Ulcerative Colitis

Ulcerative colitis is a chronic inflammatory and ulcerative disease arising in the

colonic mucosa, characterized most often by bloody diarrhea. Extraintestinal
symptoms, particularly arthritis, may occur. Long-term risk of colon cancer is high.
Diagnosis is by colonoscopy. Treatment is with 5-aminosalicylic acid,
corticosteroids, immunomodulators, anticytokines, antibiotics, and occasionally
surgery.
Pathophysiology
Ulcerative colitis (UC) usually begins in the rectum. It may remain localized to the
rectum (ulcerative proctitis) or extend proximally, sometimes involving the entire
colon. Rarely, it involves most of the large bowel at once.
The inflammation caused by UC affects the mucosa and submucosa, and there is a
sharp border between normal and affected tissue. Only in severe disease is the
muscularis involved. In early cases, the mucous membrane is erythematous, finely
granular, and friable, with loss of the normal vascular pattern and often with
scattered hemorrhagic areas. Large mucosal ulcers with copious purulent exudate
characterize severe disease. Islands of relatively normal or hyperplastic
inflammatory mucosa (pseudopolyps) project above areas of ulcerated mucosa.
Fistulas and abscesses do not occur.
Toxic or fulminant colitis occurs when transmural extension of ulceration results in
localized ileus and peritonitis. Within hours to days, the colon loses muscular tone
and begins to dilate.
Pseudopolyps

