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182
P. Rooney and N. Pranesh
often for SCPRT than surgery alone patients. Postoperatively, both vaginal dryness
and pain during intercourse worsened for all women. Subgroup analyses for APR
and LAR patients demonstrated a similar overall outcome.
APR patients had more diffi culties with voiding and erection and reported more
pain during intercourse compared with patients undergoing low anterior resection
but had signifi cantly fewer physical and psychological problems. The incidence of
fecal incontinence at 24 months was signifi cantly more in SCPRT patients than
those having surgery alone (51.3% vs. 36.5%, P = 0.002) The authors found no dif-
ferences in perceived health between patients who underwent APR versus LAR and
concluded that sphincter sparing surgery might not always improve HRQL [
31 ] .
An analysis of the benefi ts and harm of SCPRT in patients with resectable rectal
cancer was performed by Bakx et al.; they concluded that approximately 10% of
patients benefi t (with no harm) or are harmed (with no benefi t) from SCPRT. Thus,
the majority of patients are neither benefi tted nor harmed by this treatment [ 32 ] .
Currently we are unable to select in advance of treatment, those who will benefi t
and those who will be harmed.
In a recent Cochrane review of preoperative radiotherapy and surgery for the
management of localized rectal cancer, the proportion of patients with no acute
toxicities postoperatively favored the surgery alone group with a relative risk of
0.88 (95% CI 0.82–0.94), number needed to harm = 14. (This is the inverse of the
attributable risk, i.e., the number of patients who need to be treated by SCPRT +
Surgery to cause harm to one patient who would not have been harmed if not given
SCPRT.) Gerard et al. compared preoperative long-course RT (45 Gy in 25 frac-
tions) with the same RT and 5FU/folinic acid (CRT) in patients with a T3/T4 rectal
cancer. All patients also received four cycles of adjuvant 5FU/folinic acid. Acute
toxicity was signifi cantly higher in the CRT arm (14.6 vs. 2.7 grade ¾ toxicity,
P < 0.0001) [ 19 ] .
In the German trial comparing preoperative CRT with postoperative CRT for
rectal cancer, the acute and long-term toxic effects of preoperative CRT included
gastrointestinal and skin complaints in about 5% of patients.
13.6 Surgery: Where to Resect; When to Anastomose
For tumors in the upper rectum, a 5-cm distal mesorectal margin is adequate, anas-
tomosis is performed in almost all patients, and a defunctioning stoma avoided in
the vast majority.
For lesions in the mid and low rectum, a TME is performed, and an anastomosis
at or near to the top of the anal canal is performed. Anastomoses within 6 cm of the
anal verge are associated with an increased risk of anastomotic leaks, and as a result,
many surgeons now routinely cover the anastomosis with a covering loop stoma. A
recent meta-analysis of randomized controlled trials has demonstrated lower clinical
anastomotic leak rate (risk ratio 0.39, 95% CI 0.23–0.66, P < 0.001) and lower
183
13 Evidence-Based Management of Rectal Cancer
reoperation rate (risk ratio 0.29 (0.16–0.53), P < 0.001) in the stoma group. Meta-
analysis of the nonrandomized studies arrived at similar conclusions and also showed
a lower mortality rate (risk ratio 0.42 (0.28–0.61), P < 0.001) [ 33 ] . Even when there
are no anastomotic complications, anorectal function can be poor. Early postopera-
tive function (for the fi rst year after surgery) is improved by the use of a colon pouch.
After this time, function for patients with and without a pouch is similar [
34 ] .
Acceptance that the distal resection margin in low tumors can be 1 cm or even
less has resulted in increased use of ultralow anterior resections. In selected cases in
patients with small tumors, it is even possible to excise the cancer with a cuff of
internal anal sphincter and achieve oncological clearance and preserve adequate
sphincter function [ 35 ] .
