Colorectal Cancer Lancet 2010 PDF

Seminar
Colorectal cancer
David Cunningham, Wendy Atkin, Heinz-Josef Lenz, Henry T Lynch, Bruce Minsky, Bernard Nordlinger, Naureen Starling
Lancet 2010; 375: 103047
Gastrointestinal Unit, Royal
Marsden Hospital National
Health Service Foundation
Trust, London and Surrey, UK
(Prof D Cunningham MD,
N Starling MRCP); Department
of Surgery and Cancer, Imperial
College, London, UK
(Prof W Atkin PhD); Sharon
Carpenter Laboratory,
University of Southern
California/Norris
Comprehensive Cancer Center,
Keck School of Medicine, Los
Angeles, CA, USA
(Prof H-J Lenz MD); Department
of Preventive Medicine and
Public Health, Creighton
University School of Medicine,
Omaha, NE, USA
(Prof H T Lynch MD); University
of Chicago Medical Centre,
Chicago, IL, USA
(Prof B Minsky MD); and Service
de Chirurgie Gnrale et
Digestive, Hpital Ambroise
Par, Boulogne, France
(Prof B Nordlinger MD)
Correspondence to:
Prof David Cunningham,
Department of Medicine, Royal
Marsden Hospital, Downs Road,
Sutton SM2 5PT, UK
David.cunningham@rmh.
nhs.uk
Substantial progress has been made in colorectal cancer in the past decade. Screening, used to identify individuals
at an early stage, has improved outcome. There is greater understanding of the genetic basis of inherited colorectal
cancer and identication of patients at risk. Optimisation of surgery for patients with localised disease has had a
major eect on survival at 5 years and 10 years. For rectal cancer, identication of patients at greatest risk of local
failure is important in the selection of patients for preoperative chemoradiation, a strategy proven to improve
outcomes in these patients. Stringent postoperative follow-up helps the early identication of potentially radically
treatable oligometastatic disease and improves long-term survival. Treatment with adjuvant uoropyrimidine for
colon and rectal cancers further improves survival, more so in stage III than in stage II disease, and oxaliplatinbased combination chemotherapy is now routinely used for stage III disease, although ecacy must be carefully
balanced against toxicity. In stage II disease, molecular markers such as microsatellite instability might help
select patients for treatment. The integration of targeted treatments with conventional cytotoxic drugs has
expanded the treatment of metastatic disease resulting in incremental survival gains. However, biomarker
development is essential to aid selection of patients likely to respond to therapy, thereby rationalising treatments
and improving outcomes.
Introduction
Worldwide, every year, more than 1 million individuals
will develop colorectal cancer,1 and the disease-specic
mortality rate is nearly 33% in the developed world. Here
we summarise some of the important developments and
advances in molecular carcinogenesis, prognostic and
predictive molecular markers, hereditary predispositions,
screening, diagnosis, and treatment during the past
5 years.
Molecular carcinogenesis
The classic description of colorectal carcinogenesis is the
adenoma-carcinoma sequence and multistep tumourigenesis that is determined by gatekeeper and caretaker
molecular pathways, which takes years to decades.2
Colorectal cancer is increasingly classied into specic
phenotypes on the basis of molecular proles (table 1), two
of which represent genetic instability classes. Most sporadic
cases (about 85%) have chromosomal instability, an allelic
imbalance at several chromosomal loci (including 5q, 8p,
17p, and 18q), and chromosome amplication and
translocation, which together contribute to tumour
aneuploidy.47 By contrast, the remaining cases (about 15%)
have high-frequency microsatellite instability phenotypes
Search strategy and selection criteria

We searched Medline, PubMed, ASCO abstracts, ESMO abstracts, and the Cochrane
database, between 2004 and 2009, for papers published in English. We used the search
terms colorectal cancer, colon cancer, rectal cancer, carcinogenesis,
epidemiology, genetics, screening, diagnosis, staging, surgery, radiation
therapy, chemotherapy (adjuvant, metastatic, and neoadjuvant), and molecular
prognostic and predictive markers. We cross-checked reference lists we found, and asked
other colleagues to recommend references. We selected papers on the basis that they
provided a major contribution to colorectal cancer or drew attention to evolving ideas,
particularly papers in the past 5 years since publication of the previous seminar about
colorectal cancer published in The Lancet in 2005.
1030
ie, frameshift mutations and base-pair substitutions that

commonly arise in short tandemly repeated nucleotide
sequences (microsatellites).8,9 Microsatellite instability is a
measure of the inability of the DNA nucleotide mismatchrepair system to correct errors that often occur during
DNA replication, which is controlled by several genes
(including MLH1, MSH2, and MSH6), and is characterised
by the accumulation of single nucleotide mutations and
length alterations in repetitive microsatellite nucleotide
sequences that are common throughout the genome.10
These tumours are characterised by proximal location,
mucinous histology, poor dierentiation, and lymphocytic
inltration. The genetic mechanism that contributes to
this phenotype is mutation or loss of function through
epigenetic gene silencing of DNA mismatch-repair
genes.11,12 In most sporadic cases, microsatellite instability
occurs when the promoter region of the genes in the
mismatch-repair system (often MLH1) is silenced by hypermethylation of CpG islands.12 The analysis of methylation
of CpG islands as a mechanism of silencing genes in colon
tumours has resulted in the identication of the CpG
island methylator phenotype, which seems to be complex,
and its prognostic signicance in patients with colon
cancer has not been thoroughly investigated.13,14
The serrated pathway, often arising in a serrated
precursor lesion (pathological classication is controversial but includes hyperplastic polyp, sessile serrated
polyp, and serrated adenoma), usually occurs in the right
colon,15 and seems to be governed by progression of
dierent molecular mechanisms to the classic adenomacarcinoma sequence.3 Clinical management of these
precursor lesions is not clear.
Epidemiology
Risk factors
Most cases of colorectal cancer arise sporadically. Risk
factors include increasing age, male sex, previous
colonic polyps, or previous colorectal cancer, and
www.thelancet.com Vol 375 March 20, 2010
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environmental factors (eg, red meat, high-fat diet,

inadequate intake of bre, obesity, sedentary lifestyle,
diabetes mellitus, smoking, and high consumption of
alcohol).16 Inammatory bowel disease (ulcerative colitis
and Crohns disease) accounts for roughly two-thirds of
the incidence,17,18 and the risk increases with duration of
illness (2% at 10 years, 18% by 30 years18), and severity
and extent of inammation.19 Although colitis-associated
colorectal cancer has many of the same molecular
carcinogenic mechanisms as has sporadic cancer, with
similar frequencies of chromosomal (about 85%) and
microsatellite instability (about 15%), there are important
molecular dierences.20
Of the hereditary syndromes, the frequencies for
inherited syndromes are as follows; the Lynch
syndrome, also known as hereditary non-polyposis
colorectal cancer, occurs in roughly one in 300 people
with colorectal cancer. Familial adenomatous polyposis
is much less frequent, and arises in about one in
7000 people aected by colorectal cancer, whereas
MYH-associated polyposis occurs in about one in
18 000 individuals with colorectal cancer. All familial
cases of colorectal cancer of the syndrome type account
for nearly 6% of casesnamely, 3% of those with Lynch
syndrome, 2% with familial colorectal cancer nonLynch syndrome, and about 1% constitute all of the
others, including the TACSTD1 deletion of MSH2. At
this time, there is no reliable quantitative estimate of
the frequency of TACSTD1 deletion of MSH2 in
Lynch syndrome.
Genetic epidemiology: Lynch syndrome as model

More than a fth of patients with colorectal cancer might
have a familial component, and about 3% of cases will
develop Lynch syndrome,21 which is the most common
hereditary syndrome associated with this cancer (panel 1).
Less than 1% of cases will have familial adenomatous
polyposis or one of the hereditary syndromes of
hamartomatous polyposis.24,25 At least 20% of cases of
colorectal cancer are familial (dened by two or more
rst-degree relatives with this cancer). Although this
familial category remains aetiologically elusive, it is
estimated to have a two-fold to three-fold greater risk
than has the general population. Type X familial colorectal
cancer, a new susceptibility category, meets the
Amsterdam criteria26 for Lynch syndrome but lacks the
molecular genetic features.27,28 The Amsterdam criteria26
and Bethesda guidelines29 are widely used as clinical
screening methods for assessment of risk (panel 2).
The public health implications of hereditary colorectal
cancer are substantial because close relatives of an index
patient could benet from genetic counselling and,
potentially, from mutation testing. Once a diagnosis is
strongly suspected on the basis of family pedigree or
molecular conrmation in the index patient, the next
question is which family members should be tested.30
Many physicians might not be cognisant of the molecular
Chromosomal
instability pathway
Mismatch
repair pathway
Serrated pathway
Hereditary and sporadic
Hereditary
Hereditary
Sporadic
CIMP status
Negative
Negative
High
MSI status
MSS
MSI-H
MSI-H
MSI-L
Chromosomal instability
+++
---
---
---
KRAS mutation
+++
+/-
---
---
BRAF mutation
---
---
+++
+++
MLH1 status
Normal
Mutation
Methylated
Partial
methylation
Adapted from Nosinger.3 CIMP=CpG island methylator phenotype. MSS=microsatellite stability. MSI=microsatellite
instability. MSI-H=high-level microsatellite instability. MSI-L=low-level microsatellite instability. +++=present. +/-=might
or might not be present. ---=absent.
Table 1: Molecular classication of colorectal carcinoma
Panel 1: Cardinal features of Lynch syndrome (hereditary non-polyposis