The terms toxic megacolon or toxic dilation are discouraged because the toxic
inflammatory state and its complications can occur without frank megacolon
(defined as transverse colon > 6 cm diameter during an exacerbation). Toxic colitis
is a medical emergency that usually occurs spontaneously in the course of very
severe colitis but is sometimes precipitated by opioid or anticholinergic antidiarrheal
drugs. Colonic perforation may occur, which increases mortality significantly.
Symptoms and Signs
Bloody diarrhea of varied intensity and duration is interspersed with asymptomatic
intervals. Usually an attack begins insidiously, with increased urgency to defecate,
mild lower abdominal cramps, and blood and mucus in the stools. Some cases
develop after an infection (eg, amebiasis, bacillary dysentery).
When ulceration is confined to the rectosigmoid, the stool may be normal or hard
and dry, but rectal discharges of mucus loaded with RBCs and WBCs accompany or
occur between bowel movements. Systemic symptoms are absent or mild. If
ulceration extends proximally, stools become looser and the patient may have > 10
bowel movements per day, often with severe cramps and distressing rectal tenesmus,
without respite at night. The stools may be watery or contain mucus and frequently
consist almost entirely of blood and pus.
Toxic or fulminant colitis presents with sudden violent diarrhea, fever to 40° C
(104° F), abdominal pain, signs of peritonitis (eg, rebound tenderness), and profound
toxemia.
Systemic symptoms and signs, more common with severe UC, include malaise,
fever, anemia, anorexia, and weight loss. Extraintestinal manifestations (particularly
joint and skin complications—see Inflammatory Bowel Disease (IBD):
Extraintestinal Manifestations) are most common when systemic symptoms are
present.
Diagnosis
• Stool cultures and microscopy (to exclude other causes)
• Sigmoidoscopy with biopsy
Initial presentation: Diagnosis is suggested by typical symptoms and signs,
particularly when accompanied by extraintestinal manifestations or a history of
previous similar attacks. UC should be distinguished from Crohn's disease (see
Table 1: Inflammatory Bowel Disease (IBD): Differentiating Crohn's Disease and
Ulcerative Colitis ) but more importantly from other causes of acute colitis (eg,
infection; in elderly patients, ischemia).
In all patients, stool cultures for enteric pathogens should be obtained, and
Entamoeba histolytica should be excluded by examination of fresh stool specimens.
When amebiasis is suspected because of epidemiologic or travel history, serologic
titers and biopsies should be obtained. History of prior antibiotic use or recent
hospitalization should prompt stool assay for Clostridium difficile toxin. Patients at
risk should be tested for HIV, gonorrhea, herpesvirus, chlamydia, and amebiasis.
Opportunistic infections (eg, cytomegalovirus, Mycobacterium avium-intracellulare)
or Kaposi's sarcoma must also be considered in immunosuppressed patients. In
women using oral contraceptives, contraceptive-induced colitis is possible; it usually
resolves spontaneously after hormone therapy is stopped.
Sigmoidoscopy should be performed; it allows visual confirmation of colitis and
permits direct sampling of stool or mucus for culture and microscopic evaluation, as
well as biopsy of affected areas. Although visual inspection and biopsies may be
nondiagnostic, because there is much overlap in appearance among different types of
colitis, acute, self-limited, infectious colitis can usually be distinguished
histologically from chronic idiopathic UC or Crohn's colitis. Severe perianal disease,
rectal sparing, absence of bleeding, and asymmetric or segmental involvement of the
colon indicate Crohn's disease rather than UC (see Table 1: Inflammatory Bowel
Disease (IBD): Differentiating Crohn's Disease and Ulcerative Colitis ).
Colonoscopy is usually unnecessary initially but should be performed electively if
inflammation has extended proximal to the reach of the sigmoidoscope.
Laboratory tests should be done to screen for anemia, hypoalbuminemia, and
electrolyte abnormalities. Liver function tests should be done; elevated alkaline
phosphatase and γ–glutamyl transpeptidase levels suggest possible primary
sclerosing cholangitis. Perinuclear antineutrophil cytoplasmic antibodies are
relatively specific (60 to 70%) for UC. Anti–Saccharomyces cerevisiae antibodies
are relatively specific for Crohn's disease. However, these tests do not reliably
separate the two diseases and are not recommended for routine diagnosis. Other
possible laboratory abnormalities include leukocytosis, thrombocytosis, and elevated
acute-phase reactants (eg, ESR, C-reactive protein).
X–rays are not diagnostic but occasionally show abnormalities. Plain x–rays of the
abdomen may show mucosal edema, loss of haustration, and absence of formed stool
in the diseased bowel. Barium enema shows similar changes, albeit more clearly,
and may also demonstrate ulcerations, but the enema should not be performed
during an acute presentation. A shortened, rigid colon with an atrophic or
pseudopolypoid mucosa is often seen after several years' illness. X–ray findings of
thumbprinting and segmental distribution are more suggestive of intestinal ischemia
or possibly Crohn's colitis rather than of UC.
Recurrent symptoms: Patients with known disease and a recurrence of typical
symptoms should be examined, but extensive testing is not always required.
Depending on duration and severity of symptoms, sigmoidoscopy or colonoscopy
may be done and a CBC obtained. Cultures, ova and parasite examination, and C.
difficile toxin assay should be done when there are atypical features to the relapse or
when there is an exacerbation after prolonged remission, during a contagious
outbreak, after antibiotic exposure, or whenever the clinician is suspicious.
Fulminant symptoms: Patients require further evaluation during severe flare-ups.
Flat and upright abdominal x–rays should be obtained; they may show megacolon or
intraluminal gas accumulated over a long, continuous, paralyzed segment of colon—
a result of lost muscle tone. Colonoscopy and barium enema should be avoided
because of the risk of perforation. CBC, ESR, electrolytes, PT, PTT, and type and
crossmatch should be obtained.
The patient must be watched closely for progressive peritonitis or perforation.
Percussion over the liver is important because loss of hepatic dullness may be the
first clinical sign of free perforation, especially in a patient whose peritoneal signs
are suppressed by high-dose corticosteroids. Abdominal x–rays are obtained every 1
or 2 days to follow the course of colonic distention and to detect free or intramural
air.
Prognosis
Usually, UC is chronic with repeated exacerbations and remissions. In about 10% of
patients, an initial attack becomes fulminant with massive hemorrhage, perforation,
or sepsis and toxemia. Complete recovery after a single attack occurs in another
10%.
Patients with localized ulcerative proctitis have the best prognosis. Severe systemic
manifestations, toxic complications, and malignant degeneration are unlikely, and
late extension of the disease occurs in only about 20 to 30%. Surgery is rarely
required, and life expectancy is normal. The symptoms, however, may prove
stubborn and refractory. Moreover, because extensive UC may begin in the rectum
and spread proximally, proctitis should not be considered localized until it has been
observed for ≥ 6 mo. Localized disease that later extends is often more severe and
more refractory to therapy.
Colon cancer: The risk of colon cancer is proportional to the duration of disease and
amount of colon affected, but not necessarily to the clinical severity of the attacks.
Some recent studies suggest that sustained microscopic inflammation is a risk factor,
and that use of aminosalicylate to control inflammation is protective. Cancer begins
to appear by 7 yr from onset of illness in patients with extensive colitis. The
cumulative likelihood of cancer is about 3% at 15 yr, 5% at 20 yr, and 9% at 25 yr,
representing an annual risk of about 0.5 to 1% after the 10th yr. There is probably no
higher absolute cancer risk among patients with childhood-onset colitis independent
of the longer duration of disease. However, patients who have inflammatory bowel
disease and primary sclerosing cholangitis (PSC) are at a higher risk of cancer from
the time of colitis diagnosis.
Regular colonoscopic surveillance, preferably during remission, is advised for
patients with disease duration > 8 to 10 yr (except for those with isolated proctitis).
Endoscopic biopsies should be taken every 10 cm throughout the colon. Newer
techniques, especially chromoendoscopy, may better identify areas of suspicion in
preference to totally random biopsies. Any grade of definite dysplasia within an area
affected by colitis is liable to progress to more advanced neoplasia and even cancer
and is a strong indication for total colectomy unless the dysplasia is strictly confined
to a discrete, completely excisable polyp. It is important to distinguish definite
neoplastic dysplasia from reactive or regenerative atypia secondary to inflammation.
However, if the dysplasia is unequivocal, delaying colectomy in favor of repeated
follow-up surveillance is a risky strategy. Pseudopolyps have no prognostic
