Colon Cancer, Adenocarcinoma
Introduction
Background
Invasive colorectal cancer is a preventable disease. Early
detection through widely applied screening programs is the
most important factor in the recent decline of colorectal
cancer in developed countries (seeDeterrence/Prevention).
Full implementation of the screening guidelines1can cut
mortality rate from colorectal cancer in the United States by
an estimated additional 50%; even greater reductions are
estimated for countries where screening tests may not be
widely available at present. New and more comprehensive
screening strategies are also needed.
Fundamental advances in understanding the biology and
genetics of colorectal cancer are taking place. This knowledge
is slowly making its way into the clinic and being employed to
better stratify individual risks of developing colorectal cancer,
discover better screening methodologies, allow for better
prognostication, and improve one’s ability to predict benefit
from new anticancer therapies.
In the past 10 years, an unprecedented advance in systemic
therapy for colorectal cancer has dramatically improved
outcome for patients with metastatic disease. Until the mid
1990s, the only approved agent for colorectal cancer was 5fluorouracil. New agents that became available in the past 10
years include cytotoxic agents such as irinotecan and
oxaliplatin,2 oral fluoropyrimidines (capecitabine and
tegafur), and biologic agents such as bevacizumab,
cetuximab, and panitumumab.3
Though surgery remains the definitive treatment modality,
these new agents will likely translate into improved cure
rates for patients with early stage disease (stage II and III)
and prolonged survival for those with stage IV disease.
Further advances are likely to come from the development of
new targeted agents and integration of those agents with
other modalities such as surgery, radiation therapy, and liverdirected therapies.
Pathophysiology
Genetically, colorectal cancer represents a complex disease,
and genetic alterations are often associated with progression
from premalignant lesion (adenoma) to invasive
adenocarcinoma. Sequence of molecular and genetic events
leading to transformation from adenomatous polyps to overt
malignancy has been characterized by Vogelstein and
Fearon.4 The early event is a mutation of APC (adenomatous
polyposis gene), which was first discovered in individuals with
familial adenomatous polyposis (FAP). The protein encoded
by APC is important in activation of oncogene c-myc and
cyclin D1, which drives the progression to malignant
phenotype. Although FAP is a rare hereditary syndrome
accounting for only about 1% of cases of colon
cancer, APC mutations are very frequent in sporadic
colorectal cancers.
In addition to mutations, epigenetic events such as abnormal
DNA methylation can also cause silencing of tumor
suppressor genes or activation of oncogenes, compromising
the genetic balance and ultimately leading to malignant
transformation.
Other important genes in colon carcinogenesis
include KRAS oncogene , chromosome 18 loss of
heterozygosity (LOH) leading to inactivation
of SMAD4 (DPC4), and DCC (deleted in colon cancer) tumor
suppression genes. Chromosome arm 17p deletion and
mutations affecting p53 tumor suppressor gene confer
resistance to programmed cell death (apoptosis) and are
thought to be late events in colon carcinogenesis.
A subset of colorectal cancers is characterized with deficient
DNA mismatch repair. This phenotype has been linked to
mutations of genes such as MSH2, MLH1, and PMS2. These
mutations result in so-called high frequency microsatellite
instability (H-MSI), which can be detected with an
immunocytochemistry assay. H-MSI is a hallmark of
hereditary nonpolyposis colon cancer syndrome (HNPCC,
Lynch syndrome), which accounts for about 6% of all colon
cancers. H-MSI is also found in about 20% of sporadic colon
cancers.
Frequency
International
In 2003, the World Health Organization estimated that
approximately 940,000 individuals were be diagnosed with
colorectal cancer worldwide and 492,000 died from it that
year.
Mortality/Morbidity
Colorectal cancer is a major health burden worldwide. The
incidence and mortality from colon cancer has been on a
slow decline over the past 20 years in the United States;
however, colon cancer remained the third most common
cause of cancer-related mortality in 2008. A multitude of risk
factors have been linked to colorectal cancer, including
heredity, environmental exposures, and inflammatory
syndromes affecting gastrointestinal tract.
Race
Recent trends in the United States suggest a
disproportionally higher incidence and death from colon
cancer in African Americans than in whites. Hispanic persons
have the lowest incidence and mortality from colorectal
cancer.
Sex
The incidence of colorectal cancer is about equal for males
and females.
Age
Age is a well-known risk factor for colorectal cancer, as it is
for many other solid tumors. The timeline for progression
from early premalignant lesion to malignant cancer ranges
from 10-20 years. The incidence of colorectal cancer peaks at
about age 65 years.
Clinical
animal fat, low-fiber diet, and low overall intake of fruits and
vegetables. Factors associated with lower risk include folate
intake, calcium intake, and estrogen replacement therapy.
However, most of these studies were retrospective
epidemiological studies and have yet to be validated in
prospective, placebo-controlled, interventional trials.
History
Due to increased emphasis on screening practices, colon
cancer is now often detected during screening procedures.
Other common clinical presentations include iron-deficiency
anemia, rectal bleeding, abdominal pain, change in bowel
habits, and intestinal obstruction or perforation. Right-sided
lesions are more likely to bleed and cause diarrhea, while
left-sided tumors are usually detected later and could
present with bowel obstruction.
Physical
Physical findings could be very nonspecific (fatigue, weight
loss) or absent early in the disease course. In more advanced
cases, abdominal tenderness, macroscopic rectal bleeding,
palpable abdominal mass, hepatomegaly, and ascites could
be present on physical examination.
Causes
Colorectal cancer is a multifactorial disease process, with
etiology transcending genetic factors, environmental
exposures (including diet), and inflammatory conditions of
digestive tract.
Lifestyle choices such as alcohol and tobacco
consumption, obesity, and sedentary habits have also been
associated with increased risk for colorectal cancer.