Rectal tumors (lower one third) treated by means of an abdominoperineal exci-
sion (APE) have higher rates of CRM positivity, local recurrence, and lower survival
rates compared with anterior resection [ 36, 37 ] . There is also a higher rate of intra-
operative perforation of the specimen in APE compared to anterior resection. The
technique of extralevator AP resection (ELAP) produces a cylindrical specimen with
consequent increase in the volume of tissue resected and decrease in perforation and
CRM rates [ 38 ] . The principles of operation are that the mesorectum is not dissected
off the levator muscles, the perineal dissection is done in the prone position, and the
levator muscles are resected en bloc with the anus and lower rectum [ 39 ] . The tech-
nique results in an increased risk of perineal wound complications [ 37 ] .
Although there is no evidence from randomized trials to support cytocidal rectal
lavage prior to anastomosis, there is clear evidence that cancer cells are shed by
tumors with the potential for implantation [ 40 ] , for example, cancer cell implanta-
tion in hemorrhoidectomy wounds. This is also the basis for not performing endo-
scopic polypectomy distal to a colonic malignancy.
Lateral lymph node metastasis (LLNM) is reported to develop in 10–25% of
patients with locally advanced rectal cancer. It is thought to be a result of spread of
tumor cells from cancers of the mid/lower rectum through the lateral lymphatic
drainage along the internal iliac artery, outside the mesorectum. It represents dis-
ease that would not be removed by a TME and is thought to be a cause of local
recurrence [ 41 ] (see comments on benefi ts of SCPRT in the CR07 trial). This led
to the development of lateral pelvic lymph node dissection (LPLD). A study by
Sato where this technique was performed demonstrated the presence of involved
LLNMs in patients with rectal cancer. LPLD is associated with increased operat-
ing times and blood loss with a high risk of bladder and sexual dysfunction with
resulting deterioration in quality of life. Who can get the benefi cial effect from
lateral lymph node dissection for Duke C rectal carcinoma below the peritoneal
refl ection [ 42 ] . As the results of treatment for most patients with rectal cancer are
now good, recent studies have focused on selecting patients who may benefi t from
this treatment. One such study found lateral lymph node metastases were a major
cause of locoregional recurrence following preoperative CRT and curative resec-
tion and that the size of the lateral lymph nodes and the presence of pathologically
positive lymph nodes (ypN+) predicted lateral pelvic recurrence [ 41 ] .
184
P. Rooney and N. Pranesh
LLNM may be considered to be a sign of systemic disease because in studies
where LLNM were present and local control was achieved with LPLD, 5-year sur-
vival rates were only 20–45% due to distant metastases [ 42 ] .
Laparoscopic rectal cancer surgery has reopened the debate about high (above
the origin of the left colic artery) vs. low ligation of the inferior mesenteric artery
[
43 ] . Several studies have compared these two approaches and found no oncological
benefi t to high ligation; however this will maximize lymph node harvest. The ratio-
nale for high ligation is a technical one. In open surgery, preservation of the (rela-
tively short) left colic artery can limit the descending colon from reaching the anus
for a low tension-free anastomosis or formation of colon pouch. Some laparoscopic
surgeons preserve the upper branches of the inferior mesenteric artery and do not
report the same mobility problems [ 44 ] .
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The routine use of MRI to stage rectal cancer coupled with MDT evalua-•
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High-quality TME surgery will achieve low recurrence rates. •
There is abundant evidence from randomized trials that the use of SCPRT •
reduces local recurrence.
There is also evidence of an increase in morbidity associated with •
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185
13 Evidence-Based Management of Rectal Cancer
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therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg.
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rectal carcinoma treated with neoadjuvant chemoradiotherapy. Ann Surg Oncol.
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27. Hiotis SP, et al. Assessing the predictive value of clinical complete response to neoadjuvant
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29. Marijnen CA, et al. Acute side effects and complications after short-term preoperative radio-
therapy combined with total mesorectal excision in primary rectal cancer: report of a multi-
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life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial. J
Clin Oncol. 2005;23(9):1847–58.
32. Bakx R, et al. Harm and benefi ts of short-term pre-operative radiotherapy in patients with
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cer. Br J Surg. 2009;96(5):462–72.
34. Koh PK, et al. A systematic review of the function and complications of colonic pouches. Int
J Colorectal Dis. 2007;22(5):543–8.