significance but may be difficult to distinguish from neoplastic polyps; thus, any
suspect polyp should undergo excision biopsy.
The optimal frequency of colonoscopic surveillance has not been established, but
some authorities recommend every 2 yr during the 2nd decade of disease and
annually thereafter.
Long-term survival after diagnosis of colitis-related cancer is about 50%, a figure
comparable to that for colorectal cancer in the general population.
Treatment
• Loperamide Some Trade Names
IMODIUM
Click for Drug Monograph
and dietary management for symptom relief
• 5-Aminosalicylic acid (5-ASA)
• Corticosteroids and other drugs depending on symptoms and severity
• Sometimes surgery
Details of specific drugs and regimens are discussed above (see Approach to the
Patient with Upper GI Complaints: Treatment).
General management: Avoiding raw fruits and vegetables limits trauma to the
inflamed colonic mucosa and may lessen symptoms. A milk-free diet may help but
need not be continued if no benefit is noted. Loperamide Some Trade Names
IMODIUM
Click for Drug Monograph
2 mg po bid to qid is indicated for relatively mild diarrhea; higher oral doses (4 mg
in the morning and 2 mg after each bowel movement) may be required for more
intense diarrhea. Antidiarrheal drugs must be used with extreme caution in severe
cases because they may precipitate toxic dilation.
Mild left-sided disease: Patients with proctitis, or colitis that does not extend
proximally beyond the splenic flexure, are treated with 5–ASA ( mesalamine Some
Trade Names
ASACOL
ROWASA
Click for Drug Monograph
) enemas once/day or bid depending on severity. Suppositories are effective for more
distal disease and are usually preferred by patients. Corticosteroid and budesonide
Some Trade Names
PULMICORT
RHINOCORT
Click for Drug Monograph
enemas are slightly less effective but should be used if 5–ASA is unsuccessful or not
tolerated. Once remission is achieved, dosage is slowly tapered to maintenance
levels. Oral 5–ASA drugs theoretically have some incremental benefit in lessening
the probability of proximal spread of disease.
Moderate or extensive disease: Patients with inflammation proximal to the splenic
flexure or left-sided disease unresponsive to topical agents should receive an oral 5–
ASA formulation in addition to 5–ASA enemas. High-dose corticosteroids are added
for more severe symptoms; after 1 to 2 wk, the daily dose is reduced by about 5 to
10 mg each wk. Immunomodulater therapy with azathioprine Some Trade Names
IMURAN
Click for Drug Monograph
or 6- mercaptopurine Some Trade Names
PURINETHOL
Click for Drug Monograph
can be used in patients who are refractory to maximal doses of 5-ASA and would
otherwise need long-term corticosteroid therapy. Additionally, infliximab Some
Trade Names
REMICADE
Click for Drug Monograph
is beneficial in some patients and may be considered for those refractory to
immunomodulator or corticosteroid therapy as well as those who are corticosteroid
dependent.
Severe disease: Patients with > 10 bloody bowel movements per day, tachycardia,
high fever, or severe abdominal pain require hospitalization to receive high-dose IV
corticosteroids. 5–ASA may be continued. IV fluids and blood transfusion are given
as needed for dehydration and anemia. The patient must be observed closely for the
development of toxic megacolon. Parenteral hyperalimentation is sometimes used
for nutritional support but is of no value as primary therapy; patients who can
tolerate food should eat.
Patients who do not respond within 3 to 7 days should be considered for IV
cyclosporine Some Trade Names
NEORAL
SANDIMMUNE
Click for Drug Monograph
or infliximab Some Trade Names
REMICADE
Click for Drug Monograph
or else for surgery. Patients who do respond to a medical regimen are switched
within a week or so to prednisone Some Trade Names
DELTASONE
Click for Drug Monograph
60 mg po once/day, which may be gradually reduced at home based on clinical
response. Patients who are started on IV cyclosporine Some Trade Names
NEORAL
SANDIMMUNE
Click for Drug Monograph
and respond to therapy are switched to oral cyclosporine Some Trade Names
NEORAL
SANDIMMUNE
Click for Drug Monograph
and concomitant azathioprine Some Trade Names
IMURAN
Click for Drug Monograph
or 6- mercaptopurine Some Trade Names
PURINETHOL
Click for Drug Monograph
. Oral cyclosporine Some Trade Names
NEORAL
SANDIMMUNE
Click for Drug Monograph
is continued for about 3 to 4 mo, during which time corticosteroids are tapered and
cyclosporine Some Trade Names
NEORAL
SANDIMMUNE
Click for Drug Monograph
levels are closely monitored. Some clinicians recommend prophylaxis against
Pneumocystis jiroveci pneumonia during the interval of overlapping treatment with
corticosteroids, cyclosporine Some Trade Names
NEORAL
SANDIMMUNE
Click for Drug Monograph
, and an antimetabolite.
Fulminant colitis: If fulminant colitis or toxic megacolon is suspected, the patient
should (1) discontinue all antidiarrheal drugs; (2) take nothing by mouth and have
inserted a long intestinal tube attached to intermittent suction; (3) undergo
aggressive IV fluid and electrolyte therapy with 0.9% NaCl, and potassium chloride
Some Trade Names
K-LOR
K-TAB
KLOR-CON
Click for Drug Monograph
and blood as needed; (4) be treated with high-dose IV corticosteroids; and (5)
receive antibiotics (eg, metronidazole Some Trade Names
FLAGYL
Click for Drug Monograph
500 mg IV q 8 h and ciprofloxacin Some Trade Names
CILOXAN
CIPRO
Click for Drug Monograph
500 mg IV q 12 h).
Having the patient roll over in bed from the supine to prone position every 2 to 3 h
may help redistribute colonic gas and prevent progressive distention. Passage of a
soft rectal tube may also be helpful but must be done with extreme caution to avoid
bowel perforation.
If intensive medical measures do not produce definite improvement within 24 to 48
h, immediate surgery is required or the patient may die of sepsis caused by bacterial
translocation or even perforation.
Maintenance therapy: After effective treatment of a flare-up, corticosteroids are
tapered based on clinical response and then discontinued because they are
ineffective as maintenance. Patients should remain on 5–ASA drugs indefinitely—
oral or rectal, depending on location of disease—because stopping maintenance
therapy often allows disease relapse. Dosage intervals for rectal preparations may be
gradually lengthened to every second or third day.
Patients who cannot be withdrawn from corticosteroids should be given azathioprine
Some Trade Names
IMURAN
Click for Drug Monograph
or 6– mercaptopurine Some Trade Names
PURINETHOL
Click for Drug Monograph
.
Surgery: Nearly 33% of patients with extensive UC ultimately require surgery. Total
proctocolectomy is curative: Life expectancy and quality of life are restored to
normal, the disease does not recur (unlike Crohn's disease), and the risk of colon
cancer is eliminated.
Emergency colectomy is indicated for massive hemorrhage, fulminating toxic
colitis, or perforation. Subtotal colectomy with ileostomy and rectosigmoid closure
or mucous fistula is usually the procedure of choice because most critically ill
patients cannot tolerate more extensive surgery. The rectosigmoid stump may be
electively removed later or may be used for ileoanal anastomosis with a pouch. The
intact rectal stump should not be allowed to remain indefinitely because of the risk
of disease activation and malignant transformation.
Elective surgery is indicated for cancer, symptomatic strictures, growth retardation
in children, or most commonly, intractable chronic disease resulting in invalidism or
corticosteroid dependence. Colectomy is also performed for high-grade and perhaps
even low-grade mucosal dysplasia confirmed on pathologic consultation, unless the
dysplasia is limited exclusively to a completely excisable polyp. Severe colitis-
related extraintestinal manifestations (eg, pyoderma gangrenosum), now better
controlled by intensive medical therapies, are only rarely indications for surgery.
The elective procedure of choice in patients with normal sphincter function is
restorative proctocolectomy with ileoanal anastomosis. This procedure creates a
pelvic reservoir or pouch from distal ileum, which is connected to the anus. The
intact sphincter allows continence, typically with 8 to 10 bowel movements/day.
 Pouchitis is an inflammatory reaction occurring after this procedure in about 50% of
patients. It is thought to be related to bacterial overgrowth and is treated with
antibiotics (eg, quinolones). Probiotics may be protective. Most cases of pouchitis
are readily controlled, but 5 to 10% prove refractory to all medical therapy and
require conversion to a conventional (Brooke) ileostomy. For a minority of patients
who are older, who have well-established families and lifestyles, who have poor
sphincter tone or cannot tolerate frequent bowel movements, or who are simply
unable or unwilling to face the consequences of frequent or chronic pouchitis, the
Brooke ileostomy remains the procedure of choice.
In any event, the physical and emotional burdens imposed by any form of colon
resection must be recognized, and care should be taken to see that the patient
receives all the instructions and all the medical and psychologic support that is
necessary before and after surgery.