Though much about colorectal cancer genetics remains
unknown, current research indicates that genetic factors
have the greatest correlation to colorectal cancer. Hereditary
mutation of the APC gene is the cause of familial
adenomatous polyposis (FAP), where affected individuals
carry an almost 100% risk of developing colon cancer by age
40 years.
Hereditary nonpolyposis colon cancer syndrome (HNPCC,
Lynch syndrome) carries about 40% lifetime risk of
developing colorectal cancer; individuals with this syndrome
are also at increased risk for urothelial cancer, endometrial
cancer, and other less common cancers. Lynch syndrome is
characterized by deficient mismatch repair (dMMR) due to
inherited mutation in one of the mismatch repair genes, such
as hMLH1, hMSH2, hMSH6, hPMS1, hPMS2, and possibly
other undiscovered genes. HNPCC is a cause of about 6% of
all colon cancers. Although the use of aspirin may reduce the
risk of colorectal neoplasia in some populations, a study by
Burn et al found no effect on the incidence of colorectal
cancer among carriers of Lynch syndrome with use of aspirin,
resistant starch, or both.6
Dietary factors are the subject of intense and ongoing
investigations.7 Epidemiological studies have linked increased
risk of colorectal cancer with a diet high in red meat and
Association between body mass index (BMI) and risk of
colorectal adenomas and cancer has been reported, but few
studies have had adequate sample size for conducting
stratified analyses. Jacobs et al pooled data from 8,213
participants in 7 prospective studies of metachronous
colorectal adenomas to assess whether the association
between BMI and metachronous neoplasia varied by sex,
family history, colorectal subsite, or features of
metachronous lesions. Exploratory analyses indicated that
BMI was significantly related to most histologic
characteristics of metachronous adenomas among men but
not among women. The researchers concluded that body size
may affect colorectal carcinogenesis at comparatively early
stages, particularly among men.
Inflammatory bowel diseases such as ulcerative
colitis and Crohn’s disease also carry an increased risk of
developing colorectal adenocarcinoma. The risk for
developing colorectal malignancy increases with the duration
of inflammatory bowel disease and the greater extent of
colon involvement.
Differential Diagnoses
Arteriovenous malformation (AVM)
Ileus
Carcinoid/Neuroendocrine Tumors and
Rare Tumors of GI Tract
Small Intestinal
Carcinomas
Crohn Disease
Ischemic bowel
Diverticulosis, Small Intestinal
Ulcerative Colitis
Gastrointestinal Lymphoma
Workup
Laboratory Studies
Laboratory studies are done with a goal of assessing patients
organ function (liver, kidneys) in anticipation of diagnostic
and therapeutic procedures (imaging, biopsy, surgery,
chemotherapy) and also to estimate tumor burden (CEA
level).
1. Complete blood cell count
2. Chemistries and liver function tests
3. Serum carcinoembryonic antigen (CEA) should be
obtained preoperatively as it carries prognostic value
and when highly elevated may indicate more advanced,
disseminated disease.
Imaging Studies
1. Adequate imaging of the chest and abdomen should be
obtained for staging purposes, ideally preoperatively.
 Chest radiograph or chest CT scan
 Abdominal barium study to better delineate primary
lesion preoperatively
 Abdominal/pelvic computerized tomography (CT scan),
contrast ultrasound of the abdomen/liver, and
abdominal/pelvic MRI are appropriate for imaging
abdomen and liver, for the purpose of staging.
2. Positron emission tomography (PET) scans are emerging
as a very useful modality for staging and assessment of
colorectal cancers. The newest addition, a fusion PET-CT
scan, allows for detection of metastatic deposits and has
added tissue-based resolution of CT scan. Of note, some
histologies, especially a mucinous signet-ring cell variant
of colorectal cancer, may not be well visualized on a PET
scan.
Procedures
1. A suspicion of colorectal cancer diagnosis warrants rectal
examination and colonoscopy with a biopsy of suspicious
lesion.
o Colonoscopy
o Sigmoidoscopy
o Double contrast barium enema
2. After tissue diagnosis is confirmed, further workup is
driven by the clinical setting (eg, profuse bleeding and
obstruction may require an emergent surgery), patient
status and comorbidities, and presenting symptoms.
Histologic Findings
The microscopic appearance of colon adenocarcinomas may
be that of well-differentiated or poorly differentiated
glandular structures. Normal topological architecture of
colonic epithelium in terms of a crypt-villous axis is lost.
Staging
The TNM staging system has become the international
standard for staging of colorectal cancer. It uses 3
descriptors: T for primary tumor, N for lymph nodal
involvement, and M for metastasis.
In turn, these are divided into the following categories:
Tumor categories
1. Tx:No description of the tumor's extent is possible
because of incomplete information.
2. Tis: In situ carcinoma; the tumor involves only the
muscularis mucosa
3. T1: The cancer has grown through the muscularis
mucosa and extends into the submucosa
4. T2:The cancer has grown through the submucosa and
extends into the muscularis propria
5. T3: The cancer has grown through the muscularis propria
and into the outermost layers of the colon but not
through them; it has not reached any nearby organs or
tissues
6.
T4a: The cancer has grown through the serosa (visceral
peritoneum)
7. T4b: The cancer has grown through the wall of the colon
and is attached to or invades nearby tissues or organs
Node categories
1. Nx:No description of lymph node involvement is possible
because of incomplete information
2. N0:No cancer in nearby lymph nodes
3. N1a:Cancer cells found in 1 nearby lymph node
4. N1b:Cancer cells found in 2 to 3 nearby lymph nodes
5. N1c:Small deposits of cancer cells found in areas of fat
near lymph nodes, but not in the lymph nodes
themselves.