colorectal cancer)
Autosomal dominant inheritance pattern of syndrome cancers in the family pedigree.
Onset of colorectal cancer at a younger average age than in the general population:
average age of 45 years in individuals with Lynch syndrome versus 63 years in the
general population.
Proximal (right-sided) colonic cancer predilection: 7085% of colorectal cancers in people
with Lynch syndrome are proximal to the splenic exure.
Accelerated carcinogenesis (small adenomas can develop into carcinomas quickly):
within 23 years in Lynch syndrome versus 810 years in the general population.
High risk of additional colorectal cancers: 2530% of patients having surgery for a cancer
associated with Lynch syndrome will have a second primary colorectal cancer within
10 years of surgical resection if the surgery was less than a subtotal colectomy.
Increased risk of malignancy at specic extracolonic sites:22,23 endometrium
(4060% lifetime risk in carriers of mutation); ovary (1215% lifetime risk in mutation
carriers); stomach (increased risk in Oriental families, reason not known); small bowel;
hepatobiliary tract; pancreas; upper uroepithelial tract (transitional cell carcinoma of
the ureter and renal pelvis); and brain (in Turcots syndrome, a variant of Lynch
syndrome).
Sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas in
Muir-Torres syndrome, a variant of Lynch syndrome.
Pathology of colorectal cancer is often poorly dierentiated, with an excess of mucoid
and signet cell features, a Crohns-like reaction, and an excess of inltrating
lymphocytes within the tumour.
Increased survival when compared by stage in non-Lynch-syndrome-associated
colorectal cancer.
The requirement for diagnosis is the identication of a germline mutation in a
mismatch repair gene (most commonly MLH1, MSH2, or MSH6) that segregates in the
familyie, members who have the mutation have a much higher rate of syndromerelated cancers than do those who do not have the mutation.
genetic and phenotypic features of the syndromes

associated with hereditary colorectal cancer, or their
clinical implications for the patient and family.
Referral should be made to a cancer geneticist so that
sensitive and appropriate counselling, and appropriate
management and surveillance, can be oered.
The genetic basis of Lynch syndrome is germline
mutation in one of the genes in the DNA nucleotide
1031
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Panel 2: Revised Bethesda guidelines29 and Amsterdam criteria26 for identication of

patients at risk of developing Lynch syndrome
Traditionally, one Bethesda criterion or all Amsterdam criteria should be met to
potentially identify individuals at risk of Lynch syndrome.
Bethesda guidelines:
Colorectal cancer diagnosed in a patient who is younger than 50 years
Presence of synchronous, metachronous colorectal, or other tumours associated with
Lynch syndrome, irrespective of age
Diagnosis of colorectal cancer with histologically high-level microsatellite instability
in a patient younger than 60 years
Colorectal cancer diagnosed in one or more rst-degree relatives with a Lynch
syndrome-associated tumour, with one of the cancers diagnosed before age 50 years
Colorectal cancer diagnosed in two or more rst-degree or second-degree relatives
with Lynch-syndrome-related tumours irrespective of age
Amsterdam I and II criteria:
One individual diagnosed with colorectal cancer (or extracolonic Lynch-syndromeassociated tumours) before age 50 years
Three aected relatives, one a rst-degree relative of the other two
Two successive aected generations
Familial adenomatous polyposis should be excluded
Tumours should be veried by pathological examination
mismatch-repair system, most commonly MSH2 and

MLH1 (accounting for roughly two-thirds of the known
mutations) and less commonly MSH6, PMS1, and PMS2.
Several environmental factors or yet-to-be-identied lowpenetrant gene mutations might aect the ultimate
phenotypic expression of this syndrome. Most cases of
familial adenomatous polyposis are caused by germline
mutations in the APC tumour suppressor gene. Almost all
colorectal tumours associated with Lynch syndrome have
microsatellite instability. Immunohistochemistry can be
used to identify loss of mismatch-repair proteins, such as
MSH2 and MLH1, in tumours positive for microsatellite
instability, and thereby direct mutational testing for a
specic gene, which cannot be done with tests for
microsatellite instability.31 If the tumour is microsatellite
stable, the low probability of an informative immunohistochemistry test needs to be weighed against the cost of
doing the test.32 Microsatellite instability should not be used
as the only basis for selection of patients for mutational
testing for Lynch syndrome, because some patients with
microsatellite-stable tumours can have mutations.32 This
diculty can be resolved more cost eectively with tests for
the BRAF V600E mutation than with those for the genes in
the mismatch-repair system, since the presence of this
mutation excludes Lynch syndrome.33
The clinical phenotypes in Lynch syndrome might
dier according to the mutations. MSH2 is associated
with an increased frequency of extracolonic types of
cancer and includes Muir-Torres syndrome. Expression
of MLH1 in colorectal cancer is higher than the expression
of MSH2, and lower in extracolonic cancer. MSH6 shows
a reduction in expression in colorectal cancer but an
1032
increase in endometrial cancer. PMS2 mutations

contribute importantly to the development of Lynch
syndrome, although penetrance in carriers of monoallelic
PMS2 mutations seems to be lower than that for other
genes in the DNA nucleotide mismatch-repair system.34
These clinical and molecular genetic changes in Lynch
syndrome, and in many other hereditary cancer
syndromes, have led to a new era of genetic counselling.
In 500 consecutive patients with colorectal cancer,21
18 (36%) had Lynch syndrome and were positive for
microsatellite instability, 17 (94%) were correctly predicted
with immunohistochemistry for the presence of mismatch
repair proteins, eight (44%) were diagnosed when they
were younger than 50 years, and 13 (72%) met the revised
Bethesda guidelines29 (table 2). The investigators
concluded that one in 35 patients with colorectal cancer
had Lynch syndrome (a high prevalence for a highly
penetrant, lethal autosomal dominant condition), and
each of these patients had at least three relatives with this
syndrome. These relatives could potentially benet from
increased cancer surveillance and management.
Restriction of molecular screening to patients meeting
the Bethesda guidelines would not identify 28% of cases
of Lynch syndrome. The authors also showed that
immunohistochemistry for mismatch-repair proteins was
almost as sensitive as microsatellite instability for
identication of this syndrome. This nding has
important implications for potential large-scale screening
because immunohistochemistry is readily available in
most pathology laboratories and is useful for directing
gene testing, whereas tests for microsatellite instability
require specialist molecular diagnostics. This nding
supports the argument that all patients with colorectal
cancer, irrespective of family history, should be screened
for microsatellite instability or mismatch-repair protein
deciency by immunohistochemistry. Similar evidence
for molecular genetic screening of all newly diagnosed
cases of colorectal cancer was reported by the Evaluation
of Genomic Applications in Practice and Prevention
Working Group,43 linking such screening with improved
health outcomes in relatives of identied individuals.
However, currently large-scale molecular screening of all
patients is not done.
Surveillance for colorectal cancer in individuals with a
germline mutation in the DNA nucleotide mismatchrepair system is highly eective and cheaper than a lack of
surveillance.44,45 Because of the early age of onset of this
cancer in Lynch syndrome and proximal colon occurrence,
full colonoscopy should be started by age 2025 years in
individuals with mutations in the mismatch-repair system,
and in those thought to be at risk on the basis of pedigree
analysis. Colonoscopy should be done at least every
12 years until 40 years of age, and yearly thereafter,
because of accelerated colorectal carcinogenesis in Lynch
syndrome.46 Similar guidelines apply to familial
adenomatous polyposis. Women with a germline mutation
for Lynch syndrome should have yearly screening for
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endometrial cancer (4060% lifetime risk) beginning at

3035 years. This screening should include endometrial
aspiration and transvaginal ultrasound, although evidencebased data showing survival benet from such screening
is lacking. Prophylactic hysterectomy and salpingooophorectomy in women with germline mutations in the
mismatch repair system substantially reduce the
occurrence of endometrial and ovarian cancer in women
with conrmed Lynch syndrome.47 These surgeries can be
considered when childbearing is complete. Evidencebased data showing survival advantage for urological,
gastric, and small bowel screening are not available.
Screening of colorectal cancer