Colorectal cancer
From Wikipedia, the free encyclopedia
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Colorectal cancer
Classification and external resources

Diagram of the stomach, colon, and rectum

ICD-10 C18.-C20.
ICD-9 153.0-154.1
ICD-O: M8140/3 (95% of cases)
OMIM 114500
DiseasesDB 2975
MedlinePlus 000262
eMedicine med/413 med/1994 ped/3037
Colorectal cancer, also called colon cancer or large bowel cancer, includes cancerous growths
in the colon, rectum and appendix. With 655,000 deaths worldwide per year, it is the fourth most
common form of cancer in the United States and the third leading cause of cancer-related death
in the Western world.[1][2] Colorectal cancers arise from adenomatous polyps in the colon. These
mushroom-shaped growths are usually benign, but some develop into cancer over time.
Localized colon cancer is usually diagnosed through colonoscopy.
Invasive cancers that are confined within the wall of the colon (TNM stages I and II) are curable
with surgery. If untreated, they spread to regional lymph nodes (stage III), where up to 73% are
curable by surgery and chemotherapy. Cancer that metastasizes to distant sites (stage IV) is
usually not curable, although chemotherapy can extend survival, and in rare cases, surgery and
chemotherapy together have seen patients through to a cure.[3] Radiation is used with rectal
cancer.
On the cellular and molecular level, colorectal cancer starts with a mutation to the Wnt signaling
pathway. When Wnt binds to a receptor on the cell, that sets in motion a chain of molecular
events that ends with β-catenin moving into the nucleus and activating a gene on DNA. In
colorectal cancer, genes along this chain are damaged. Usually, a gene called APC, which is a
"brake" on the Wnt pathway, is damaged. Without a working APC brake, the Wnt pathway is
stuck in the "on" position.[3]

Contents
[hide]
• 1 Signs and symptoms
○ 1.1 Local
○ 1.2 Constitutional
○ 1.3 Metastatic
• 2 Risk factors
○ 2.1 Alcohol
• 3 Pathogenesis
• 4 Diagnosis
○ 4.1 Other screening methods
○ 4.2 Monitoring
○ 4.3 Pathology
○ 4.4 Staging
  4.4.1 Dukes system
• 5 Prevention
○ 5.1 Surveillance
○ 5.2 Lifestyle and nutrition
○ 5.3 Chemoprevention
 5.3.1 Aspirin chemoprophylaxis
 5.3.2 Calcium
○ 5.4 Vitamin D
• 6 Management
○ 6.1 Surgery
○ 6.2 Chemotherapy
○ 6.3 Radiation therapy
○ 6.4 Immunotherapy
○ 6.5 Cancer Vaccine
○ 6.6 Treatment of liver metastases
○ 6.7 Aspirin
○ 6.8 Cimetidine
○ 6.9 Support therapies
• 7 Prognosis
○ 7.1 Follow-up
• 8 Epidemiology
• 9 Society and culture
○ 9.1 Notable patients
• 10 See also
• 11 References
• 12 External links