6. N2a:Cancer cells found in 4 to 6 nearby lymph nodes
7. N2b: Cancer cells found in 7 or more nearby lymph
nodes
Metastasis categories
1. M0:No distant spread seen
2. M1a: The cancer has spread to 1 distant organ or set of
distant lymph nodes
3. M1b:The cancer has spread to more than 1 distant organ
or set of distant lymph nodes, or has spread to distant
parts of the peritoneum
Table 1. TNM Staging System for Colon Cancer
Stage
(T)
Stage 0
Carcinoma in situ (Tis)
Tumor may invade submucosa
Stage I
(T1) or muscularis propria (T2)
Tumor invades muscularis T3 or
Stage II
adjacent organs or structures T4
Stage IIA
T3
Stage IIB
T4a
Stage IIC
Stage IIIA
Stage IIIB
Stage IIIC
Stage IVA
Stage IVB
T4b
T1-4
T1-4
T3-4
T1-4
T1-4
(N)
N0
(M)
M0
N0
M0
N0
N0
N0
M0
M0
M0
N0
N1-2
N1-2
N1-2
N1-3
N1-3
M0
M0
M0
M0
M1a
M1b
Prognostic factors associated with staging
Patient prognosis is a function of clinical and histopathologic
stage of colon cancer at diagnosis. In addition to the wellestablished significance of standard pathological features
such as depth of bowel wall penetration (T), number of
locoregional lymph nodes involved (N), and presence of
extra-colonic metastases (M), several other factors have
been proven to be of importance (see list below). These
include number of harvested and processed lymph nodes,
histologic grade, and evidence of lymphovascular and
perineural invasion.
Bowel obstruction at diagnosis, ulcerative growth pattern,
perforation, and elevated preoperative CEA level have all
been shown to be associated with worse prognosis.
Molecular prognostic factors such as p53, loss of
heterozygosity for 18q,9mutations of deleted in colon cancer
gene (DCC), EGFR amplification, and KRAS mutations have all
been investigated but are not currently used as prognostic
factors in standard clinical practice.
Deficient mismatch repair (dMMR), which is associated with
high frequency microsatellite instability (H-MSI), has been
recently shown to be associated with better clinical outcome
for patients with resectable colon cancer; this was based on a
retrospective analysis of several large randomized trials of
adjuvant therapy for colon cancer.10,11 In addition, it appears
that patients with dMMR (H-MSI) did not benefit from
fluorouracil-based adjuvant therapy.12 This may become a
useful test for prognosis and treatment planning in patients
with resectable colon cancer.
Selected prognostic factors and 5-year relapse-free survival in
patients with colorectal cancer, based on the Mayo Clinic
calculator (http://www.mayoclinic.com/calcs) for population
of patients aged 60-69 years (data regarding numbers of
lymph nodes analyzed is from Le Voyer el al, 200313 ) are as
follows (prognostic factor, 5-year relapse-free survival):
 T3N0 (11-20) nodes analyzed – 79%
 T3N0 low grade – 73%
 T3N0 (≤ 10 lymph nodes examined) – 72%
 T3N0 high grade – 65%
 T4N0 low grade – 60%
 T4N0 high grade – 51%
 T3N1 – 49%
 T3N2 – 15%
A review of Surveillance, Epidemiology, and End Results
(SEER) population-based data on colon cancer by the AJCC
Hindgut Taskforce found that that T1-2N2 cancers have a
better prognosis than T3-4N2,T4bN1 have a similar prognosis
to T4N2, T1-2N1 have a similar prognosis to T2N0/T3N0, and
T1-2N2a have similar prognosis to T2N0/T3N0 (T1N2a) or
T4aN0 (T2N2a); in addition, prognosis for T4a lesions is better
than T4b by N category. The number of positive nodes affects
prognosis. The Taskforce proposed the following revisions of
the TN categorization for colon cancer14 :
 Shift T1-2N2 lesions from IIIC to IIIA/IIIB
 Shift T4bN1 from IIIB to IIIC
 Subdivide T4/N1/N2
 Revise substaging of stages II/III.
Treatment
Medical Care
Systemic chemotherapy
5-Fluorouracil remains the backbone of chemotherapy
regimens for colon cancer, both in the adjuvant and
metastatic setting. In the past 10 years, it was established
that combination regimens provide improved efficacy and
prolonged progression-free survival in patients with
metastatic colon cancer. In addition to 5-fluorouracil, oral
fluoropyrimidines such as capecitabine (Xeloda) and tegafur
are increasingly used as monotherapy or in combination with
oxaliplatin (Eloxatin) and irinotecan (Camptosar). Some of the
standard combination regimens employ prolonged
continuous infusion of fluorouracil (FOLFIRI, FOLFOX)15 or
capecitabine (CAPOX, XELOX, XELIRI). Availability of new
classes of active drugs and biologics for colorectal cancer
pushed the expected survival for patients with metastatic
disease from 12 months 2 decades ago to about 22 months
currently.
A meta-analysis of 6 randomized phase II and II trials
examined the efficacy of capecitabine with oxaliplatin
(CAP/OX) compared with fluorouracil with oxaliplatin
(FU/OX) in metastatic colorectal cancer. CAP/OX resulted in a
lower response rate but overall progression-free survival and
overall survival were not affected and were similar in both
treatment regimens. Characteristic toxicity occurred in the
FU schedules and thrombocytopenia and hand-foot
syndrome were more prominent in the CAP regimens.16
In a phase III multicenter trial, Kim et al compared overall
survival of second-line therapy for patients with advanced
colorectal carcinoma refractory to fluorouracil. Fluorouracil,
leucovorin, and oxaliplatin (FOLFOX4) (n=246) versus
irinotecan (n=245) was compared (crossover to the other
treatment was mandated if disease progression occurred).
Overall survival did not significantly differ between FOLFOX4
and irinotecan; however, FOLFOX 4 improved response rate
(RR) and time to progression (TTP) compared with irinotecan
(P=0.0009 for each RR and TTP). FOLFOX4 was associated
with more neutropenia and paresthesias. 17
Key clinical questions relate to the most advantageous
selection of drug combination and the sequence of different
treatment options in individual patients with colorectal
cancer. This information is to be derived from information on
tumor biology, patient performance status, organ function,
and pharmacogenomics testing.