Survival rates in individuals with colorectal cancer have
increased substantially in the past few years, possibly as a
result of early diagnosis and improved treatment. Although
substantial information about risk factors exists, about
75% of diagnoses are in patients with no apparent risk
factors other than older age.48 5-year survival is still less
than 60% in most European countries.49 Population
screening therefore continues to oer the best prospects
for reduction in mortality rates.
The aim of screening for colorectal cancer is to prevent
the development of advanced cancers through detection
of localised cancers or premalignant adenomas, from
which at least 80% of cancers are thought to arise. Several
technologies exist. Those that are used to target cancers
early reduce mortality rates, but cause a temporary
increase in incidence rates as cancers are typically
diagnosed at screening 23 years earlier than in
symptomatic cases. These tests need to be oered at least
biennially, which has implications for costs and
compliance rates. Tests that are used to detect adenomas
can be oered less frequently and because these tests
should reduce incidence rates of colorectal cancer, they
also reduce the costs of treatment and, thereby, of the
screening programme.50,51 However, since most adenomas
do not develop into symptomatic cancers, screening for
them can result in overtreatment, which can increase the
risk of complications.
The guaiac-based faecal occult blood test is the most
extensively studied, but possibly least sensitive, screening
method. Several randomised trials and a Cochrane
review52 have provided high-quality evidence that this test,
if oered every 2 years, has the potential to reduce
mortality rates associated with colorectal cancer by 16%.
For this home-test kit, two samples are collected from
three consecutive stools and sent for processing in an
accredited laboratory. Collection of one stool sample by a
physician during digital rectal examination is ineective
and is strongly discouraged.53 Investigation by colonoscopy
is recommended if a specic number of the test cards are
positive; the exact number varies according to local
practice.54,55 Several countries have introduced screening
with the faecal occult blood test.55 Costs have been
assessed in the European and US contexts, and were well
below the commonly used threshold of US$50 000 per

life-year gained.50,56 Immunochemical faecal occult blood
tests have several improved features compared with the
standard test. They are not subject to interference from
animal blood in the diet, only one or two stool samples
are needed, and they are more sensitive for detection of
colorectal cancer and advanced adenomas, though at the
expense of lower specicity.57 Some tests can be automated,
and the cuto for positivity can be adjusted according to
available endoscopy resources.58
Flexible sigmoidoscopy, with a 60 cm endoscope,
allows examination of the sigmoid colon and rectum
where 60% of cancers and adenomas are located. Bowel
preparation for this sigmoidoscopy requires only one
self-administered enema.59 Results from epidemiological
studies suggest that sigmoidoscopy screening reduces
incidence and mortality rates of distal colorectal cancer
by roughly 6080%;60,61 four large trials are in
progress.6265 Screening is recommended every 5 years
from 50 years of age in the USA,66 although the
protection aorded by one exible sigmoidoscopy
might last for many years.60,61,67 The value of a once-in-alifetime screen with this method at about 60 years of
age is being investigated in UK and Italian trials.62,63
Small polyps are removed during the sigmoidoscopy
screening, and colonoscopy follows only if several or
advanced adenomas are found. The results of both trials
will be reported this year. Colonoscopy every 10 years is
the most common method of screening in the USA
despite evidence that it has little ecacy in reducing
rates of proximal colon cancer.68,69 This method is
associated with a higher risk of serious complications
than are other methods,70 and about 48 h are needed for
bowel preparation and recovery from sedation.
Population screening with colonoscopy also presents
manpower diculties that have yet to be resolved,
although high-quality programmes are available in
Germany and Poland.71,72 CT colonography (virtual
colonoscopy) is as sensitive as colonoscopy for the
detection of cancers and large adenomas, but includes
exposure to radiation, requires full bowel preparation,
and colonoscopy is necessary to conrm and remove
detected lesions.57,73 CT colonography also detects
extracolonic lesions, which might lead to further
invasive tests without any clinical benet.74 It is thus an
expensive option for screening.75
Investigations of DNA-based tests of blood or stool are
in progress.76,77 The sensitivity and specicity of markers
need to be optimised, and automated systems need to be
developed to reduce costs and ensure reliability. Many
other colonic imaging technologies are being
investigated78 to improve the acceptability of colonoscopy
or increase the detection of at lesions.
Whatever technology or combination of technologies is
used, population screening is costly with the risk of
exposing healthy individuals to potential harm. To obtain
the maximum benets and cost eectiveness of any
1033
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Treatment
Number
Phase
Radiation dose
(Gy)/ fraction size
pCR
Local
failure
Grade 3 or more acute toxicity
Gerard et al35 (ACCORD)
Capecitabine vs CAPEOX
379 vs 368
45/18 vs 50/18
14% vs
19%
11% vs 25% (p<0001)
Aschele et al36 (STAR)
CI 5-FU vs FOLFOX
295 vs 291
503/18 vs 504/18
16% vs
15%
15% vs 24% (p<0001)
Crane et al37
Capecitabine+bevacizumab
25
505/18
32%
7% (2 years)
3% wound complication, requiring surgery
Willett et al38
CAPEOX+bevacizumab
32
504/18
16%
22% diarrhoea, 9% hypertension, 6% skin, 3% dehydration,

3% abscess, 3% pain, 3% neuropathy
Rodel et al39
CAPEOX+cetuximab
48
504/18
9%
19% diarrhoea, 4% rash, 4% neuropathy
Mohiuddin et al40 (RTOG

0012)
FOLFIRI vs CI 5-FU
54 vs 52
2R
50454/18 vs
55260/12 BID
28% vs
28%
57% haematological and non-haematological toxicities vs

51% haematological and non-haematological toxicities
Wong et al41 (RTOG 0247)
CAPIRI vs CAPEOX
48 vs 48
2R
504/18 vs 504/18
10% vs
21%
8% haematological, 24% non-haematological toxicities vs

4% haematological, 29% non-haematological toxicities
Fernandez-Martos et al42
(GCR-3)
Induction CAPEOX vs
postoperative CAPEOX
56 vs 52
2R
504/18 vs 504/18
14% vs
13%
17% vs 51% (p=000004)
pCR=pathological complete response rate. CAPEOX= capecitabine and oxaliplatin. CI 5-FU=continuous infusion of uorouracil. FOLFOX=uorouracil and oxaliplatin. FOLFIRI=uorouracil and irinotecan. R=randomised.
BID=twice a day. CAPIRI=capecitabine and irinotecan.
Table 2: Selected novel preoperative chemoradiation regimens
Figure: High-resolution MRI of rectal cancer

Red arrow shows T2 (tumour invading muscularis propria) rectal tumour; white arrow shows lymph node in the
mesorectum; and yellow dotted line shows the rectal fascia.
scheme, delivery of screening within a high-quality

programme is essential.55
Diagnosis and staging

Colorectal cancer is diagnosed on the basis of the results
of colonoscopy or sigmoidoscopy with tumour biopsy.
Treatment strategy is guided by adequate staging. The
pretreatment workup of a newly diagnosed cancer
includes physical examination, a complete colonoscopy
1034
to rule out metachronous tumour, and CT of the chest,

abdomen, and pelvis to identify metastatic disease.79
CT colonography is valuable for precise localisation of
the tumour and can help surgical approaches, especially
in patients who are candidates for laparoscopic resection.
It might also be used to identify other colonic lesions or
polyps that are not detected at colonoscopy, for instance
because of an obstructive lesion.8082 Routine use of PET
with the 18-uoro-2-deoxy-D-glucose (FDG-PET) is not
recommended at the time of initial diagnosis.83 In
patients with rectal cancer, assessment of local tumour
extension is essential for optimum treatment. Highresolution MRI can be used to accurately measure the
spread of tumour in the surrounding mesorectum, and
to assess the circumferential resection margin between
the edge of tumour and the fascia recti (gure).84
Measurement of the depth of invasion in the bowel wall
with endorectal ultrasound is particularly useful for early
rectal cancers.85 Panel 3 shows the advantages and
limitations of pelvic MRI and endorectal ultrasound for
the assessment of local spread of rectal cancer.
In patients with suspected liver metastases from
colorectal cancer, extent of disease is determined by
ultrasound, CT, and MRI. Although these imaging
methods are used to detect metastases, new methods can
be useful to dene the characteristics of liver metastases.
In particular, enhanced hepatic ultrasound86 and enhanced
MRI can help to characterise liver nodules.87 FDG-PET
can be used to rule out occult extrahepatic spread of the
disease that could change the treatment strategy.88,89
Detection of peritoneal carcinomatosis with imaging
remains a challenge, and performance of the dierent
diagnostic methods is inadequate.90 Involvement of the
multidisciplinary team from the start helps to provide the
best treatment. Once diagnosis is made, staging is
described according to the TNM (tumour, node,
metastases) system (panel 4).91
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Panel 3: Advantages and limitations of MRI and endorectal