[edit] Signs and symptoms

The symptoms of colorectal cancer depend on the location of tumor in the bowel, and whether it
has spread elsewhere in the body (metastasis). Most of the symptoms may occur in other diseases
as well, and hence none of the symptoms mentioned here is diagnostic of colorectal cancer.
Symptoms and signs are divided into local, constitutional (affecting the whole body) and
metastatic (caused by spread to other organs).
[edit] Local
Local symptoms are more likely if the tumor is located closer to the anus. There may be a change
in bowel habit (new-onset constipation or diarrhea in the absence of another cause), and a feeling
of incomplete defecation (rectal tenesmus) and reduction in diameter of stool; tenesmus and
change in stool shape are both characteristic of rectal cancer. Lower gastrointestinal bleeding,
including the passage of bright red blood in the stool, may indicate colorectal cancer, as may the
increased presence of mucus. Melena, black stool with a tarry appearance, normally occurs in
upper gastrointestinal bleeding (such as from a duodenal ulcer), but is sometimes encountered in
colorectal cancer when the disease is located in the beginning of the large bowel.
A tumor that is large enough to fill the entire lumen of the bowel may cause bowel obstruction.
This situation is characterized by constipation, abdominal pain, abdominal distension and
vomiting. This occasionally leads to the obstructed and distended bowel perforating and causing
peritonitis.
Certain local effects of colorectal cancer occur when the disease has become more advanced. A
large tumor is more likely to be noticed on feeling the abdomen, and it may be noticed by a
doctor on physical examination. The disease may invade other organs, and may cause blood or
air in the urine (invasion of the bladder) or vaginal discharge (invasion of the female
reproductive tract).
[edit] Constitutional
If a tumor has caused chronic occult bleeding, iron deficiency anemia may occur; this may be
experienced as fatigue, palpitations and noticed as pallor (pale appearance of the skin).
Colorectal cancer may also lead to weight loss, generally due to a decreased appetite.
More unusual constitutional symptoms are an unexplained fever and one of several
paraneoplastic syndromes. The most common paraneoplastic syndrome is thrombosis, usually
deep vein thrombosis.
[edit] Metastatic
Colorectal cancer most commonly spreads to the liver. This may go unnoticed, but large deposits
in the liver may cause jaundice and abdominal pain (due to stretching of the capsule). If the
tumor deposit obstructs the bile duct, the jaundice may be accompanied by other features of
biliary obstruction, such as pale stools.
[edit] Risk factors

Micrograph of a tubular adenoma (left of image), a type of colonic polyp and a precursor of
colorectal cancer. Normal colorectal mucosa is seen on the right. H&E stain.
The lifetime risk of developing colon cancer in the United States is about 7%. Certain factors
increase a person's risk of developing the disease.[4] These include:
• Age. The risk of developing colorectal cancer increases with age. Most cases occur in the
60s and 70s, while cases before age 50 are uncommon unless a family history of early
colon cancer is present.[5]
• Polyps of the colon, particularly adenomatous polyps, are a risk factor for colon cancer.
The removal of colon polyps at the time of colonoscopy reduces the subsequent risk of
colon cancer.
• History of cancer. Individuals who have previously been diagnosed and treated for colon
cancer are at risk for developing colon cancer in the future. Women who have had cancer
of the ovary, uterus, or breast are at higher risk of developing colorectal cancer.
• Heredity:
○ Family history of colon cancer, especially in a close relative before the age of 55
or multiple relatives.[6]
○ Familial adenomatous polyposis (FAP) carries a near 100% risk of developing
colorectal cancer by the age of 40 if untreated
○ Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome
○ Gardner syndrome
• Smoking. Smokers are more likely to die of colorectal cancer than non-smokers. An
American Cancer Society study found that "Women who smoked were more than 40%
more likely to die from colorectal cancer than women who never had smoked. Male
smokers had more than a 30% increase in risk of dying from the disease compared to men
who never had smoked."[7][8]
• Diet. Studies show that a diet high in red meat[9] and low in fresh fruit, vegetables, poultry
and fish increases the risk of colorectal cancer. In June 2005, a study by the European
Prospective Investigation into Cancer and Nutrition suggested that diets high in red and
processed meat, as well as those low in fiber, are associated with an increased risk of
colorectal cancer. Individuals who frequently eat fish showed a decreased risk.[10]
However, other studies have cast doubt on the claim that diets high in fiber decrease the
risk of colorectal cancer; rather, low-fiber diet was associated with other risk factors,
leading to confounding.[11] The nature of the relationship between dietary fiber and risk of
colorectal cancer remains controversial.
• Lithocholic acid. Lithocholic acid is a bile acid that acts as a detergent to solubilize fats
for absorption. It is made from chenodeoxycholic acid by bacterial action in the colon. It
has been implicated in human and experimental animal carcinogenesis.[12] Carbonic acid
type surfactant easily combine with calcium ion and become detoxication.
• Physical inactivity. People who are physically active are at lower risk of developing
colorectal cancer.
• Virus. Exposure to some viruses (such as particular strains of human papilloma virus)
may be associated with colorectal cancer.
• Primary sclerosing cholangitis offers a risk independent to ulcerative colitis
• Low levels of selenium.[13][14]
• Inflammatory bowel disease.[15][16] About one percent of colorectal cancer patients have a
history of chronic ulcerative colitis. The risk of developing colorectal cancer varies
 inversely with the age of onset of the colitis and directly with the extent of colonic
involvement and the duration of active disease. Patients with colorectal Crohn's disease
have a more than average risk of colorectal cancer, but less than that of patients with
ulcerative colitis.[17]
• Environmental factors.[15] Industrialized countries are at a relatively increased risk
compared to less developed countries that traditionally had high-fiber/low-fat diets.
Studies of migrant populations have revealed a role for environmental factors,
particularly dietary, in the etiology of colorectal cancers.
• Exogenous hormones. The differences in the time trends in colorectal cancer in males and
females could be explained by cohort effects in exposure to some gender-specific risk
factor; one possibility that has been suggested is exposure to estrogens.[18] There is,
however, little evidence of an influence of endogenous hormones on the risk of colorectal
cancer. In contrast, there is evidence that exogenous estrogens such as hormone
replacement therapy (HRT), tamoxifen, or oral contraceptives might be associated with
colorectal tumors.[19]
• Alcohol. Drinking, especially heavily, may be a risk factor.[20]
• Vitamin B6 intake is inversely associated with the risk of colorectal cancer.[21]
[edit] Alcohol
The WCRF panel report Food, Nutrition, Physical Activity and the Prevention of Cancer: a
Global Perspective finds the evidence "convincing" that alcoholic drinks increase the risk of
colorectal cancer in men.[22]
The NIAAA reports that: "Epidemiologic studies have found a small but consistent dose-
dependent association between alcohol consumption and colorectal cancer[23][24] even when
controlling for fiber and other dietary factors.[25][26] Despite the large number of studies, however,
causality cannot be determined from the available data."[20]
"Heavy alcohol use may also increase the risk of colorectal cancer" (NCI). One study found that
"People who drink more than 30 grams of alcohol per day (and especially those who drink more
than 45 grams per day) appear to have a slightly higher risk for colorectal cancer."[27] Another
found that "The consumption of one or more alcoholic beverages a day at baseline was
associated with approximately a 70% greater risk of colon cancer."[28][29][27]
One study found that "While there was a more than twofold increased risk of significant
colorectal neoplasia in people who drink spirits and beer, people who drank wine had a lower
risk. In our sample, people who drank more than eight servings of beer or spirits per week had at
least a one in five chance of having significant colorectal neoplasia detected by screening
colonoscopy.".[30]
Other research suggests that "to minimize your risk of developing colorectal cancer, it's best to
drink in moderation."[20]
On its colorectal cancer page, the National Cancer Institute does not list alcohol as a risk factor;
[31]
however, on another page it states, "Heavy alcohol use may also increase the risk of colorectal
cancer".[32]
Drinking may be a cause of earlier onset of colorectal cancer.[33]
[edit] Pathogenesis
Colorectal cancer is a disease originating from the epithelial cells lining the colon or rectum of
the gastrointestinal tract, as a result of mutations along the 'Wnt signaling pathway. Some of the
mutations are inherited, and others are acquired.[34][35] The most commonly mutated gene in all
colorectal cancer is the APC gene, which produces the APC protein. The APC protein is the
"brake" on the β-catenin protein. Without APC, β-catinin moves into the nucleus, binds to DNA,
and activates more proteins. (If APC is not mutated in colorectal cancer, then β-catinin itself is.)
[3]