Adjuvant (postoperative) chemotherapy
The standard therapy for patients with stage III and some
patients with stage II colon cancer for the last 2 decades
consisted of fluorouracil in combination with adjuncts such as
levamisole and leucovorin.18,19,20 This approach has been
tested in several large randomized trials and has been shown
to reduce individual 5-year risk of cancer recurrence and
death by about 30%.
Two recent large randomized trials (MOSAIC and NASBP-C06)
investigated the addition of oxaliplatin to fluorouracil
(FOLFOX4 and FLOX, respectively) and demonstrated a
significant improvement in 3-year disease-free survival for
patients with stage III colon cancer. The addition of
irinotecan to fluorouracil in the same patient population
provided no benefit based on the results from two large
randomized trials (CALGB 89803 and PETACC 3). Another
randomized study, XACT, demonstrated noninferiority of
capecitabine (Xeloda) compared to 5-FU/leucovorin as
adjuvant therapy for patients with stage III colon cancer. A
large trial comparing capecitabine plus oxaliplatin (XELOX)
versus FOLFOX has completed accrual, but survival data have
not yet been reported.
The role of adjuvant chemotherapy for stage II colon cancer
is controversial. A large European trial (QUASAR)
demonstrated small but significant benefit (3.6%) in terms of
absolute 5-year survival rate for those patients who received
5-fluorouracil/leucovorin versus those in the control group.
Ongoing adjuvant trials are investigating additional risk
stratification of stage II colon cancer based on
clinicopathological and molecular markers (ECOG 5202 trial).
Though information on results of adjuvant therapy in stage II
and III colon cancer is limited, a data set assembled by the
Adjuvant Colon Cancer Endpoints group with fluorouracilbased adjuvant therapy was recently analyzed. The authors
concluded that adjuvant chemotherapy provides significant
disease-free survival benefit because it reduces the
recurrence rate particularly within the first 2 years of
adjuvant therapy but with some benefit in years 3-4.21
Biologic agents
Bevacizumab (Avastin) was the first anti-angiogenesis drug to
be approved in clinical practice and the first indication was
for metastatic colorectal cancer. This is a humanized
monoclonal antibody to vascular endothelial growth factor
(VEGF) and a pivotal trial demonstrated improved
progression-free and overall survival when bevacizumab was
added to chemotherapy (IFL, fluorouracil plus irinotecan).
A pooled analysis of cohorts of older patients (aged 65 years
or older) from 2 randomized clinical trials examined the
benefit of bevacizumab plus fluorouracil-based
chemotherapy in first-line treatment of metastatic colorectal
cancer. The study concluded that adding bevacizumab to
fluorouracil-based chemotherapy improved overall survival
and progression-free survival in older patients as it does in
younger patients, without increased risks of treatment in the
older age group.22
Two other biologic agents approved for colorectal cancer are
epidermal growth factor receptor (EGFR)-targeted
monoclonal antibodies. Cetuximab (Erbitux) is a chimeric
monoclonal antibody approved as monotherapy or in
combination with irinotecan (Camptosar) in patients with
metastatic colorectal cancer refractory to fluoropyrimidine
and oxaliplatin therapy.23
Panitumumab (Vectibix) is fully human monoclonal antibody
and the current indication as a monotherapy for patients
with colorectal cancer in whom combination chemotherapy
failed or was not tolerated. A recent trial by Hecht et al
evaluated panitumumab added to bevacizumab and
chemotherapy (oxaliplatin- and irinotecan-based) as first-line
treatment of metastatic colorectal cancer and concluded that
the addition of panitumumab resulted in increased toxicity
and decreased progression-free survival.24
Intratumoral KRAS gene mutation can predict sensitivity to
anti-EGFR antibodies.25 Investigators from a large
international trial exploring the benefit of adding cetuximab
to first-line chemotherapy with FOLFIRI (CRYSTAL Trial)
reported that only patients with wild-type KRAS derived
clinical benefit from cetuximab. Patients with
mutant KRAS had no clinical benefit from adding cetuximab
to chemotherapy and experienced only unnecessary
toxicity. KRAS mutations are present in about 40% of colon
adenocarcinomas. Based on these results, testing
for KRAS mutation has been already added to cetuximab
indication by European regulatory agency (EMEA) and is
expected to be added to United States indication by the FDA
as well.
Bokemeyer et al examined the overall response rate when
combining cetuximab with oxaliplatin, leucovorin, and
fluorouracil (FOLFOX-4), as opposed to the regimen without
cetuximab, for first-line treatment of metastatic colorectal
cancer in a randomized study. They also examined the
influence of the KRAS mutation status. They concluded that
the overall response rate for cetuximab plus FOLFOX-4 was
higher than with FOLFOX-4 alone though a statistically
significant increase in odds for a response with the addition
of cetuximab could not be established, except in patients
with KRAS wild-type tumors, for whom the addition of
cetuximab increased chance of response and lowered risk of
disease progression.26
Other mutations that involve some of the kinases
downstream from KRAS (such as BRAF and PI3K) are being
investigated and may result in even more selective methods
to identify patients that may benefit from EGFR inhibition.
Radiation therapy
While radiation therapy remains a standard modality for
patients with rectal cancer, the role of radiation therapy is
limited in colon cancer. It does not have a role in the
adjuvant setting, and in metastatic settings, it is limited to
palliative therapy for selected metastatic sites such as bone
or brain metastases. Newer, more selective ways of
administering radiation therapy such as stereotactic
radiotherapy (CyberKnife) and tomotherapy are currently
being investigated and may extend indications for
radiotherapy in the management of colon cancer in the
future.