35. Tiret E, et al. Ultralow anterior resection with intersphincteric dissection – what is the limit of
safe sphincter preservation? Colorectal Dis. 2003;5(5):454–7.
36. Marr R, et al. The modern abdominoperineal excision: the next challenge after total mesorectal
excision. Ann Surg. 2005;242(1):74–82.
37. West NP, et al. Multicentre experience with extralevator abdominoperineal excision for low
rectal cancer. Br J Surg. 2010;97(4):588–99.
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39. Holm T, et al. Extended abdominoperineal resection with gluteus maximus fl ap reconstruction
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187
S.R. Brown et al. (eds.), Contemporary Coloproctology,
DOI 10.1007/978-0-85729-889-8_14, © Springer-Verlag London Limited 2012
Abbreviations
5-FU 5-Fluorouracil
ASCO American Society of Clinical Oncology
CEA Carcinoembryonic antigen
CRC Colorectal cancer
CRUK Cancer Research UK
CTC Circulating tumor cell
DNA Deoxyribonucleic acid
EGF Epidermal growth factor
EGFR Epidermal growth factor receptor
EGTM European Group on Tumor Markers
HNPCC Hereditary nonpolyposis colorectal cancer
F. E. Marti , LMS, MRCP (*)
Department of Medical Oncology , The Christie Hospital NHS Foundation Trust
and Paterson Institute for Cancer Research ,
Wilmslow Road , Manchester , M20 4BX , UK
e-mail: kalenamm@doctors.org.uk
M. P. Saunders
Department of Oncology , Christie Hospital NHS Foundation Trust ,
Wilmslow Road , Manchester , M20 4BX , UK
e-mail: mark.saunders@christie.nhs.uk
Chapter 14
Chemotherapy and Biomarkers
Biomarkers in Colorectal Cancer: Present and Future
Francisca E. Marti and Mark P. Saunders
188
F.E. Marti and M.P. Saunders
IHC Immunohistochemistry
KRAS V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
MMR Mismatch repair
MSI Microsatellite instability
MSS Microsatellite stable
PCR Polymerase chain reaction
14.1 Introduction
Traditionally, clinicians have relied on histological and radiological parameters to
assign prognosis to patients and to predict outcomes. In colorectal cancer, this has
classically been represented by the TNM and Dukes’ classifi cation. Although in
most cases this is a good estimation of recurrence risk and overall outcome, clinical
practice tells us that within each stage of the disease, there is a wide spectrum of
outcomes. Important issues like the selection of adjuvant chemotherapy for patients
with stage II colorectal cancer remain unanswered. Current chemotherapy regimens
and radiotherapy used in the treatment of both early and advanced disease have vari-
able rates of response within populations, and a priori, there is no objective way to
predict response. The only exception to this is the recent discovery of the impor-
tance of the KRAS status (mutant or wild-type) in treatment with cetuximab, a
monoclonal antibody targeting the epidermal growth factor receptor. It is this lack
of additional prognostic and predictive information that has driven the research into
biomarkers.
14.2 Biomarkers : Defi nition and Types
A biomarker is a characteristic that is objectively measured and evaluated as an
indicator of normal biological processes, pathogenic processes, or pharmacologic
responses to a therapeutic intervention [ 1 ] .
Biomarkers are classifi ed according the type of information they relay (see Table
14.1 ) and also according to the test/material used in the analysis (serological bio-
markers; imaging biomarkers, tissue biomarkers, etc.). In clinical practice, biomark-
ers that are useful are those with prognostic and/or predictive properties that
infl uence the treatment a patient is offered. For example, if a biomarker panel pre-
dicts a poor outcome (prognostic biomarker), more intensive treatments might be
proposed; a predictive biomarker of response, however, might spare some patients
toxicities from ineffective drugs.
The rest of this chapter will look at commonly used biomarkers in colorectal
cancer (CRC) and ongoing research in the fi eld.
