, the
activity of the anti-EGFR antibodies is confined to KRAS wild
type tumors. Approximately 30–40 % of CRCs harbor a mu-
tation in the KRAS gene and do not respond to anti-EGFR
antibodies. In a randomized trial, 1,198 chemotherapy-naïve
patients were randomly received FOLFIRI with or without
cetuximab. Combination of FOLFIRI and cetuximab in pa-
tients with KRAS wild-type tumor was associated with a
significantly better median overall survival of 23.5 months
compared with 20 months with FOLFIRI alone [109].
Likewise, patients with KRAS wild tumor and chemorefractory
Int J Colorectal Dis
disease who were treated with cetuximab monotherapy had a
median overall survival of 9.5 months compared with
4.8 months with best supportive care [124].
Although continuation of bevacizumab with a second-line
fluoropyrimidine-based chemotherapy regimen is associated
with survival benefit without an increase in bevacizumab-
related adverse events [125], it should not be administered
concurrently with an EGFR-targeting monoclonal antibody.
Two randomized phase 3 trials have evaluated the role of
concurrent use of dual antibodies targeting VEGF and the
EGFR in chemotherapy-naïve patients and demonstrated in-
ferior outcomes [126, 127]. Recently, two other novel agents,
aflibercept and regorafenib, have demonstrated modest benefit
in previously treated patients with advanced CRC [110, 111].
In patients with good performance status who are candidate
of combination of therapy, FOLFIRI or FOLFOX ±
bevacizumab or alternatively, in KRAS wild type tumor,
FOLFIRI in combination with cetuximab can be consid-
ered as first line therapy; on progression alternate regi-
men can be used (Fig. 2). In selected patients, continuation of
bevacizumab with a second-line fluoropyrimidine-based che-
motherapy regimen or alternatively aflibercept in combination
with second-line chemotherapy or in EGFR monoclonal anti-
bodies treatment naïve patients with KRAS wild tumors,
cetuximab or panitumumab in combination with second-line
therapy can be considered. In patients with KRAS wild tumor
who progress on two lines of therapy and if previously not
received anti-EGFR monoclonal antibodies, cetuximab or
panitumumab as single agent or in combination with
irinotecan can be considered otherwise regorafenib is an op-
tion for such patients with good performance status or patients
with KRAS mutant cancer who are not candidate for anti-
EGFR monoclonal antibodies. Trials are ongoing to determine
best first line regimen in patients with advanced CRC and
KRAS wild tumor.
Is PaƟent candidate for combinaƟon
chemotherapy?
Yes No
Fleuropyramidine
KRAS Status ± bevacizumab
Unavailable Wild Mutant
FOLFIRI or FOLFOX
FOLFIRI or FOLFOX ± bevacizumab FOLFIRI or FOLFOX
± bevacizumab
Or FOLFIRI ± anƟ- ± bevacizumab
EFGR mabs
Fig. 2 A proposed algorithm for first-line treatment of patients with
advanced CRC
Int J Colorectal Dis
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