ultrasound for staging of primary tumours (T) and regional
lymph nodes (N) in rectal cancer
MRI
Advantages:
Global staging of rectal tumour
Circumferential resection margin assessment
Assessment of extramural venous invasion
Guide the indication for radiation treatment
Few contraindications
Assessment of pelvic spread of the tumour (iliac nodes)
Limitations:
Node stagingMRI is more accurate than is endorectal
ultrasound, but there are some limitations in correlation
between radiological and pathological ndings
Endorectal ultrasound
Advantages:
Measure of depth of invasion in the bowel wall
Measurement of T staging
Early rectal cancer
Limitations:
Obstructing lesions
User-dependent imaging modality
Measurement of node staging
Assessment of circumferential resection margin assessment
and extramural venous invasion
Surgery
For colon cancer, total resection of the tumour should be
done with adequate margins, and lymphadenectomy.
Distal margins of 5 cm or more are recommended. At least
12 lymph nodes should be taken and analysed to allow
appropriate nodal staging;9395 analysis of fewer than ten
nodes might understage the tumour.12 En-bloc resection of
invaded adjacent organs might be needed for T4 tumours
to obtain R0 resection (no evidence of microscopic cancer
at the margins). Surgical resection of the rectum for
invasive rectal cancer should include total excision of the
mesorectum (TME) with adequate circumferential and
distal margins, and inferior mesenteric lymphadenectomy.
TME is associated with a reduced risk of local recurrence
whether or not combined with preoperative radiotherapy
or chemoradiotherapy.9698 Sphincter-saving surgery is
feasible in most patients with mid and low rectal cancers if
the distal margin is 1 cm or more. Intestinal continuity can
be restored with colorectal or coloanal anastomosis
according to the level of the tumour. For very low tumours,
TME can be combined with resection of the internal
sphincter of the anus without increasing the rate of local
recurrence.99,100 Abdominoperineal resection is a valuable
alternative for very low tumours.101 Functional results after
TME are associated with the level of the anastomosis.
Risk of faecal incontinence is increased in patients
with very low coloanal anastomosis, particularly after
preoperative radiation.102,103
Panel 4: TMN classication of colon cancer91

T=primary tumour
TX=primary tumour cannot be assessed
T0=no evidence of primary tumour
Tis=carcinoma in situ: intraepithelial or invasion of lamina propria
T1=tumour invades submucosa
T2=tumour invades muscularis propria
T3=tumour invades through the muscularis propria into subserosa or into nonperitonealised pericolic or perirectal tissues
T4a=tumour penetrates the surface of the visceral peritoneum
T4b=tumour directly invades or is histologically adherent to other organs or structures
N=regional lymph nodes
NX=regional lymph nodes cannot be assessed
N0=no regional lymph node metastasis
N1a=metastasis in one regional lymph node
N1b=metastasis in two to three regional lymph nodes
N2a=metastasis in four to six regional lymph nodes
N2b=metastasis in seven or more regional lymph nodes
M=distant metastasis
MX=distant metastasis cannot be assessed
M0=no distant metastasis
M1a=distant metastasis to one site
M1b=distant metastasis to more than one site
Surveillance, Epidemiology and End Results Program data for 5-year stage-specic relative
survival rates in colon cancers:91,92
Stage I (T1, T2, N0): 971%
Stage IIA (T3, N0): 875%
Stage IIB (T4, N0): 715%
Stage IIIA (T1, T2, N1): 877%
Stage IIIB (T1, T2, N2): 750%
Stage IIIB (T3, N1): 687%
Stage IIIC (T3, N2): 473%
5-year stage-specic relative survival rates were similar for rectal cancer as compared with
colon cancer.
In patients with early rectal cancer, the choice of

treatment is complete local excision or TME, and
depends on the risk of lymph-node involvement, which
is associated with the depth of invasion of the tumour in
the rectal wall. Local excisiontransanal excision or
endoscopic microsurgery for tumours in the upper-third
layer of the submucosa (T1Sm1) and some in the middle
layer (T1Sm2)is valuable if excision is completed with
adequate margins.104106
Laparoscopic colectomy is safe for colon cancer,
particularly left-sided cancer. The long-term oncological
results of this surgery are similar to those of the open
approach.107110 Although laparoscopic colectomy is
technically demanding, advantages are reduced pain,
length of hospital stay, and duration of ileus.111 Comparison
of laparoscopic and open resection (with TME) of rectal
cancer112 showed similar 3-year local recurrence rates and
1035
Seminar
survival despite earlier reports of an increased rate of R1

resection (ie, microscopic tumour present at the resection
margin) with the laparoscopic approach.108 There was a
non-signicantly higher risk of sexual complications
after laparoscopy than after open TME.113
The liver is the most common site of relapse after
surgery for colorectal cancer, and lung recurrence is
common. Resection of the liver and lung metastases is the
standard of care for potentially resectable oligometastatic
disease, and, when feasible, substantially improves 5-year
and 10-year survival rates. Improvement of strategies for
liver surgery, including preoperative embolisation, twostage liver resections, and renements of non-surgical
techniques, such as radiofrequency ablation of small
lesions, have increased the number of patients undergoing
complete local treatment of liver metastases. Important
progress has been made in the treatment of this disease
with use of multimodality and multidisciplinary methods.
Chemotherapy (oxaliplatin-based) given before and after
surgery versus surgery alone reduced the risk of cancer
relapse after surgery (progression-free survival at 3 years
was improved by 73% in all patients [p=0058], and by
92% in patients undergoing resection [p=0025]) in the
EORTC 40983 study.114 In patients with unresectable liver
metastases, initial or conversion chemotherapy can render
metastases resectable if the response to treatment is good.
Preoperative chemotherapy for resectable lung metastases
could improve outcomes, but there are few supporting
data.115 Radiofrequency ablation might also have a role in
non-resectable liver-only metastatic disease, and the
survival outcomes with local radiofrequency ablation
added to systemic palliative chemotherapy are being
assessed in the EORTC CLOCC trial.116
Radiation treatment for rectal cancer

The risk of local failure in treatment of rectal cancer is
aected by involvement of the circumferential resection
margin, lymph-node status, and extramural venous
invasion.84 Since a signicantly lower incidence of local
recurrence and toxicity, and a higher incidence of
sphincter preservation were reported with preoperative
than with postoperative chemoradiation in the German
CAO/ARO/AIO 94 trial,117 the conventional treatment for
clinical stage T3 (cT3) or node-positive rectal cancer is
preoperative treatment, and is the choice in most
countries. Radiation, a local control strategy, is used with
conventional fractionation (504 Gy in 28 fractions) since
short-course radiation (5 Gy5) cannot be safely used
with adequate doses of chemotherapy. Systemic
chemotherapy improves survival. In Scandinavia and
most northern European countries, treatment depends
on preoperative MRI assessment of the circumferential
resection margin.118120 Generally, if this margin is likely to
be negative at the time of surgery, patients undergo
surgery alone or are given ve doses of 5 Gy. If the margin
is likely to be positive, patients are given preoperative
radiation (5 Gy5) or chemoradiation. A positive
1036
circumferential resection margin is not suciently

controlled with postoperative treatment.121,122
Overstaging is a disadvantage of preoperative
treatment (18% in the German trial117), thereby patients
with pathological stage T1-2N0 disease are at risk of
being overtreated. Preoperative treatment is still
preferred to surgery rst since even after preoperative
chemoradiation 22% of patients still have node-positive
disease.123 These patients would then need postoperative
chemoradiation, which has inferior outcome and higher
toxicity than preoperative chemoradiation.
There are no prospective randomised data for local
recurrence based on distance from the anal verge, only
subset analysis from randomised trials that were not
stratied by distance. With univariate analysis, high
tumours (1011 cm) had a lower incidence of local
recurrence than did mid and lower tumours.122,124 By
contrast, there was no signicant dierence between mid
and upper tumours in the German trial.125 On the basis of
the conicting data and the fact that the incidence of
positive nodes after preoperative chemoradiation is the
same from 012 cm from the anal verge,123 treatment
decisions should not be based on distance if it is shorter
than 12 cm.
Chemoradiation and short-course radiotherapy have
been the main preoperative strategies assessed in
randomised studies. Short-course preoperative radiation
in patients with rectal cancer resulted in a survival
advantage for the total treatment group in a Swedish
trial.124 Despite TME, the local recurrence rate with nodepositive disease was 21% in the Dutch CKVO 95-04
trial.126 Therefore patients with node-positive tumours
need adjuvant radiation. The challenge is accurate
identication of positive nodes to allow proper selection
of patients for preoperative treatment. In the randomised
study by Bujko and colleagues,127 patients given
chemoradiation compared with radiation (5 Gy5) had a
signicantly lower incidence of positive circumferential
resection margin (4% vs 13%), but no signicant
dierence in local failure (14% vs 9%) or 4-year survival
(66% vs 67%). Furthermore, although the rate of
pathological complete response was much higher (16% vs
1%), the incidence of sphincter preservation was not
increased. However, because the number of patients
(n=316) was small, surgeons were not encouraged to
modify the operation on the basis of tumour response,
and there was a lack of central review of the quality of
the radiotherapy.
Use of adjuvant chemotherapy after preoperative
chemoradiation has been contentious. Although data
from randomised trials showed a 1015% survival
benet with postoperative uorouracil-based chemotherapy in colon and rectal trials, this result was not
conrmed in the EORTC 22921128 and FFCD 9203129
randomised trials. The negative results might be
partly attributable to the diculty in patients tolerating full doses of chemotherapy after preoperative
Seminar
chemoradiation. Chemotherapy was better tolerated in