189
14 Chemotherapy and Biomarkers
14.3 Risk Assessment/Predisposition Biomarkers
14.3.1 Microsatellite Instability
Microsatellites are repetitive sequences of nucleotides (one or more) that are distrib-
uted and found throughout the genome. These areas of repetition are prone to the
accumulation of mutations which eventually might lead to instability. The majority of
Table 14.1 CRUK-accepted defi nitions for biomarkers
Type of biomarker
Defi nition
Risk
a
Biomarker that identifi es individuals at
increased risk of developing cancer
Screening
b
Biomarker able to identify disease at an early
stage
Diagnostic
c
Biomarker used to defi ne the type of cancer
the patient has
Pharmacological
d
Biomarker of drug effect on a target or a
feature of tumor biology
Predictive
e
Biomarker that identifi es the subpopulations
of patients who are most likely to respond
to a given therapy
Prognostic
f
Biomarker that indicates the likely course of
the disease
Surrogate response Biomarkers that can be used as a substitute
for a clinically meaningful endpoint
a
Risk assessment/predisposition BMs: biomarkers that can be used to defi ne individuals or popula-
tions that are at increased risk of developing a disease. These may be markers of a genetic predis-
position or a measure of exposure to a substance that increases that individual’s risk. For example,
the adenomatous polyposis coli (APC) gene and familial adenomatous polyposis (FAP).
b
Screening/early detection BMs: biomarkers used to aid early diagnosis of a condition, thus allow-
ing detection at a more treatable stage. For example, fecal occult blood testing in colorectal
cancer.
c
Diagnostic BMs: biomarkers used to defi ne the type of cancer or disease. These can be used
alongside standard imaging techniques. For example, PSA, CEA, and CA-125. Diagnostic bio-
markers can also be utilized to detect recurrent or relapsing disease.
d
Pharmacological BMs: biomarkers used to assess pharmacokinetics; measure the effects of drug
treatment on a specifi c target, for example. enzyme inhibition, receptor blockade, induction of
apoptosis, or reduction in angiogenesis (proof of mechanism); or demonstrate clinical effects of
that drug. These BMs can be used to aid dose optimization and reduction in side effects.
e
Predictive BMs: biomarkers that can predict a subpopulation of patients who are likely to respond
to a given therapy. For example, KRAS and response to anti-EGFR therapy in metastatic colorectal
cancer.
f
Prognostic BMs: biomarkers used to predict the likely course of a disease. For example, a bio-
marker that may refl ect a cancer’s metastatic potential or likely growth rate. This may be used to
estimate outcome and guide treatment and surveillance decisions. A number of these have been
suggested in colorectal disease, but many lack validation.
190
F.E. Marti and M.P. Saunders
errors found in these sequences are base-to-base mismatch that have escaped the con-
trol activity of the DNA polymerases. Defects in the DNA mismatch repair (MMR)
machinery, usually in charge of dealing with mismatch errors, compromise the effec-
tive repair of these resulting ultimately in microsatellite instability (MSI) [ 2 ] .
About 15% of colorectal cancers (CRC) harbor a defi cient MMR system. Three
percent of these represent inherited MMR defects (hereditary nonpolyposis colorec-
tal cancer or HNPCC or Lynch syndrome), and the other 12% correspond to sporadic
cases [ 3 ] . Lynch syndrome is an autosomal dominant disease which is linked to an
increased risk of several malignancies especially colorectal and endometrial cancers.
This increased risk is due to defects in the MMR system. The MMR genes that are
commonly found altered in inherited cases of MSI are MLH1, MSH2, and MSH6 to
a lesser extent. Alterations of MLH1 are also commonly seen in sporadic cases [ 4 ] .
MSI tumors have a characteristic clinical presentation (see Table 14.2 ). They
tend to be found in the proximal colon and overall have a lower stage at presenta-
tion. In terms of age distribution, the familial cases tend to present earlier than the
sporadic ones.
The Amsterdam criteria were originally devised by the International Collaborative
Group on HNPCC in 1991 [ 5 ] as a fi rst attempt to unify diagnosis and research efforts
in this area. The original Amsterdam criteria had a sensitivity and specifi city of around
60% and 70% respectively [ 6 ] . This initial version of the guidelines did not take into
account important factors such as extracolonic malignancies and a second set of
guidelines named the “Amsterdam II criteria” were proposed (see Table 14.3 ) [ 7 ] . The
estimated sensitivity and specifi city for these are 78% and 61%, respectively [ 6 ] .