Beyond the defects in the Wnt-APC-beta-catinin signaling pathway, other mutations must occur
for the cell to become cancerous. The TP53 protein, produced by the p53 gene, normally
monitors cell division and kills cells if they have Wnt pathway defects. Eventually, a cell line
acquires a mutation in the p53 gene and transforms the tissue from an adenoma into an invasive
carcinoma. (Sometimes p53 is not mutated, but another protective protein named BAX is.)[3]
Other apoptotic proteins commonly deactivated in colorectal cancers are TGF-β and DCC
(Deleted in Colorectal Cancer). TGF-β has a deactivating mutation in at least half of colorectal
cancers. Sometimes TGF-β is not deactivated, but a downstream protein named SMAD is.[3]
DCC commonly has deletion of its chromosome segment in colorectal cancer.[36]
Some genes are oncogenes -- they are overexpressed in colorectal cancer. For example, RAS,
RAF, and PI3K, which normally encourage the cell to divide in response to growth factors, can
become mutated with mutations that make them oversignal the cell. PTEN normally inhibits
PI3K, but sometimes PTEN gets mutated.[3]
[edit] Diagnosis

Endoscopic image of colon cancer identified in sigmoid colon on screening colonoscopy in the
setting of Crohn's disease.
Colorectal cancer can take many years to develop and early detection of colorectal cancer greatly
improves the chances of a cure. The National Cancer Policy Board of the Institute of Medicine
estimated in 2003 that even modest efforts to implement colorectal cancer screening methods
would result in a 29 percent drop in cancer deaths in 20 years. Despite this, colorectal cancer
screening rates remain low.[37] Therefore, screening for the disease is recommended in
individuals who are at increased risk. There are several different tests available for this purpose.
 • Digital rectal exam (DRE): The doctor inserts a lubricated, gloved finger into the rectum
to feel for abnormal areas. It only detects tumors large enough to be felt in the distal part
of the rectum but is useful as an initial screening test.
• Fecal occult blood test (FOBT): a test for blood in the stool. Two types of tests can be
used for detecting occult blood in stools i.e. guaiac based (chemical test) and
immunochemical. The sensitivity of immunochemical testing is superior to that of
chemical testing without an unacceptable reduction in specifity.[38]
• Endoscopy:
○ Sigmoidoscopy: A lighted probe (sigmoidoscope) is inserted into the rectum and
lower colon to check for polyps and other abnormalities.
○ Colonoscopy: A lighted probe called a colonoscope is inserted into the rectum and
the entire colon to look for polyps and other abnormalities that may be caused by
cancer. A colonoscopy has the advantage that if polyps are found during the
procedure they can be removed immediately. Tissue can also be taken for biopsy.
In the United States, colonoscopy or FOBT plus sigmoidoscopy are the preferred screening
options.
[edit] Other screening methods
• Double contrast barium enema (DCBE): First, an overnight preparation is taken to
cleanse the colon. An enema containing barium sulfate is administered, then air is
insufflated into the colon, distending it. The result is a thin layer of barium over the inner
lining of the colon which is visible on X-ray films. A cancer or a precancerous polyp can
be detected this way. This technique can miss the (less common) flat polyp.
• Virtual colonoscopy replaces X-ray films in the double contrast barium enema (above)
with a special computed tomography scan and requires special workstation software in
order for the radiologist to interpret. This technique is approaching colonoscopy in
sensitivity for polyps. However, any polyps found must still be removed by standard
colonoscopy.
• Standard computed axial tomography is an x-ray method that can be used to determine
the degree of spread of cancer, but is not sensitive enough to use for screening. Some
cancers are found in CAT scans performed for other reasons.
• Blood tests: Measurement of the patient's blood for elevated levels of certain proteins can
give an indication of tumor load. In particular, high levels of carcinoembryonic antigen
(CEA) in the blood can indicate metastasis of adenocarcinoma. These tests are frequently
false positive or false negative, and are not recommended for screening, it can be useful
to assess disease recurrence. CA19-9 and CA 242 biomarkers can indicate e-selectin
related metastatic risks, help follow therapeutic progress, and assess disease recurrence.
• Genetic counseling and genetic testing for families who may have a hereditary form of
colon cancer, such as hereditary nonpolyposis colorectal cancer (HNPCC) or familial
adenomatous polyposis (FAP).
• Positron emission tomography (PET) is a 3-dimensional scanning technology where a
radioactive sugar is injected into the patient, the sugar collects in tissues with high
metabolic activity, and an image is formed by measuring the emission of radiation from
the sugar. Because cancer cells often have very high metabolic rates, this can be used to
 differentiate benign and malignant tumors. PET is not used for screening and does not
(yet) have a place in routine workup of colorectal cancer cases.
• Whole-body PET imaging is the most accurate diagnostic test for detection of recurrent
colorectal cancer, and is a cost-effective way to differentiate resectable from
nonresectable disease. A PET scan is indicated whenever a major management decision
depends upon accurate evaluation of tumour presence and extent.
• Stool DNA testing is an emerging technology in screening for colorectal cancer.
Premalignant adenomas and cancers shed DNA markers from their cells which are not
degraded during the digestive process and remain stable in the stool. Capture, followed
by PCR amplifies the DNA to detectable levels for assay. Clinical studies have shown a
cancer detection sensitivity of 71%–91%.[39]
• High C-Reactive Protein levels is risk marker [40]
[edit] Monitoring
Carcinoembryonic antigen (CEA) is a protein found on virtually all colorectal tumors. CEA may
be used to monitor and assess response to treatment in patients with metastatic disease. CEA can
also be used to monitor recurrence in patients post-operatively.[citation needed]
[edit] Pathology

Gross appearance of a colectomy specimen containing two adenomatous polyps (the brownish
oval tumors above the labels, attached to the normal beige lining by a stalk) and one invasive
colorectal carcinoma (the crater-like, reddish, irregularly shaped tumor located above the label).