the neoadjuvant than in the adjuvant setting in the
GCR-3 phase II trial (table 2).42 A potential advantage of
neoadjuvant chemotherapy is the early treatment of
micrometastatic disease.
Conventional chemoradiation regimens include
continuous-infusion uorouracil or capecitabine (an
oral uorouracil prodrug). New cytotoxic and targeted
treatments are being investigated (table 2).3542 Most
show higher rates of pathological complete response
than with uorouracil alone. However, acute toxicity
was signicantly higher without a benet in the rate
of pathological complete remission with the addition
of oxaliplatin to continuous-infusion uorouracilbased36
or
capecitabine-based
chemoradiation
(ACCORD 12-040535). Local control and survival data
were not available, but the rate of distant metastases
was lower in the oxaliplatin-combination group than
in the group not given oxaliplatin in the STAR trial.35
Most clinical series indicate improved outcome with
increasing response to preoperative chemoradiation.130 Use
of molecular markers131,132 has had varying success in the
prediction of response rates. Clinical or radiological
responses to preoperative chemoradiation do not
suciently correlate with pathological response.133
Adjuvant treatment should be based on the initial T and N
stages. In one series, the value of radical surgery in patients
(with cT13 disease) with a biopsy-proven complete
response was questioned,134 and although not conrmed by
other investigators remains a pertinent research question.
Novel fractionation and delivery techniques might
improve outcomes in the future. Generally, hyperfractionated radiation improves the rates of pathological
complete response but increases acute toxicity.135 Threedimensional treatment allows planning and localisation of
the target and normal tissues at all levels of the treatment
volume, and to obtain dose-volume histograms.136,137
Intensity-modulated radiotherapy can further reduce the
volume of the small bowel in the eld.138 The clinical
benet of this treatment compared with three-dimensional
or conventional treatment is yet to be determined.
Current and simple guidelines or algorithms for the
multimodality management of rectal cancer, including
surgery and radiation, and all stages of disease have
been reported by the US National Comprehensive
Cancer Network.139
Adjuvant treatment for early stage disease

Surgery is the cornerstone for cure in localised colorectal
cancer. In node-positive (stage III) disease, administration
of adjuvant uorouracil for 6 months reduces the risk of
death by 30%, which is equivalent to an additional 1015%
survival gain.140 The alternative oral uoropyrimidine,
capecitabine, has shown similar ecacy to uorouracil
alone.141 The establishment of 3-year disease-free survival
as a validated surrogate for 5-year overall survival142,143 and
primary endpoint has expedited the timely reporting of
adjuvant trials and uptake of eective treatments.

However, the magnitude of benet in disease-free survival
is not necessarily matched by that in overall survival
because of various factors.143 Oxaliplatin (a third-generation
platinum) added to infused uorouracil versus infused
uorouracil alone improved 3-year disease-free survival
by 7% in the MOSAIC study,144 leading to a 25% gain in
overall survival at 6 years for stage II and III disease, and
a survival increment of 42% in stage III alone.145 Results
for disease-free survival were replicated in the NSABP
C-07 study of uorouracil and oxaliplatin.146 In the
XELOXA study147 of oral capecitabine plus oxaliplatin
versus uorouracil and folinic acid (stage III disease),
there was an improvement in 3-year disease-free survival
(709% vs 665%, hazard ratio 080, p=00045) but a nonsignicant 5 year benet in overall survival (34%). The
choice between one drug (intravenous uorouracil or
oral capecitabine) or two will depend on the patients
tness or preference, potential for compliance, and
toxicity considerationseg, handfoot syndrome with
capecitabine, and risk of permanent peripheral sensory
neuropathy with oxaliplatin (155% all grades of peripheral
sensory neuropathy at 48 months after treatment145), with
patient-reported improvement in hand peripheral sensory
neuropathy but worsening of foot numbness, tingling, or
discomfort by 18 months.148 Results from the MOSAIC
study144 did not suggest a survival benet with adjuvant
oxaliplatin and uorouracil in patients older than 65 years,
a nding supported for individuals older than 70 years in
an analysis of the ACCENT group database of more than
12 500 patients (17% older than 70 years) given adjuvant
treatment in six randomised studies (including NSABP
C-07 and MOSAIC).149 These data and toxicity
considerations imply uoropyrimidine monotherapy
might be considered in older patients with stage III
colorectal cancer. Irinotecan added to uorouracil did not
signicantly improve disease-free or overall survival,150152
although there was a non-signicant improvement with
combination treatment in the PETAAC-3 trial.152
Adjuvant chemotherapy for node-negative (stage II)
colon cancer (40% of resected cancers) has been
controversial because of the small gains in survival for
this subgroup in studies in which patients with stage II
and III cancer were combined, although high-risk
patients with stage II tumours (T4 tumours, obstructing
presentation, poor dierentiation, extramural venous
invasion, fewer than 1012 harvested lymph nodes,
indeterminate or positive resection margins) are often
oered treatment.153 However, in the QUASAR study154
of 3239 patients (with mostly stage II colorectal cancer)
randomly assigned to uorouracil and folinic acid or to
observation (20% had central pathology review), there
was a signicant improvement in overall survival (risk
reduction of 18% and 36% overall survival gain), with
a similar benet for colon and rectal cancers. This
small benet weighted against treatment toxicities and
logistics, and comorbidities, should be included in
1037
Seminar
Study population
Treatment groups
Patients (n)
Response rate
Median PFS
(months*)
Median OS
(months)
Hazard ratio p value for

primary
for primary
endpoint
endpoint
BOND172
Pretreated
(irinotecanrefractory)
Cetuximab alone vs irinotecan-based

chemotherapy+cetuximab
111 vs 218
108% vs 229%
15 vs 41
69 vs 86
054 (TTP),
091 (OS)
<0001 (TTP),
048 (OS)
NCIC CO.17173
Pretreated
(uorouracil,
irinotecan, and
oxaliplatin)
Best supportive care vs cetuximab
285 vs 287
0 vs 8%
NR
46 vs 61
077
0005 (OS)
EPIC174
Pretreated
(uorouracil/
oxaliplatin)
Irinotecan vs irinotecan+cetuximab
650 vs 648
42% vs 164%
26 vs 40
10 vs 107
098
071 (OS)
Van Cutsem
et al175
Pretreated
(uorouracil,
irinotecan, and
oxaliplatin)
Best supportive care vs panitumumab
232 vs 231
0 vs 10%
73 weeks vs
80 weeks
NR
054
<0001 (PFS)
CRYSTAL176
Untreated
FOLFIRI vs FOLFIRI+cetuximab
599 vs 599
387% vs 469%
80 vs 89
186 vs 199
085
0048 (PFS)
OPUS177
Untreated
FOLFOX vs FOLFOX+cetuximab
168 vs 169
36% vs 46%
72 vs 72
NR
NR
064 (ORR)
CELIM178
Untreated liver-only FOLFOX+cetuximab vs FOLFIRI+

non-resectable
cetuximab vs either regimen for wildmetastases
type KRAS
53 vs 53 vs
67
68% (95% CI 5480) vs

57% (95% CI 4270) vs
70% (95% CI 5881)
COIN179
Untreated wild-type FOLFOX or CAPEOX vs

KRAS
FOLFOX/CAPEOX+cetuximab
367 vs 362
50% vs 59%
86 vs 86
179 vs 170
104
068 (OS)
PRIME180
Untreated wild-type FOLFOX vs FOLFOX+panitumumab

KRAS
331 vs 325
48% vs 55%
80 vs 96
197 vs 239
08
002 (PFS)
181 Study181
Pretreated wild-type FOLFIRI vs FOLFIRI+panitumumab

KRAS
294 vs 303
10% vs 35%
39 vs 59
125 vs 145
073 (PFS),
085 (OS)
0004 (PFS),
012 (OS)
Hurwitz et al182
Untreated
IFL vs IFL+bevacizumab
411 vs 402
348% vs 448%
62 vs 106
156 vs 203
066
<0001 (OS)
E3200183
Treated
FOLFOX vs FOLFOX+bevacizumab vs
bevacizumab
291 vs 286 vs 86% vs 227% vs 33%