In 1996, the Bethesda guidelines were published by the National Cancer Institute
that included the reported clinical and histological characteristics of these tumors
(Table 14.4 ) [ 4 ] . These guidelines were much less restrictive than the Amsterdam
criteria and aim to identify the families that should be offered MSI testing prior to
proceeding to MMR mutation testing. The sensitivity of these guidelines is esti-
mated at 94% with a specifi city of 25% [ 6 ] .
Table 14.2 Clinical characteristics of MSI tumors
Proximal colon Diagnosis at lower stage
High histological grade Mucinous phenotype
High number of tumor infi ltrating lymphocytes Crohn’s-like host response
Familial <50 years of age Sporadic >70 years of age
Table 14.3 Amsterdam II criteria
There are at least three relatives with an HNPCC-associated cancer (large and small bowel,
endometrium, ureter, or renal pelvis, though not including stomach, ovary, brain, bladder,
or skin)
One affected person is a fi rst-degree relative of the other two
At least two successive generations are affected
At least one person was diagnosed before the age of 50 years
Familial adenomatous polyposis has been excluded
Tumors have been verifi ed by pathologic examination
All the above criteria must be met before a putative diagnosis of HNPCC can be made
191
14 Chemotherapy and Biomarkers
It is important to remember that both the Amsterdam criteria and the Bethesda
guidelines are only designed for those suspected cases of HNPCC and cannot be
extrapolated to sporadic cases of MSI.
MSI can be diagnosed either by PCR amplifi cation of specifi c microsatellite repeats
or by immunohistochemical analysis of MMR proteins. The criteria for DNA testing
were agreed upon during a consensus conference and are known as the Bethesda panel.
The Bethesda panel includes fi ve microsatellite loci that provide enough sensitivity
and specifi city for the diagnosis of MSI. Some laboratories have now expanded the
number of loci to a total of ten [ 4 ] in order to make the diagnosis easier. Based on these
criteria, MSI status is classifi ed into three separate categories: MSI-high (MSI-H),
MSI-low (MSI-L), or microsatellite stable (MSS) (see Table 14.5 ).
Initially used as a research tool, immunohistochemistry of individual MMR proteins
in tumor tissue is now increasingly used in a clinical setting. Absence of immunoreac-
tivity of a specifi c MMR protein identifi es the most likely candidate gene to harbor a
mutation, thus guiding mutational analysis. Immunohistochemistry is cheaper than
MSI, more likely to identify patients carrying MSH6 mutations, and has the potential
to be performed in most clinical pathology laboratories. Monoclonal antibodies to the
MMR proteins MLH1, MSH2, MSH6, and PMS2 are widely commercially available.
14.4 Diagnostic Biomarkers
14.4.1 Carcinoembryonic Antigen (CEA)
The oncofetal antigen CEA is probably best classifi ed in this section; however, due to
his poor sensitivity and specifi city, it is not a particularly good diagnostic biomarker.
Table 14.4 Bethesda guidelines for MSI testing
Individuals with cancer in families that meet the Amsterdam criteria
Individuals with two HNPCC-associated cancers including synchronous and metachronous
CRC or associated extracolonic cancers
Individuals with CRC and a fi rst-degree relative with CRC and/or HNPCC-related extracolonic
cancer and/or colorectal adenoma diagnosed at age <40 years
Individuals with CRC or endometrial cancer diagnosed at age <45 years
Individuals with right-sided CRC with an undifferentiated patter (solid or cribriform) on
histopathology diagnosed at age <45 years
Individuals with a signet-ring-cell-type CRC at age <45 years
Individuals with adenomas diagnosed at age <40 years
Any of the above should be tested for MSI and, if positive, proceed to MMR testing
Table 14.5 Original Bethesda 5 loci panel and revised 10 loci panel
Bethesda 5 loci panel
Extended 10 loci criteria
MSI-high Instability in ³ 2 loci
Instability in ³ 30% of loci
MSI-low Instability at 1 locus Instability 10–130% of loci
MSS No loci with instability Instability in <10% of loci
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