A prospective, multicenter, randomized phase III study by
Hendlisz et al compared the addition of yttrium-90 resin to a
treatment regimen of fluorouracil 300 mg/m2 IV infusion
(days 1-14 q8wk) with fluorouracil IV alone. Yytrium-90 was
injected intra-arterially into the hepatic artery. Findings
showed that the addition of radioembolization with yytrium90 significantly improved time to liver progression and
median time to tumor progression. 27
Surgical Care
Surgery is the only curative modality for localized colon
cancer (stage I-III) and potentially provides the only curative
option for patients with limited metastatic disease in liver
and/or lung (stage IV disease). The general principles for all
operations include removal of the primary tumor with
adequate margins including areas of lymphatic drainage.
1. For lesions in the cecum and right colon, a right
hemicolectomy is indicated. During a right
hemicolectomy, the ileocolic, right colic, and right branch
of the middle colic vessels are divided and removed.
Care must be taken to identify the right ureter, the
ovarian or testicular vessels, and the duodenum. If the
omentum is attached to the tumor, it should be removed
en bloc with the specimen.
2. For lesions in the proximal or middle transverse colon, an
extended right hemicolectomy can be performed where
the ileocolic, right colic, and middle colic vessels are
divided and the specimen is removed with its mesentery.
3. For lesions in the splenic flexure and left colon, a left
hemicolectomy is indicated. The left branch of the
middle colic vessels, the inferior mesenteric vein, and
the left colic vessels along with their mesenteries are
included with the specimen.
4. For sigmoid colon lesions, a sigmoid colectomy is
appropriate. The inferior mesenteric artery is divided at
its origin, and dissection proceeds toward the pelvis until
adequate margins are obtained. Care must be taken
during dissection to identify the left ureter and the left
ovarian or testicular vessels.
5. Total abdominal colectomy with ileorectal anastomosis
may be required for patients who have been diagnosed
with HNPCC, attenuated familial adenomatous polyposis,
and metachronous cancers in separate colon segments
or at times in acute malignant colon obstructions with
unknown status of the proximal bowel.
The advent of laparoscopy has revolutionized the surgical
approach of colonic resections for cancers. The same
oncologic principles are respected. Large prospective
randomized trials have demonstrated that there are no
significant differences with regard to intraoperative or
postoperative complications, perioperative mortality rates,
readmission or reoperation rates, or rate of surgical wound
recurrence. At a median follow-up of 7 years, no significant
differences existed in the 5-year disease-free survival rate
(69% versus 68% in the laparoscopy-assisted colectomy [LAC]
and open colectomy groups, respectively) or overall survival
(76% versus 75%). Overall laparoscopic colectomy provides
comparable oncologic outcomes (cause-specific survival,
disease recurrence, number of lymph nodes harvested) to
those achieved with an open approach.28,29,30,31,32,33
Standard management of patients with metastatic disease is
systemic chemotherapy. The proper use of elective
colon/rectal resections in nonobstructed patients with stage
IV disease is a source of continuing debate. Medical
oncologists properly note the major drawbacks to palliative
resection, such as loss of performance status and risks of
surgical complications that potentially lead to delay in
chemotherapy. However, surgeons understand that elective
operations have lower morbidity than emergent operations
on patients who are receiving chemotherapy. Only
randomized prospective data could eventually demonstrate
the survival benefit of palliative resection for patients with
stage IV colon cancer. Data presented at the American
Society of Clinical Oncology 45th Annual Meeting in 2009
indicated that patients with asymptomatic surgically
incurable colorectal cancer do not require immediate surgery
for primary tumor removal. 34
During the past decade, colonic stents have introduced an
effective method of palliation for obstruction in patients with
unresectable liver metastasis.
Curative intent resections of liver metastases have
significantly improved long-term survival with acceptable
postoperative morbidity. A multivariate analysis of 1001
patients who underwent potentially curative resection of
liver metastases identified 5 factors as independent
predictors of worse outcome: size greater than 5 cm, diseasefree interval of less than a year, more than one tumor,
primary lymph-node positivity, and CEA greater than 200
ng/mL.35
Although resection is the only potentially curative treatment
for patients with colon metastases, other therapeutic
options, for those who are not surgical candidates, include
thermal ablation techniques. Cryotherapy uses probes to
freeze tumors and surrounding hepatic parenchyma. It
requires laparotomy and can potentially have significant
morbidity including liver cracking, thrombocytopenia, and
disseminated intravascular coagulation (DIC). Radiofrequency
ablation (RFA) uses probes that heat liver tumors and the
surrounding margin of tissue to create coagulation necrosis.
RFA can be performed percutaneously, laparoscopically, or
through an open approach. Although RFA has minimal
morbidity, local recurrence is a significant problem and is
correlated with tumor size. Hepatic arterial infusion (HAI) of
chemotherapeutic agents such as FUDR is a consideration
following partial hepatectomy.
Consultations
1. Surgical consultation
 Colorectal cancer, especially early stage disease, can be
cured surgically. Following diagnosis and staging,
obtaining surgical consultation for the possibility of
resection may be appropriate. After surgery, the stage of
the tumor may be advanced depending on the operative
findings (eg, lymph node involvement, palpable liver
masses, peritoneal spread).
 In the care of patients with colorectal cancer and
isolated liver metastases, consider surgical consultation
for possible resection. In some cases, resection of
previously unresectable liver metastases may become
feasible after cytoreduction with neoadjuvant
chemotherapy. Therefore, ongoing involvement of the
surgical oncologist is very important in patient care, even
if the tumor is not considered resectable at the time of
diagnosis.
 In advanced disease, surgical intervention may be helpful
in palliative care of bleeding or obstruction.
2. Gastroenterology consultation
 Gastroenterology consultation is critical for screening of
high-risk individuals (ie, people with family history of
colorectal cancer or polyposis syndromes) and those
individuals who are found to be inappropriately iron
deficient or to have occult blood on screening fecal
examination. A colonoscopy or sigmoidoscopy is
necessary to visualize the colon endoscopically, to obtain
biopsies, or to resect polyps. GI consultation may be
necessary in the management of advanced disease.
Recent advent of colorectal stents allows a nonsurgical
management of impending obstruction in patients who
present with unresectable, metastatic disease.