Gross appearance of a colectomy specimen containing one invasive colorectal carcinoma (the
crater-like, reddish, irregularly shaped tumor).
Micrograph of an invasive adenocarcinoma (the most common type of colorectal cancer). The
cancerous cells are seen in the center and at the bottom right of the image (blue). Near normal
colon-lining cells are seen at the top right of the image.

Histopathologic image of colonic carcinoid stained by hematoxylin and eosin.

The pathology of the tumor is usually reported from the analysis of tissue taken from a biopsy or
surgery. A pathology report will usually contain a description of cell type and grade. The most
common colon cancer cell type is adenocarcinoma which accounts for 95% of cases. Other, rarer
types include lymphoma and squamous cell carcinoma.
Cancers on the right side (ascending colon and cecum) tend to be exophytic, that is, the tumour
grows outwards from one location in the bowel wall. This very rarely causes obstruction of
feces, and presents with symptoms such as anemia. Left-sided tumours tend to be
circumferential, and can obstruct the bowel much like a napkin ring.
Adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the
colorectal mucosa. It invades the wall, infiltrating the muscularis mucosae, the submucosa and
thence the muscularis propria. Tumor cells describe irregular tubular structures, harboring
pluristratification, multiple lumens, reduced stroma ("back to back" aspect). Sometimes, tumor
cells are discohesive and secrete mucus, which invades the interstitium producing large pools of
mucus/colloid (optically "empty" spaces) - mucinous (colloid) adenocarcinoma, poorly
differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery -
"signet-ring cell." Depending on glandular architecture, cellular pleomorphism, and
mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of
differentiation: well, moderately, and poorly differentiated.[41]
Most colorectal cancer tumors are thought to be cyclooxygenase-2 (COX-2) positive. This
enzyme is generally not found in healthy colon tissue, but is thought to fuel abnormal cell
growth.
[edit] Staging
Colon cancer staging is an estimate of the amount of penetration of a particular cancer. It is
performed for diagnostic and research purposes, and to determine the best method of treatment.
The systems for staging colorectal cancers depend on the extent of local invasion, the degree of
lymph node involvement and whether there is distant metastasis.
Definitive staging can only be done after surgery has been performed and pathology reports
reviewed. An exception to this principle would be after a colonoscopic polypectomy of a
malignant pedunculated polyp with minimal invasion. Preoperative staging of rectal cancers may
be done with endoscopic ultrasound. Adjunct staging of metastasis include Abdominal
Ultrasound, CT, PET Scanning, and other imaging studies.
The most common staging system is the TNM (for tumors/nodes/metastases) system, from the
American Joint Committee on Cancer (AJCC). The TNM system assigns a number based on
three categories. "T" denotes the degree of invasion of the intestinal wall, "N" the degree of
lymphatic node involvement, and "M" the degree of metastasis. The broader stage of a cancer is
usually quoted as a number I, II, III, IV derived from the TNM value grouped by prognosis; a
higher number indicates a more advanced cancer and likely a worse outcome. Details of this
system are in the graph below:
AJCC
TNM stage TNM stage criteria for colorectal cancer[42]
stage
Stage 0 Tis N0 M0 Tis: Tumor confined to mucosa; cancer-in-situ
Stage I T1 N0 M0 T1: Tumor invades submucosa
Stage I T2 N0 M0 T2: Tumor invades muscularis propria
T3: Tumor invades subserosa or beyond (without other organs
Stage II-A T3 N0 M0
involved)
T4: Tumor invades adjacent organs or perforates the visceral
Stage II-B T4 N0 M0
peritoneum
Stage III-A T1-2 N1 M0 N1: Metastasis to 1 to 3 regional lymph nodes. T1 or T2.
Stage III-B T3-4 N1 M0 N1: Metastasis to 1 to 3 regional lymph nodes. T3 or T4.
Stage III-C any T, N2 M0 N2: Metastasis to 4 or more regional lymph nodes. Any T.
any T, any N,
Stage IV M1: Distant metastases present. Any T, any N.
M1
[edit] Dukes system
Micrograph of a colorectal adenocarcinoma metastasis to a lymph node. The cancerous cells are
at the top center-left of the image, in glands (circular/ovoid structures) and eosinophilic (bright
pink). H&E stain.
Dukes classification is an older and less complicated staging system, that predates the TNM
system, and was first proposed by Dr. Cuthbert Dukes in 1932; it identifies the stages as:[43]
• A - Tumour confined to the intestinal wall
• B - Tumour invading through the intestinal wall
• C - With lymph node(s) involvement (this is further subdivided into C1 lymph node
involvement where the apical node is not involved and C2 where the apical lymph node
is involved)
• D - With distant metastasis
A few cancer centers still use this staging system.
Astler-Coller
A: Tumor limited to mucosa; carcinoma in situ B1: Tumor grows through muscularis mucosae
but not through muscularis propria B2: Tumor grows beyond muscularis propria C1: Stage B1
with regional lymph node metastases C2: Stage B2 with regional lymph node metastases D:
Distant metastases.
Additional Staging
venous invasion (v)
v0 no venous invasion
v1 microscopic venous invasion
v2 macroscopic venous invasion
lymphatic invasion (l)
l0 no lymphatic vessel invasion
l1 lymphatic vessel invasion
histologic grade (G)
g1 well differentiated
g2 moderately differentiated
g3 poorly differentiated
g4 undiffererentiated