243
47 vs 73 vs 27
108 vs 129 vs
102
075 (NR)
00011 (OS)
N016966184
Untreated
XELOX/FOLFOX vs XELOX/
FOLFOX+bevacizumab
701 vs 699
49% vs 47%
80 vs 94
199 vs 213
083
00023 (PFS)
Anti-EGFR trials
Anti-VEGF trials
Combined anti-EGFR and anti-VEGF trials

BOND 2185
Treated (irinotecanrefractory)
Cetuximab+bevacizumab vs irinotecan 40 vs 43
+cetuximab+bevacizumab
20% vs 37%
49 vs 73 (TTP)
114 vs 145
NR
NR
PACCE186
Untreated
Oxaliplatin-based
chemotherapy+bevacizumab vs
oxaliplatin-based chemotherapy+
bevacizumab+ panitumumab
410 vs 413
48% vs 46%
114 vs 100
245 vs 194
127
NR on PFS
CAIRO-2187
Untreated
XELOX+ bevacizumab vs XELOX+

bevacizumab+cetuximab
368 vs 368
50% vs 527%
107 vs 94
203 vs 194
122
p=001 (PFS)
PFS=progression-free survival. OS=overall survival. EGFR=epidermal growth factor receptor. TTP=time to progression. NR=not reported. FOLFIRI=uorouracil and irinotecan. FOLFOX=uorouracil and oxaliplatin.
ORR=overall response rate. CAPEOX=capecitabine and oxaliplatin. VEGF=vascular growth factor receptor. IFL=bolus uorouracil and irinotecan. XELOX=capecitabine and oxaliplatin. *Unless otherwise indicated. For
comparison between control and investigational groups (all-comers and not according to KRAS status). Patients with wild-type or mutated KRAS were randomised in the intent-to-treat population, but data shown
are for the primary and secondary efficacy analyses done in the KRAS wild-type population only. Coprimary endpoints. 230 additional patients were treated with irinotecan-based chemotherapy but the primary
efficacy analysis was restricted to the oxaliplatin cohort (n=823).
Table 3: Selected randomised trials of targeted drugs for metastatic colorectal cancer
discussions of adjuvant chemotherapy. Tests of

microsatellite instability might contribute to the riskbenet assessment of treatment in stage II disease. In
QUASAR,154 patients with stage II colorectal cancer
older than 70 years did not seem to benet from
chemotherapy, and the question is whether to treat or
not to treat this age group. In the MOSAIC study, the
benet of adjuvant oxaliplatin and uorouracil in stage
II disease seemed small (no gain in 6-year overall
survival, hazard ratio for 5-year disease-free survival
1038
084), with a non-signicant benet in patients with

high-risk stage II cancer (23% gain in 6-year overall
survival, hazard ratio for 5-year disease-free survival
072).145 Central to the decision-making process
for adjuvant treatment (monotherapy or oxaliplatinbased) in all patients (stage II and III disease, older
patients, and those with comorbidities) is discussion
with the patient, and incorporation of the patients
preference after accurate communication of benets
and risks of treatment.
Seminar
KRAS
assessed
n (%)
Treatment
groups (control
vs EGFR mAB)
KRAS
Wild
type
Mutated
Response rate
All
KRAS wild
type
Progression-free survival (months*)
Overall survival (months)
KRAS
mutated
All
KRAS wild type
KRAS
mutated
All
KRAS wild type
KRAS
mutated
NCIC CO17190
394
(69%)
230
(58%)
164
(42%)
BSC vs cetuximab
0 vs 8% 0 vs
128%
0 vs 12%
NR
19 vs 37, HR
040, p<0001
18 vs 18, HR
099, p=096
46 vs 48 vs 95, HR
61
055, p<0001
EPIC191
300
(23%)
192
(64%)
108
(36%)
Irinotecan vs
cetuximab+
irinotecan
42% vs 74% vs
164% 103%,
p=061
51% vs
122%,
p=029
26 vs 40
28 vs 40,
HR 077,
p=0095
27 vs 26, HR
100, p=098
10 vs
107
116 vs 109,
107 vs 84,
HR 129, p=018 HR 128,
p=029
Amado, et al192
427
(92%)
243
(57%)
184
(43%)
BSC vs
panitumumab
0 vs
10%
0 vs 17%
0 vs 0
73 weeks
vs 80
weeks
73 weeks vs 123 73 weeks vs

weeks, HR 045, 74 weeks,
HR 099
p<0001
NR
76 vs 81,
HR 099
44 vs 49,
HR 102
CRYSTAL189,193
(200910
update)
1063
(89%)
666
(63%)
397
(37%)
FOLFIRI vs
cetuximab+
FOLFIRI
397% vs
593%,
p<00001
361% vs
313%,
p=0348
84 vs 99, HR
77 vs 74, HR
0696, p=00012 1171,
p=02761
20 vs 235, HR
0796,
p=00093
167 vs 162,
HR 1035,
p=07551
OPUS189 (2009
update)
315
(93%)
179
(57%)
136
(43%)
FOLFOX vs
cetuximab+
FOLFOX
34% vs
573%,
p=00027
525% vs
328%,
p=0290
72 vs 83, HR
85 vs 55, HR
0567, p=00064 1720,
p=00153
185 vs 228, HR 175 vs 134,

HR 1290,
0855,
p=02004
p=03854
COIN179
1305
(80%)
724
(56%)
561
(43%)
FOLFOX+CAPEOX
vs cetuximab/OX
50% vs
59%
41% vs
40%
86 vs 86, HR
0959, p=060
69 vs 65, HR
1065,
p=046
179 vs 170, HR
104, p=068
PRIME180
1096
(93%)
656
(60%)
440
(40%)
FOLFOX vs
panitumumab+
FOLFOX
48% vs
55%
40% vs
40%
80 vs 96, HR
08, p=002
88 vs 73, HR
129, p=002
197 vs 239,
193 vs 155,
HR 083, p=007 HR 124,
p=007
181 study181
1083
(91%)
597
(55%)
486
(45%)
FOLFIRI vs
panitumumab+
FOLFIRI
10% vs
35%
14% vs
13%
39 vs 59, HR
073, p=0004
49 vs 50, HR
085, p=014
125 vs 145, HR
085, p=012
46 vs 45, HR
098, p=089
148 vs 136,
HR 098,
p=08
111 vs 118,
HR 094,
p=055
Data are number (%) or %, unless otherwise indicated. mAB=monoclonal antibody. BSC=best supportive care. FOLFIRI=uorouracil and irinotecan. FOLFOX=uorouracil and oxaliplatin. CAPEOX=capecitabine
and oxaliplatin. HR=hazard ratio for comparison between control and EGFR-directed treatment. OX=oxaliplatin-based chemotherapy. NR=not reported. *Unless otherwise indicated. Refers to the unselected
intention-to-treat population. Have been prospectively analysed according to KRAS status.
Table 4: KRAS mutation status as a predictive marker of outcome to epidermal growth factor receptor (EGFR)-directed monoclonal antibodies
Of the targeted treatments assessed, addition of

adjuvant edrecolomab (a monoclonal antibody against
the epithelial cell adhesion molecule ) and bevacizumab
(a humanised monoclonal antibody against vascular
endothelial factor [VEGF]) to chemotherapy did not
improve disease-free survival.155,156 Ecacy results from
another study of adjuvant bevacizumab (AVANT study)
are awaited, and an interim analysis of a randomised
study of cetuximab (a monoclonal antibody targeted at
the epidermal growth factor receptor [EGFR]) added to
adjuvant uorouracil and oxaliplatin has indicated a lack
of benet with the cetuximab combination.157
Disease relapse after surgery, with or without adjuvant
chemotherapy, mostly occurs within 3 years.143 Intensive
follow-up strategies for patients with colorectal cancer can
improve
survival,
with
the
early
detection
of oligometastatic disease (commonly liver or lung)
and potential for further radical treatment in a third of
patients.158160 5-year survival after liver and lung resection
is about 3658% and 2741%, respectively.159,160
Surveillance should be through a combination of clinical
review, monitoring of serum carcinoembryonic antigen
every 36 months for 3 years and then every 612 months
until 5 years, imaging (most commonly CT) once a year
for the rst 3 years, and colonoscopy 1 year after surgery
and then every 35 years.160162
Treatment of metastatic disease