 GI consultation is necessary in the follow-up of patients
after surgical resection and adjuvant chemotherapy.
Patients must be screened for recurrent disease in the
colon by colonoscopic examination at 1 year after
surgery and then every 3 years.
Diet
Abundant epidemiological literature suggests association of
risk for developing colorectal cancer with dietary habits,
environmental exposures, and level of physical activity. Less
is known about effect of diet and physical activity on the
recurrence of colon cancer. A prospective observational
study involving patients from the CALGB 89803 adjuvant trial
demonstrated adverse effect with regards to risk for
recurrence and increased mortality for patients following a
"Western" diet (high intake of red meat, refined grains, fat,
and sweets) compared to patients with a "prudent" diet (high
intake of fruits and vegetables, poultry, and fish).
In another observational study from the same cohort of
patients, patients were prospectively monitored and physical
activity was recorded. The study concluded that physical
activity reduces the risk of recurrence and mortality in
patients with resected stage III colon cancer.
These interesting and important observations pave the way
for future interventional studies involving diet and physical
activity in patients with stage II and III colon cancer.
Medication
Commonly used combination regimens
Adjuvant therapy
1. 5-Fluorouracil + leucovorin (weekly schedule, low dose
leucovorin)
 5-Fluorouracil: 500 mg/m2 IV weekly for 6 weeks
 Leucovorin: 20 mg/m2 IV weekly for 6 weeks,
administered before 5-fluorouracil
 Repeat cycle every 8 weeks for a total of 24 weeks.
2. LV5FU2 (de Gramont regimen)
 5-Fluorouracil: 400 mg/m2 IV bolus, followed by 600
mg/m2 IV continuous infusion for 22 hours on days 1 and
2
 Leucovorin: 200 mg/m2 IV on days 1 and 2 as a 2-hour
infusion before 5-fluorouracil
 Repeat cycle every 2 weeks for a total of 12 cycles.
3. Oxaliplatin + 5-fluorouracil + leucovorin (FOLFOX4)
 Oxaliplatin: 85 mg/m2 IV on day 1
 5-Fluorouracil: 400 mg/m2 IV bolus, followed by 600
mg/m2 IV continuous infusion for 22 hours on days 1 and
2
 Leucovorin: 200 mg/m2 IV on days 1 and 2 as a 2-hour
infusion before 5-fluorouracil
 Repeat cycle every 2 weeks for a total of 12 cycles.
Metastatic disease
1. Irinotecan + 5-fluorouracil + leucovorin (FOLFIRI
regimen)
 Irinotecan: 180 mg/m2 IV on day 1
 5-Fluorouracil: 400 mg/m2 IV bolus on day 1, followed by
2400 mg/m2 IV continuous infusion for 46 hours
 Leucovorin: 400 mg/m2 IV on day 1 as a 2-hour infusion,
prior to 5-fluorouracil
 Repeat cycle every 2 weeks.
2. Oxaliplatin + 5-fluorouracil + leucovorin (FOLFOX6)
 Oxaliplatin: 100 mg/m2 IV on day 1
 5-Fluorouracil: 400 mg/m2 IV bolus on day 1, followed by
2400 mg/m2 IV continuous infusion for 46 hours
 Leucovorin: 400 mg/m2 IV on day 1 as a 2-hour infusion,
before 5-fluorouracil
 Repeat cycle every 2 weeks.
3. Oxaliplatin + 5-fluorouracil + leucovorin (mFOLFOX7)
 Oxaliplatin: 100 mg/m2 IV on day 1
 5-Fluorouracil: 3000 mg/m2 IV continuous infusion on
day 1 for 46 hours
 Leucovorin: 400 mg/m2 IV on day 1 as a 2-hour infusion,
before 5-fluorouracil
 Repeat cycle every 2 weeks.
4.



5.





Capecitabine + oxaliplatin (XELOX)
Capecitabine: 850-1000 mg/m2 PO bid on days 1-14
Oxaliplatin: 100-130 mg/m2 IV on day 1
Repeat cycle every 21 days.
FOLFOX4 + bevacizumab
Oxaliplatin: 85 mg/m2 IV on day 1
5-Fluorouracil: 400 mg/m2 IV bolus, followed by 600
mg/m2 IV continuous infusion on days 1 and 2
Leucovorin: 200 mg/m2 IV on days 1 and 2 as a 2-hour
infusion before 5-fluorouracil
Bevacizumab: 10 mg/kg IV every 2 weeks
Repeat cycle every 2 weeks.
Antineoplastic Agent, Antimetabolite (pyrimidine)
5-Fluorouracil (5-FU, Adrucil, Efudex)
Fluoropyrimidine analog. Cell cycle-specific with activity in
the S-phase as single agent and has for many years been
combined with biochemical modulator leucovorin. Mainstay
of medical chemotherapy for colorectal cancer for patients
for more than 40 y. Has activity as single agent that inhibits
DNA replication and transcription. Cytotoxicity is cell-cycle
nonspecific. Shown to be effective in adjuvant setting. Classic
antimetabolite anticancer drug with chemical structure
similar to endogenous intermediates or building blocks of
DNA or RNA synthesis. 5-FU inhibits tumor cell growth
through at least 3 different mechanisms that ultimately
disrupt DNA synthesis or cellular viability. These effects
depend on intracellular conversion of 5-FU into 5-FdUMP, 5FUTP, and 5-FdUTP. 5-FdUMP inhibits thymidylate synthase
(key enzyme in DNA synthesis), which leads to accumulation
of dUMP, which then gets misincorporated into the DNA in
the form of 5-FdUTP resulting in inhibition of DNA synthesis
and function with cytotoxic DNA strandbreaks. 5-FUTP is
incorporated into RNA and interferes with RNA processing.