[edit] Prevention
Most colorectal cancers should be preventable, through increased surveillance, improved
lifestyle, and, probably, the use of dietary chemopreventative agents.
[edit] Surveillance
Most colorectal cancer arise from adenomatous polyps. These lesions can be detected and
removed during colonoscopy. Studies show this procedure would decrease by > 80% the risk of
cancer death, provided it is started by the age of 50, and repeated every 5 or 10 years.[44]
As per current guidelines under National Comprehensive Cancer Network, in average risk
individuals with negative family history of colon cancer and personal history negative for
adenomas or Inflammatory Bowel diseases, flexible sigmoidoscopy every 5 years with fecal
occult blood testing annually or double contrast barium enema are other options acceptable for
screening rather than colonoscopy every 10 years (which is currently the Gold-Standard of care).
[edit] Lifestyle and nutrition
The comparison of colorectal cancer incidence in various countries strongly suggests that
sedentarity, overeating (i.e., high caloric intake), and perhaps a diet high in meat (red or
processed) could increase the risk of colorectal cancer. In contrast, a healthy body weight,
physical fitness, and good nutrition decreases cancer risk in general. Accordingly, lifestyle
changes could decrease the risk of colorectal cancer as much as 60-80%.[45]
A high intake of dietary fiber (from eating fruits, vegetables, cereals, and other high fiber food
products) has, until recently, been thought to reduce the risk of colorectal cancer and adenoma.
In the largest study ever to examine this theory (88,757 subjects tracked over 16 years), it has
been found that a fiber rich diet does not reduce the risk of colon cancer.[46] A 2005 meta-analysis
study further supports these findings.[47]
The Harvard School of Public Health states: "Health Effects of Eating Fiber: Long heralded as
part of a healthy diet, fiber appears to reduce the risk of developing various conditions, including
heart disease, diabetes, diverticular disease, and constipation. Despite what many people may
think, however, fiber probably has little, if any effect on colon cancer risk."[48]
[edit] Chemoprevention
More than 200 agents, including the above cited phytochemicals, and other food components like
calcium or folic acid (a B vitamin), and NSAIDs like aspirin, are able to decrease carcinogenesis
in pre-clinical development models: Some studies show full inhibition of carcinogen-induced
tumours in the colon of rats. Other studies show strong inhibition of spontaneous intestinal
polyps in mutated mice (Min mice). Chemoprevention clinical trials in human volunteers have
shown smaller prevention, but few intervention studies have been completed today. The
"chemoprevention database" shows the results of all published scientific studies of
chemopreventive agents, in people and in animals.[49]
[edit] Aspirin chemoprophylaxis
Aspirin should not be taken routinely to prevent colorectal cancer, even in people with a family
history of the disease, because the risk of bleeding and kidney failure from high dose aspirin
(300 mg or more) outweigh the possible benefits.[50]
A clinical practice guideline of the U.S. Preventive Services Task Force (USPSTF)
recommended against taking aspirin (grade D recommendation).[51] The Task Force
acknowledged that aspirin may reduce the incidence of colorectal cancer, but "concluded that
harms outweigh the benefits of aspirin and NSAID use for the prevention of colorectal cancer".
A subsequent meta-analysis concluded "300 mg or more of aspirin a day for about 5 years is
effective in primary prevention of colorectal cancer in randomised controlled trials, with a
latency of about 10 years".[52] However, long-term doses over 81 mg per day may increase
bleeding events.[53]
[edit] Calcium
The meta-analysis by the Cochrane Collaboration of randomized controlled trials published
through 2002 concluded "Although the evidence from two RCTs suggests that calcium
supplementation might contribute to a moderate degree to the prevention of colorectal
adenomatous polyps, this does not constitute sufficient evidence to recommend the general use
of calcium supplements to prevent colorectal cancer.".[54] Subsequently, one randomized
controlled trial by the Women's Health Initiative (WHI) reported negative results.[55] A second
randomized controlled trial reported reduction in all cancers, but had insufficient colorectal
cancers for analysis.[56]
[edit] Vitamin D
A scientific review undertaken by the National Cancer Institute found that vitamin D was
beneficial in preventing colorectal cancer, which showed an inverse relationship with blood
levels of 80 nmol/L or higher associated with a 72% risk reduction compared with lower than 50
nmol/L.[57] A possible mechanism is inhibition of Hedgehog signal transduction.[58]
[edit] Management
The treatment depends on the staging of the cancer. When colorectal cancer is caught at early
stages (with little spread) it can be curable. However, when it is detected at later stages (when
distant metastases are present) it is less likely to be curable.
Surgery remains the primary treatment while chemotherapy and/or radiotherapy may be
recommended depending on the individual patient's staging and other medical factors.
Because colon cancer primarily affects the elderly, it can be a challenge to determine how
aggressively to treat a particular patient, especially after surgery. Clinical trials suggest that
"otherwise fit" elderly patients fare well if they have adjuvant chemotherapy after surgery, so
chronological age alone should not be a contraindication to aggressive management.[59]
[edit] Surgery
Surgeries can be categorised into curative, palliative, bypass, fecal diversion, or open-and-close.
Curative Surgical treatment can be offered if the tumor is localized.
• Very early cancer that develops within a polyp can often be cured by removing the polyp
(i.e., polypectomy) at the time of colonoscopy.
• In colon cancer, a more advanced tumor typically requires surgical removal of the section
of colon containing the tumor with sufficient margins, and radical en-bloc resection of
mesentery and lymph nodes to reduce local recurrence (i.e., colectomy). If possible, the
remaining parts of colon are anastomosed together to create a functioning colon. In cases
when anastomosis is not possible, a stoma (artificial orifice) is created.
• Curative surgery on rectal cancer includes total mesorectal excision (lower anterior
resection) or abdominoperineal excision.
In case of multiple metastases, palliative (non curative) resection of the primary tumor is still
offered in order to reduce further morbidity caused by tumor bleeding, invasion, and its catabolic
effect. Surgical removal of isolated liver metastases is, however, common and may be curative in
selected patients; improved chemotherapy has increased the number of patients who are offered
surgical removal of isolated liver metastases.
If the tumor invaded into adjacent vital structures which makes excision technically difficult, the
surgeons may prefer to bypass the tumor (ileotransverse bypass) or to do a proximal fecal
diversion through a stoma.
The worst case would be an open-and-close surgery, when surgeons find the tumor unresectable
and the small bowel involved; any more procedures are thought by some to do more harm than
good to the patient. This is uncommon with the advent of laparoscopy and better radiological
imaging. Most of these cases formerly subjected to "open and close" procedures are now
diagnosed in advance and surgery avoided.
Laparoscopic-assisted colectomy is a minimally invasive technique that can reduce the size of
the incision and may reduce post-operative pain.
As with any surgical procedure, colorectal surgery may result in complications including
• wound infection, Dehiscence (bursting of wound) or hernia
• anastomosis breakdown, leading to abscess or fistula formation, and/or peritonitis
• bleeding with or without hematoma formation
• adhesions resulting in bowel obstruction. A 5-year study of patients who had surgery in
1997 found the risk of hospital readmission to be 15% after panproctocolectomy, 9%
after total colectomy, and 11% after ileostomy[60]
• adjacent organ injury; most commonly to the small intestine, ureters, spleen, or bladder
• Cardiorespiratory complications such as myocardial infarction, pneumonia, arrythmia,
pulmonary embolism etc.
[edit] Chemotherapy
Chemotherapy is used to reduce the likelihood of metastasis developing, shrink tumor size, or
slow tumor growth. Chemotherapy is often applied after surgery (adjuvant), before surgery (neo-
adjuvant), or as the primary therapy (palliative). The treatments listed here have been shown in
clinical trials to improve survival and/or reduce mortality rate and have been approved for use by
the US Food and Drug Administration. In colon cancer, chemotherapy after surgery is usually
only given if the cancer has spread to the lymph nodes (Stage III).
• Adjuvant (after surgery) chemotherapy.
○ 5-fluorouracil (5-FU) or Capecitabine (Xeloda)
○ Leucovorin (LV, Folinic Acid)
○ Oxaliplatin (Eloxatin)
• Chemotherapy for metastatic disease. Commonly used first line chemotherapy regimens
involve the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin
(FOLFOX) with bevacizumab or infusional 5-fluorouracil, leucovorin, and irinotecan
(FOLFIRI) with bevacizumab or the same chemotherapy drug combinations with
cetuximab in KRAS wild type tumors
○ 5-fluorouracil (5-FU) or Capecitabine
○ UFT or Tegafur-uracil
 ○ Leucovorin (LV, Folinic Acid)
○ Irinotecan (Camptosar)
○ Oxaliplatin (Eloxatin)
○ Bevacizumab (Avastin)
○ Cetuximab (Erbitux)
○ Panitumumab (Vectibix)
• In clinical trials for treated/untreated metastatic disease.[61]
○ Bortezomib (Velcade)
○ Oblimersen (Genasense, G3139)
○ Gefitinib and Erlotinib (Tarceva)
○ Topotecan (Hycamtin)
At the 2008 annual meeting of the American Society of Clinical Oncology, researchers
announced that colorectal cancer patients that have a mutation in the KRAS gene do not respond
to certain therapies, those that inhibit the epidermal growth factor receptor (EGFR)--namely
Erbitux (cetuximab) and Vectibix (panitumumab).[62] Following recommendations by ASCO,
patients should now be tested for the KRAS gene mutation before being offered these EGFR-
inhibiting drugs.[63] In July 2009, the US Food and Drug Administration (FDA) updated the
labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab
(Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about
KRAS mutations.[64]
However, having the normal KRAS version does not guarantee that these drugs will benefit the
patient.[62]
“The trouble with the KRAS mutation is that it’s downstream of EGFR,” says Richard Goldberg,
MD, director of oncology at the Lineberger Comprehensive Cancer Center at the University of
North Carolina. “It doesn’t matter if you plug the socket if there’s a short downstream of the
plug. The mutation turns [EGFR] into a switch that’s always on.” But this doesn’t mean that
having normal, or wild-type, KRAS is a fail-safe. “It isn’t foolproof,” cautions Goldberg. “If you
have wild-type KRAS, you’re more likely to respond, but it’s not a guarantee.” Tumors shrink in
response to these drugs in up to 40 percent of patients with wild-type KRAS, and progression-
free and overall survival is increased.
The cost benefit of testing patients for the KRAS gene could potentially save about $740 million
a year by not providing EGFR-inhibiting drugs to patients who would not benefit from the drugs.
"With the assumption that patients with mutated Kras (35.6% of all patients) would not receive
cetuximab (other studies have found Kras mutation in up to 46% of patients), theoretical drug
cost savings would be $753 million; considering the cost of Kras testing, net savings would be
$740 million."[65]
[edit] Radiation therapy
Radiotherapy is not used routinely in colon cancer, as it could lead to radiation enteritis, and it is
difficult to target specific portions of the colon. It is more common for radiation to be used in
rectal cancer, since the rectum does not move as much as the colon and is thus easier to target.
Indications include:
 • Colon cancer
○ pain relief and palliation - targeted at metastatic tumor deposits if they compress
vital structures and/or cause pain
• Rectal cancer
○ neoadjuvant - given before surgery in patients with tumors that extend outside the
rectum or have spread to regional lymph nodes, in order to decrease the risk of
recurrence following surgery or to allow for less invasive surgical approaches
(such as a low anterior resection instead of an abdomino-perineal resection). In
locally advanced adenocarcinoma of middle and lower rectum, regional
hyperthermia added to chemoradiotherapy achieved good results in terms of rate
of sphincter sparing surgery.[66]
•
○ adjuvant - where a tumor perforates the rectum or involves regional lymph nodes
(AJCC T3 or T4 tumors or Duke's B or C tumors)
○ palliative - to decrease the tumor burden in order to relieve or prevent symptoms
Sometimes chemotherapy agents are used to increase the effectiveness of radiation by sensitizing
tumor cells if present.
[edit] Immunotherapy
Bacillus Calmette-Guérin (BCG) is being investigated as an adjuvant mixed with autologous
tumor cells in immunotherapy for colorectal cancer.[67]
[edit] Cancer Vaccine
TroVax, a cancer vaccine,[68] produced by Oxford BioMedica,[69] is in Phase III trials for renal
cancers, and phase III trials are planned for colon cancers.[70]
[edit] Treatment of liver metastases
According to the American Cancer Society statistics in 2006,[71] over 20% of patients present
with metastatic (stage IV) colorectal cancer at the time of diagnosis, and up to 25% of this group
will have isolated liver metastasis that is potentially resectable. Lesions which undergo curative
resection have demonstrated 5-year survival outcomes now exceeding 50%.[72]
Resectability of a liver metastasis is determined using preoperative imaging studies (CT or MRI),
intraoperative ultrasound, and by direct palpation and visualization during resection. Lesions
confined to the right lobe are amenable to en bloc removal with a right hepatectomy (liver
resection) surgery. Smaller lesions of the central or left liver lobe may sometimes be resected in
anatomic "segments", while large lesions of left hepatic lobe are resected by a procedure called
hepatic trisegmentectomy. Treatment of lesions by smaller, non-anatomic "wedge" resections is
associated with higher recurrence rates. Some lesions which are not initially amenable to surgical
resection may become candidates if they have significant responses to preoperative
chemotherapy or immunotherapy regimens. Lesions which are not amenable to surgical resection
for cure can be treated with modalities including radio-frequency ablation (RFA), cryoablation,
and chemoembolization.
Patients with colon cancer and metastatic disease to the liver may be treated in either a single
surgery or in staged surgeries (with the colon tumor traditionally removed first) depending upon
the fitness of the patient for prolonged surgery, the difficulty expected with the procedure with
either the colon or liver resection, and the comfort of the surgery performing potentially complex
hepatic surgery.
[edit] Aspirin
A study published in 2009 found that Aspirin reduces risk of colorectal neoplasia in randomized
trials and inhibits tumor growth and metastases in animal models. The influence of aspirin on
survival after diagnosis of colorectal cancer is unknown.[73] Several reports including a
prospective cohort of 1,279 people diagnosed with stages I-III (non-metastatic) colorectal
cancer[74] have suggested a significant improvement in cancer-specific survival in a subset of
patients using aspirin.[75]
[edit] Cimetidine
Cimetidine is being investigated in Japan as an adjuvant for adenocarcinomas,[76] including for
stage III[77] and stage IV[78] colorectal cancers biomarked with overexpressed sialyl Lewis X and
A epitopes. Multiple small trials suggest a significant survival improvement in the subset of
patients with the sLeX and sLeA biomarkers that take cimetidine treatment perioperatively,
through several mechanisms [3].
[edit] Support therapies
Cancer diagnosis very often results in an enormous change in the patient's psychological
wellbeing. Various support resources are available from hospitals and other agencies which
provide counseling, social service support, cancer support groups, and other services. These
services help to mitigate some of the difficulties of integrating a patient's medical complications
into other parts of their life.
[edit] Prognosis
Survival is directly related to detection and the type of cancer involved. Survival rates for early
stage detection is about 5 times that of late stage cancers. CEA level is also directly related to the
prognosis of disease, since its level correlates with the bulk of tumor tissue.
[edit] Follow-up

Micrograph of a colorectal villous adenoma. These lesions are considered pre-cancerous. H&E
stain.
The aims of follow-up are to diagnose in the earliest possible stage any metastasis or tumors that
develop later but did not originate from the original cancer (metachronous lesions).
The U.S. National Comprehensive Cancer Network and American Society of Clinical Oncology
provide guidelines for the follow-up of colon cancer.[79][80] A medical history and physical
examination are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years.
Carcinoembryonic antigen blood level measurements follow the same timing, but are only
advised for patients with T2 or greater lesions who are candidates for intervention. A CT-scan of
the chest, abdomen and pelvis can be considered annually for the first 3 years for patients who
are at high risk of recurrence (for example, patients who had poorly differentiated tumors or
venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A
colonoscopy can be done after 1 year, except if it could not be done during the initial staging
because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a
villous polyp, polyp >1 centimeter or high grade dysplasia is found, it can be repeated after 3
years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year.
Routine PET or ultrasound scanning, chest X-rays, complete blood count or liver function tests
are not recommended.[79][80] These guidelines are based on recent meta-analyses showing that
intensive surveillance and close follow-up can reduce the 5-year mortality rate from 37% to
30%.[81][82][83]