Palliative chemotherapy for metastatic colorectal cancer
can improve survival, lessen symptoms, improve
quality of life, and downsize liver-only or lung-only
metastases in patients with potentially resectable
disease. Survival has increased from 12 months with
uorouracil monotherapy to roughly 2 years with the
addition of irinotecan, oxaliplatin, and targeted drugs.
The use of infused uorouracil added to oxaliplatin
and to irinotecan has reduced toxicity and is commonly
used.163 Fluorouracil can be safely substituted with
capecitabine when combined with oxaliplatin without
loss of ecacy.164,165 For increments in survival, the
sequence of drugs used at rst presentation of disease
and then on disease progression seems less important
than is exposure to all active drugs during the treatment
pathway.166 Although initial combination treatment
is commonly used, rst-line uoropyrimidine
monotherapy is appropriate in some patients.167,168
When the aim is liver or lung resection, conversion
regimens with high response rates are preferable.169
Treatment might continue until disease progression or
for a xed duration (usually 6 months), depending on
toxicities, preference of the patient, and tumour
response. Intermittent scheduling has also been
investigated.170,171
1039
Seminar
Location
Function
Consequence
Microsatellite
instability
MSI-H
Reduces DNA nucleotide

mismatch repair (deciency)
Improved prognosis
KRAS
Chromosome 12, mutations at Reduces GTPase activity, leading

codons 12 and 13
to constitutive activation of
downstream pathways
Resistance to anti-EGFR
mAB
BRAF
V600E mutation
Constitutive activation of
downstream pathways
Resistance to anti-EGFR
mAB
TS
TSER 28 base pairs (2R)/(3R)

tandem repeat 5UTR
TS expression increased
Response to uorouracil
reduced
TS
TSER 3R G>C single-nucleotide TS expression reduced

polymorphism
Response to uorouracil
increased
ERCC-1
mRNA expression High
DNA excision repair
Resistance to platinumbased chemotherapy
Interleukin 8
Interleukin 8 T-251A (A/A)
VEGF expression increased
Recurrence increased
VEGF
VEGF C+936T (C/C)
VEGF expression increased
Recurrence increased
MSI-H=high-level microsatellite instability. EGFR=epidermal growth factor receptor. mAB=monoclonal antibody.

TS=thymidylate synthase. 2R=two tandom repeats. 3R=three tandem repeats. UTR=untranslated region. TSER=TS
enhancer region. ERCC-1=excision-repair cross-complementing-1. VEGF=vascular-endothelial growth factor.
Table 5: Genetic markers and their clinical consequences in colorectal cancer
The main advance in the management of metastatic

colorectal cancer in the past 5 years has been the
addition of targeted treatments. Cetuximab, bevacizumab,
and panitumumab (a fully human EGFR monoclonal
antibody), the only licensed targeted drugs, have,
however, had a relatively small eect on survival
outcomes. Table 3 shows the main randomised studies
and summarises the ecacy outcomes of these drugs
when used as monotherapy or as part of combination
treatment.
In chemorefractory patients, cetuximab showed activity
when used alone, and reversal of irinotecan-resistance
when used with irinotecan.172 Activity of cetuximab alone
or in combination with irinotecan in chemorefractory
patients has been conrmed in further studies173,174,188 and
activity has now been demonstrated for cetuximab in
combination with uorouracil and irinotecan, and
uorouracil and oxaliplatin regimens in untreated
patients (table 3).176178 Crossover to a cetuximab-based
regimen might have masked survival dierences between
treatment groups in pretreated patients, and subsequent
treatments might have aected the survival results in
untreated patients. First-line treatment with cetuximab
added to uorouracil and irinotecan marginally improved
progression-free survival in the CRYSTAL study.176
However, retrospective subgroup analysis showed
signicantly improved response rates and progressionfree survival in patients with liver-only metastases and
KRAS wild-type tumours, and increased rates of liver
resection with combination treatment. With longer
follow-up, the dierence in progression-free and overall
survival between the two groups in patients with wildtype KRAS has increased and the dierence in overall
survival is now signicant (table 3).189 By contrast,
although comparison of oxaliplatin-based chemotherapy
(investigators choice) with or without cetuximab in the
1040
COIN trial179 showed a higher response rate in the

cetuximab combination group, it did not show a
signicant improvement in progression-free or overall
survival even in patients with wild-type KRAS and BRAF.
Panitumumab has been approved as monotherapy for
pretreated patients.175 It signicantly improved
progression-free and overall survivals when given with
uorouracil and oxaliplatin to untreated patients with
wild-type KRAS tumours (PRIME study).180 Panitumumab
in combination with irinotecan and uorouracil also
resulted in a signicant improvement in progressionfree but not overall survival in pretreated patients with
wild-type KRAS.181 KRAS mutation status has been
consistently identied as a predictor of patient response
to EGFR-directed monoclonal antibodies (table 4), and
cetuximab and panitumumab are now only oered to
patients with wild-type KRAS colorectal cancer. Rash,
diarrhoea, and hypomagnesaemia are characteristic
toxicities of anti-EGFR drugs.
Bevacizumab is an antiangiogenic monoclonal
antibody and can also cause normalisation of tumour
vasculature, thereby improving drug delivery to the
target.
Its
side-eects
include
hypertension,
gastrointestinal perforation, delayed wound healing,
bleeding, and thromboembolism. Bevacizumab, when
administered with chemotherapy that included bolus
irinotecan and uorouracil, improved overall survival
by 47 months and response rates by 10% in untreated
patients with metastatic colorectal cancer.182 However,
these results were not replicated when bevacizumab
was given with oxaliplatin-based chemotherapy to
untreated patients,184 whereas the combination
signicantly prolonged survival in previously treated
patients (table 3).183 Failure to continue combination
treatment until disease progression and possible
occurrence of VEGF rebound might have contributed
to these contradictory ndings.184 Whether bevacizumab
should be continued after disease progression with a
change of the cytotoxic drugs remains an important
question, and an observational series suggested
prolongation in survival with this strategy.194
Maintenance bevacizumab after initial response to
combination treatment is being investigated, but this
drug has little activity when used alone.183 The risk of
postoperative complications, including delayed wound
healing, is increased with bevacizumab. However, the
risk seems to be low when an interval of 6 weeks from
the last bevacizumab dose to surgery is allowed.195
Addition of cetuximab to capecitabine, oxaliplatin, and
bevacizumab (CAIRO trial),187 and of panitumumab to
bevacizumab in combination with irinotecan or
oxaliplatin-based chemotherapy (PACCE trial)186 in
untreated patients with metastatic disease worsened
progression-free survival and increased toxicity,
indicating a possible negative interaction of combining
these targeted drugs despite encouraging results in a
previous phase II trial (table 3).185
Seminar
Bevacizumab received regulatory approval in 2004

for rst-line treatment of metastatic colorectal cancer
in combination with uoropyrimidine-based chemotherapy, and was widely considered a standard rst-line
treatment. However, the licence for rst-line cetuximab
plus chemotherapy on the basis of the results of the
CRYSTAL study176 and increased rates of liver resection
in patients with wild-type KRAS tumours and initially
unresectable liver-only metastases provides another
treatment option. Nevertheless, the benets of
cetuximab compared with bevacizumab have not been
proven in this setting. Regulatory approval was granted
for cetuximab to be used as monotherapy or as
combination therapy in 2004 in pretreated
chemotherapy-resistant patients for whom there are
few treatment options, and for panitumumab
monotherapy in 200607 in patients with wild-type
KRAS pretreated tumours. However, outside the USA,
the cost has to some extent restricted the use of
cetuximab, panitumumab, and bevacizumab; thus,
identication of subgroups most likely to benet from
treatment could improve cost eectiveness. For
instance, in the UK, cetuximab was only approved by
the National Institute for Health and Clinical Excellence
(NICE) for wild-type KRAS non-resectable liver-only
metastatic colorectal cancer.196
Prognostic and predictive molecular markers

Prognostic biomarkers are associated with survival that
is independent of the treatment eect. Predictive
biomarkers indicate likely benet of treatment. Markers
can be prognostic and predictive. The most important
development in molecular markers for metastatic
colorectal cancer has been the validation of KRAS
mutation status as predictive of non-response to EGFRtargeted drugs. In the adjuvant setting, prognostic and
predictive molecular markers (microsatellite instability
and 18q imbalance) could potentially be used to
discriminate between molecular phenotypes in stage II
disease (clinically heterogeneous), thereby contributing
to the risk-benet assessment of adjuvant treatment
(table 5). However, complex pathways contribute to
disease progression and, in general, single markers
might not be entirely useful for prediction of ecacy
and outcome. With high-throughput genome-wide
screening, predictive and prognostic molecular
signatures are increasingly being sought but, as yet,
none have been validated for clinical use.
Roughly 40% of patients with metastatic colorectal
cancer have somatic activating KRAS mutations. These
mutations are highly predictive of non-response to
EGFR inhibitors (table 4). The updated results of
CRYSTAL189 showed a signicant improvement in
response rate, progression-free survival, and overall
survival (235 months vs 200 months, p=00094) for
patients with wild-type KRAS tumours given
uorouracil, irinotecan, and cetuximab compared with
patients with mutant KRAS tumours who did not seem