Current standard adjuvant therapy for colon cancer involves
combination 5-FU/LV chemotherapy. Saltz regimen (5FU/LV/CPT11) now standard first-line therapy for metastatic
colon cancer. Because of toxicity, maximum of 400 mg/m2 of
5-FU and 100 mg/m2 of CPT11 can be used as starting dose.
Levamisole is no longer an appropriate component of
adjuvant therapy.
Adult: Bolus schedule: 425–600 mg/m2 weekly, with or
without leucovorin
Protracted (pump) infusion: 200-300 mg/m2/24 h
continuously
46 hour infusion (pump): 2400–3000 mg/m2/46 h, repeat
every 14 days
Standard therapy: 500 mg/m2 IV weekly for 4 wk q6wk
Adjuvant therapy
Mayo Clinic regimen: 425 mg/m2/d IV bolus on days 1-5 after
LV for 5 d every 4 wk; 6 mo of therapy is current practice
Roswell Park regimen: Continuous infusion weekly for 6 wk; 2
wk off
Capecitabine (Xeloda)
Fluoropyrimidine carbamate prodrug from of 5-fluorouracil
(5-FU). Capecitabine itself is inactive. Undergoes hydrolysis in
liver and tissues to form the active moiety (fluorouracil),
inhibiting thymidylate synthetase, which in turn blocks
methylation of deoxyuridylic acid to thymidylic acid. This step
interferes with DNA and to a lesser degree with RNA
synthesis.
Adult: 1250 mg/m2 PO q12h pc for 2 wk followed by 1 wk of
rest period; administer as 3-wk cycle
Pediatric: Not established
Antidote, Folic Acid Antagonist
Leucovorin (Folinic acid, Citrovorum Factor)
Reduced form of folic acid that does not require enzymatic
reduction reaction for activation. Allows for purine and
pyrimidine synthesis, both of which are needed for normal
erythropoiesis. Current standard therapy for colon cancer
involves combination chemotherapy. Binds to and stabilizes
ternary complex of FdUTP (intracellular active metabolite of
fluoropyrimidines) and thymidylate synthetase (TS),
augmenting cytotoxic effects of 5-fluorouracil. Used as an
adjunct to fluorouracil.
Adult: 20-400 mg/m2 IV in combination with 5-fluorouracil
Standard therapy: 20 mg/m2 IV every wk for 4 wk q6wk
Adjuvant therapy: 20 mg/m2 IV before 5-FU on days 1-5 for 5
d q4wk (Mayo Clinic regimen); 6 mo of therapy is current
practice
Antineoplastic Agent, Miscellaneous
Irinotecan is a topoisomerase I inhibitor.
Irinotecan (Camptosar, CPT-11)
Semisynthetic derivative of camptothecin, an alkaloid extract
from the Camptotheca acuminate tree. Inactive in its parent
form. Converted by the carboxylesterase enzyme to its active
metabolite from, SN-38.
SN-38 binds to and stabilizes the topoisomerase I-DNA
complex and prevents the relegation of DNA after it has been
cleaved by topoisomerase I, inhibiting DNA replication.
Effective in treatment of colorectal cancer. Current standard
therapy for metastatic colon cancer involves combination of
5-FU/LV/CPT11 chemotherapy (see Standard Therapy).
Because of toxicity problems associated with Saltz regimen
(5-FU/LV/CPT11), now standard first-line therapy for
metastatic colon cancer, maximum of 400 mg/m2 of 5-FU and
100 mg/m2 of CPT11 can be used as starting dose.
Adult
Monotherapy:
125 mg/m2 IV over 90 min weekly for 4 wk, followed by a 2wk rest; schedule can be modified to 2 wk followed by a 1-wk
rest
300-350 mg/m2 IV on an every-3-wk schedule
180 mg/m2 IV as monotherapy or in combination with
infusional 5-FU/LV on an every-2-wk schedule
Antineoplastic Agent, Alkylating Agent
Oxaliplatin is a platinum analog.
Oxaliplatin (Eloxatin, Diaminocyclohexane platinum, DACHplatinum)
Third-generation platinum-based antineoplastic agent used
in combination with an infusion of 5-fluorouracil (5-FU) and
leucovorin for treatment of metastatic colorectal cancer in
patients with recurrence or progression following initial
treatment with irinotecan, 5-FU, and leucovorin. Also
indicated for previously untreated advanced colorectal
cancer in combination with 5-FU and leucovorin. Covalently
binds to DNA with preferential binding to the N-7 position of
guanine and adenine. DNA mismatch repair enzymes are
unable to recognize oxaliplatin-DNA adducts in contrast with
other platinum-DNA adducts as a result of their bulkier size.
Forms interstrand and intrastrand Pt-DNA crosslinks that
inhibit DNA replication and transcription. Cytotoxicity is cellcycle nonspecific with activity in all phases of the cell cycle.
Adult
Day 1: 85 mg/m2 IV over 2 h; administer simultaneously with
leucovorin 200 mg/m2; followed by 5-FU 400 mg/m2 IV bolus
over 2-4 min, then 5-FU 600 mg/m2 IV continuous infusion in
500 mL D5W over 22 h
Day 2: Leucovorin 200 mg/m2 IV over 2 h, followed by 5-FU
400 mg/m2 IV bolus over 2-4 min, then 5-FU 600 mg/m2IV as
a continuous infusion in 500 mL D5W over 22 h
Oxaliplatin can also be administered at 130 mg/m2 IV on a
q3wk schedule
Antineoplastic Agent, Monoclonal Antibody
Cetuximab (Erbitux)
Recombinant, human/mouse chimeric monoclonal antibody
that specifically binds to the extracellular domain of human
epidermal growth factor receptors (EGFR, HER1, c-ErbB-1).
Cetuximab-bound EGF receptor inhibits activation of
receptor-associated kinases, resulting in inhibition of cell
growth, induction of apoptosis, and decreased production of
matrix metalloproteinase and vascular endothelial growth
factor.
Indicated for treating irinotecan-refractory, EGFR-expressed,
metastatic colorectal carcinoma. Treatment is preferably
combined with irinotecan. May be administered as
monotherapy if irinotecan is not tolerated.
Adult
First dose: 400 mg/m2 IV infused over 2 h
Weekly maintenance doses: 250 mg/m2 IV infused over 1 h
Not to exceed infusion rate of 10 mg/min (ie, 5 mL/min);
must administer with low-protein–binding 0.22 μ m in-line
filter; premedication with an H1 antagonist (eg,
diphenhydramine 50 mg IV) recommended
Bevacizumab (Avastin)
Indicated in combination with a fluoropyrimidine-based
chemotherapy as a first-line or second-line treatment for
metastatic colorectal cancer. Murine derived monoclonal
antibody that inhibits angiogenesis by targeting and
inhibiting vascular endothelial growth factor (VEGF).
Inhibiting new blood vessel formation denies blood, oxygen,
and other nutrients needed for tumor growth. Used in
combination with standard chemotherapy.
Adult: 5-10 mg/kg IV over 60 min q2wk until disease
progression detected
Panitumumab (Vectibix)
Recombinant human IgG2 kappa monoclonal antibody that
binds to human epidermal growth factor receptor (EGFR).
Indicated to treat colorectal cancer that has metastasized
following standard chemotherapy.
Adult: 6 mg/kg IV infused over 60 min q2wk
Follow-up
Further Outpatient Care
Pooled analysis form several large adjuvant trials reported
that 85% of colon cancer recurrences occur within 3 years
from after resection of primary tumor. Therefore, patients
with resected colon cancer (stage II and III) should undergo
regular surveillance for at least 5 years following resection.
An update of American Society of Clinical Oncology (2005)
recommends physical examinations every 3-6 months for the
first 3 years, every 6 months during years 4 and 5, and
subsequently at the discretion of physician and based on
individual risk assessment.
Serum CEA level should be checked every 3 months in
patients with stage II or III disease for at least 3 years and
every 6 months in years 4 and 5. Computerized tomography
(CT) of the chest and abdomen should be performed annually
for at least 3 years after resection of primary tumor. All
patients with colon cancer should have preoperative or
postoperative colonoscopy to document absence of
additional primary colon tumors or polyps. In the absence of
high-risk pathology on the first colonoscopy or increased
susceptibility for colon cancer, follow-up colonoscopy should
be performed at 3 years after surgery and then, if normal,
once every 5 years thereafter.
Deterrence/Prevention
Colorectal cancer prevention strategies are based on our
understanding of colorectal carcinogenesis and availability of
pharmacologic agents that are effective yet minimally toxic.
The efficacy of these agents is usually first tested in high-risk
populations.
Celecoxib (Celebrex), a selective cyclooxygenase-2 inhibitor
was first tested in patients with familial adenomatous
polyposis (FAP). Celecoxib was effective in decreasing the
number and size of polyps on serial colonoscopies, which was
the primary surrogate endpoint for this trial. The drug was
approved for FAP patients, although it remains to be seen if
this intervention translates to reduced cancer incidence and
prolonged survival.
Other NSAIDs, such as sulindac and nonselective
cyclooxygenase inhibitors were tested in lower risk
populations. Enthusiasm for cyclooxygenase-2 inhibitors as
chemopreventive agents has dampened because of a high
incidence of cardiovascular toxicity (rofecoxib) in trial
patients. An aspirin prevention trial suggested a benefit in
terms of polyp prevention with low-dose (81 mg) aspirin.
Some recent trials focused on combined inhibition of
polyamine production and cyclooxygenase inhibition. A
recent report from a large randomized trial of a combination
of sulindac and dimethylformamine (DMFO), an inhibitor of
ornithine decarboxylase (ODC), described a dramatic effect of
this combination in reducing polyp recurrence in patients
with prior history of colon polyps. Confirmatory trials are
ongoing.36
Screening
The goal of colorectal cancer screening is to decrease
mortality through diagnosis and treatment of precancerous
lesions (adenomatous colon polyps) and early curable
cancerous lesions. The evidence for the importance of early
detection and removal of colorectal polyps in
preventing development of invasive cancer is mostly indirect
but has been corroborated by data from many trials.
In the United States, a Joint Guideline was developed by the
American Cancer Society, US Multi-Society Task Force on
Colorectal Cancer, and the American College of Radiology.
The Guideline lists appropriate screening procedures and
their indications and frequency based on projected individual
risks of developing colorectal cancer.
Their testing options for the early detection of colorectal
cancer and adenomatous
polyps for asymptomatic adults aged 50 years and older can
be summarized as follows:
1. Tests that detect adenomatous polyps and cancer
 Flexible sigmoidoscopy every 5 years, or
 Colonoscopy every 10 years, or
 Double-contrast barium enema every 5 years, or
 computed tomographic colonography every 5 years
2. Tests that primarily detect cancer
 Annual guaiac-based fecal occult blood test with high
test sensitivity for cancer, or
 Annual fecal immunochemical test with high test
sensitivity for cancer, or
 Stool DNA test with high sensitivity for cancer, interval
uncertain
For individuals who carry an increased or high risk of
developing colorectal cancer such as persons with prior
history of polyps, prior history of colorectal cancer, family
history of colon cancer, or history of inflammatory bowel
diseases screening should start at an earlier age and be more
frequent and more stringent. Those genetically diagnosed or
suspected of having hereditary familial syndromes such as
HNPCC or FAP should be treated as having high risk of
developing colon and rectal cancer and should adhere to a
more intense surveillance protocol.37
Prognosis
The approximate 5-year survival rate for colorectal cancer
patients in the United States (all stages included) is 65%.
Survival is inversely related to stage; patients with stage I
have a 95% 5-year survival rate, and those with stage III have
only a 60% survival rate. For patients with metastatic, stage
IV disease, the 5-year survival rate is estimated at
approximately 10% (see Staging).