to benet from treatment. The updated results of
OPUS189 also showed a signicant increase in response
rate and progression-free survival (hazard ratio 0567,
95% CI 03750856, p=0006), but not in overall
survival in patients with wild-type KRAS given
cetuximab plus uorouracil and oxaliplatin (table 4).
The predictive value of KRAS mutation status was
conrmed in a meta-analysis of CRYSTAL and OPUS.189
Similarly, KRAS mutation status is useful for prediction
of the response to panitumumab.180,181,192 Importantly,
patients with KRAS-mutated tumours given rst-line
oxaliplatin-based chemotherapy had worse progressionfree survival and overall survival (table 4) in the PRIME
study,180 worse progression-free survival in OPUS,177
and a non-signicantly inferior overall survival in
COIN.179 In randomised studies of irinotecan-based
chemotherapy plus EGFR-directed monoclonal
antibodies, a detrimental eect on survival in patients
with KRAS mutant tumours has not been observed.181,189
KRAS mutation status should be established before
starting treatment.
However, not all 60% of patients with wild-type KRAS
will respond to treatment. Additional factors, such as
amphiregulin and epiregulin, might contribute to
treatment response; and mutation of BRAF or NRAS,
or loss of PTEN or PIK3CA activation might contribute
to resistance to EGFR-targeted monoclonal antibodies.197
BRAF is the main downstream eector of KRAS.
Mutations that activate BRAF arise in 810% of
metastatic colorectal cancers and are mutually exclusive
of KRAS mutations. BRAF mutation was associated
with poor prognosis (reduced progression-free and
overall survival) in patients (n=113) with metastatic
colorectal cancer given anti-EGFR antibodies.198 The
predictive value of BRAF mutations is yet to be
prospectively assessed, and although the results of the
CRYSTAL study199 suggested no association with
resistance to rst-line cetuximab in combination with
chemotherapy, statistical power was low.
High-frequency microsatellite instability is present
in almost 22% of stage II colorectal cancers compared
with in 12% of stage III tumours.200 In a pooled analysis
of 7642 patients treated with adjuvant uorouracil,
tumours with high-frequency microsatellite instability
were associated with signicantly improved prognosis
compared with tumours that were microsatellite
stable.201 Data for the prognostic eect of this
microsatellite instability were contradictory in patients
given
irinotecan-based
chemotherapy,200,202
and
subgroup analysis suggested a stronger eect in stage
II than in stage III colorectal cancer, possibly
attributable to stage-specic biological eects of
microsatellite instability.200 Patients who have tumours
with high-frequency microsatellite instability do not
seem to benet from adjuvant uorouracil.203 These
ndings were corroborated in a pooled analysis, which
1041
Seminar
also showed that decient mismatch repair (a surrogate

for high-frequency microsatellite instability) was
associated with a signicant reduction in overall
survival (hazard ratio 315, p=003) in patients with
stage II disease given adjuvant uorouracil.204 Hence
microsatellite-instability status might be used to decide
which of these patients (about a fth of those with
stage II colorectal cancer) should not be treated with
adjuvant uorouracil.200
Results from studies have suggested an association
between loss of heterozygosity at chromosome 18q
with poor prognosis in patients with colorectal
cancer.205208 Although the microsatellite-stability status
was not assessed in all the studies, it is an important
covariable since loss of heterozygosity of 18q is rarely
noted in tumours with high-frequency microsatellite
instability. Allelic imbalance at 18q had a negative eect
on overall survival in patients with stage III
microsatellite-stable colorectal cancers,208 but this result
was not replicated in other studies.209212 The 18q region
contains several important candidate genes, including
SMAD7, SMAD4, SMAD2, and DCC, and, in stage III
colon cancer, reduced SMAD4 expression was
associated with poor prognosis with uorouracil-based
chemotherapy.213,214 18q imbalance might also be a
surrogate marker for the complex chromosomal
instability phenotype arising in most colon tumours.215,216
An investigation of the use of microsatellite instability
and 18q loss of heterozygosity to decide which adjuvant
treatment should be assigned in patients with stage II
colorectal cancer is in progress (no treatment if
tumour has high-frequency microsatellite instability or
retention of 18q).
Other extensively studied potential prognostic and
predictive markers include thymidylate synthase (the
primary target of the active metabolite of uorouracil),
excision-repair cross-complementing-1 (implicated in
resistance or sensitivity to platinum drugs), VEGF and its
receptors, and the interleukins (table 5).
Conclusions
There have been considerable advances in understanding
the molecular pathogenesis, in diagnosis (hereditary
and sporadic), and in treatment of colorectal cancer.
Despite the use of active targeted drugs for treatment of
metastatic colorectal cancer in the past decade, and
improvement of overall survival to nearly 2 years for
non-resectable disease, cure rates remain low. Parallel
development of predictive molecular and clinical
markers is paramount to achieve the best outcomes
from targeted treatments, and KRAS is the only
validated
predictive
molecular
marker
in
colorectal cancer for EGFR-directed monoclonal
antibodies. Clinical and translational research that is in
progress will hopefully help to provide the much
promised hope of personalised medicine in the
management of this cancer.
1042
Contributors
All authors provided nal review and approval for the Seminar, and input
into responding to reviewers comments. DC co-wrote sections about
adjuvant treatment for early disease and treatment of metastatic disease,
and also provided overall structure and editing for the Seminar. WA wrote
the section about screening. HJL wrote sections about molecular
carcinogenesis, and prognostic and predictive molecular markers. HTL
wrote the section about genetic epidemiology. BM wrote the section about
radiation for rectal cancer. BN wrote the section about diagnosis and
staging, and surgery. NS co-wrote sections about adjuvant treatment for
early disease and treatment of metastatic disease, collated individual
sections for the whole Seminar, and provided the search strategy.
Conicts of interests
BM has been on speakers bureau for Sano-Aventis, Genentech, and
Roche; and has been a consultant for Sano-Aventis. HJL is a consultant
for Response Genetics. BMS is a consultant for ImClone and Merck,
and holds stock options for Response Genetics. DC has received
research funding from Sano-Aventis, Roche, Amgen, Pzer, Merck,
Novartis. WA, BN, and NS declare that they have no conicts of interest.
Acknowledgments
DC is part funded by the National Institute for Health Research
Biomedical Research Centre.
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Seminar

Search strategy and selection criteria

ie, frameshift mutations and base-pair substitutions that

environmental factors (eg, red meat, high-fat diet,

Genetic epidemiology: Lynch syndrome as model

Hereditary and sporadic

Table 1: Molecular classication of colorectal carcinoma

Panel 1: Cardinal features of Lynch syndrome (hereditary non-polyposis

genetic and phenotypic features of the syndromes

Panel 2: Revised Bethesda guidelines29 and Amsterdam criteria26 for identication of

mismatch-repair system, most commonly MSH2 and

increase in endometrial cancer. PMS2 mutations

endometrial cancer (4060% lifetime risk) beginning at

Screening of colorectal cancer

below the commonly used threshold of US$50 000 per

Grade 3 or more acute toxicity

Gerard et al35 (ACCORD)

11% vs 25% (p<0001)

Aschele et al36 (STAR)

15% vs 24% (p<0001)

3% wound complication, requiring surgery

22% diarrhoea, 9% hypertension, 6% skin, 3% dehydration,

19% diarrhoea, 4% rash, 4% neuropathy

Mohiuddin et al40 (RTOG

57% haematological and non-haematological toxicities vs

Wong et al41 (RTOG 0247)

8% haematological, 24% non-haematological toxicities vs

17% vs 51% (p=000004)

Table 2: Selected novel preoperative chemoradiation regimens

Figure: High-resolution MRI of rectal cancer

scheme, delivery of screening within a high-quality

Diagnosis and staging

to rule out metachronous tumour, and CT of the chest,

Panel 3: Advantages and limitations of MRI and endorectal

Panel 4: TMN classication of colon cancer91

In patients with early rectal cancer, the choice of

survival despite earlier reports of an increased rate of R1

Radiation treatment for rectal cancer

circumferential resection margin is not suciently

chemoradiation. Chemotherapy was better tolerated in

Adjuvant treatment for early stage disease

adjuvant trials and uptake of eective treatments.

Hazard ratio p value for

Cetuximab alone vs irinotecan-based

Best supportive care vs cetuximab

Best supportive care vs panitumumab

Untreated liver-only FOLFOX+cetuximab vs FOLFIRI+

68% (95% CI 5480) vs

Untreated wild-type FOLFOX or CAPEOX vs

Untreated wild-type FOLFOX vs FOLFOX+panitumumab

Pretreated wild-type FOLFIRI vs FOLFIRI+panitumumab

291 vs 286 vs 86% vs 227% vs 33%

Combined anti-EGFR and anti-VEGF trials

XELOX+ bevacizumab vs XELOX+

discussions of adjuvant chemotherapy. Tests of

084), with a non-signicant benet in patients with

Progression-free survival (months*)

Overall survival (months)

KRAS wild type

KRAS wild type

73 weeks vs 123 73 weeks vs

185 vs 228, HR 175 vs 134,

Of the targeted treatments assessed, addition of