Colon Cancer article from Cleveland Clinic

[Guest guest]

Reviewed June 12, 2003

Carol A.

Burke, MD

Department of

Gastroenterology

and Hepatology

Print Chapter

Copyright 2002

The Cleveland Clinic Foundation

Colorectal cancer is one of the few preventable cancers. The removal of

precancerous adenomatous polyps during colonoscopy inhibits their progression

to

cancer. Widely available screening tests such as the fecal occult blood test

(FOBT), sigmoidoscopy, and colonoscopy are associated with a decrease in

colorectal cancer mortality. Unfortunately, fewer than 50% of eligible

Americans

have undergone screening, and more than 45% of patients are diagnosed at a

time when the cancer is incurable.

Definition

Prevalence

Pathophysiology

Signs and

Symptoms

Diagnosis

Treatment

Conclusions

References

National Guidelines

Colorectal Cancer Screening (AGA)

DEFINITION

The colorectum is the portion of the gastrointestinal tract most frequently

affected by tumors. The majority of colonic tumors are benign epithelial

polyps. " Polyp " is an inexact term that indicates a protuberance of tissue into

the colonic lumen. The most common polyp and the only one that can become an

adenocarcinoma is the adenomatous polyp. Both the size and degree of villous

features are predictive of the risk of malignancy within the polyp.

Hyperplastic polyps are the second most common type of polyp, accounting for

up to 30% of colonic polyps. Hyperplastic polyps are most often found in the

rectosigmoid and are believed to have no clinical significance.

Unfortunately, hyperplastic polyps and adenomas are indistinguishable on

endoscopy.

Therefore, all polyps detected in the colon and rectum should be removed and

sent

for histologic analysis.

This chapter will focus on the neoplastic epithelial tumors, including

adenomatous polyps and adenocarcinoma of the colon and rectum.

PREVALENCE

The incidence of colorectal carcinoma has been decreasing on an average of

1.5% annually since the mid-1980s. Research suggests that the decline may be

due to an increased use of screening and polyp removal, which prevents

progression from polyp to cancer. Adenocarcinoma of the colon and rectum is the

third most common cancer and cause of cancer deaths in the United States. Both

men and women face a lifetime risk of nearly 6% for the development of invasive

colorectal cancer (Table 1).1 It is estimated that approximately 135,000 new

cases of colorectal cancer will have been diagnosed in 2001, and that 57,000

deaths from colorectal cancer will occur. The only known race predilection

is in African Americans, who have higher colorectal cancer incidence and

mortality rates.

PATHOPHYSIOLOGY

In nearly all cases, colorectal carcinoma arises from an adenomatous polyp.

Observational studies suggest that the adenoma-to-carcinoma sequence takes

approximately 10 years. Although nearly 40% of Americans aged 50 years or older

harbor adenomatous polyps, it is estimated that only 2% of adenomas will

progress to cancer.

Colorectal cancer arises from a series of histopathologic and molecular

changes caused by complex interactions between genetic susceptibility and

environmental factors. These molecular changes include multiple, acquired

genetic

alterations within colonocyte oncogenes (promoting malignant transformation)

and tumor suppressor genes (causing loss of the inhibition of cellular

proliferation). A newly discovered pathway for carcinogenesis involves

mutations in

the genes responsible for repair of mismatched DNA base pairs (eg, mismatch

repair genes). Mismatch-repair-gene inactivation is present in approximately

15% of sporadic colorectal cancers, but is the major cause of cancers in

hereditary nonpolyposis colorectal cancer (HNPCC).

Epidemiologic studies have implicated a number of environmental cofactors in

the development of colorectal cancer. They include, in order of strength of

association, advanced age, high red-meat diet, high fat diet, smoking,

alcohol consumption, and obesity. Approximately 70% of newly diagnosed

colorectal

cancers arise in patients without known risk factors. In approximately 30% of

patients with colorectal cancer, risk factors have been identified (Table 2):

Table 2:

Risk Factors for Colorectal Cancer

Personal history of adenomas or colorectal cancer

First-degree relative age < 60 yrs with adenoma or colorectal cancer, or two

first-degree relatives of any age with colorectal cancer

Inherited colorectal cancer syndromes

Hereditary nonpolyposis colorectal cancer

Familial adenomatous polyposis

Ulcerative colitis and Crohn's colitis

A personal history of adenomatous polyps or colorectal cancer increases the

risk for metachronous colorectal cancer. First-degree relatives of patients

with colorectal cancer have a two- to threefold increased risk for colorectal

cancer and adenomatous polyps. Recent work has proven that first-degree

family members of patients with adenomatous polyps also have an increased risk

of

colorectal cancer themselves, particularly when the relative's adenoma is

diagnosed before age 60 years.

Patients with the highest risk for colorectal cancer are those who have one

of the dominantly inherited colorectal cancer syndromes:

Familial adenomatous polyposis (FAP) is due to a mutation in the tumor

suppressor gene APC on the long arm of chromosome 5. Germline mutations in APC

can

be detected in approximately 80% of patients with FAP. The APC mutation

results in the development of hundreds to thousands of colonic adenomas,

usually

by the second decade of life. Colon cancer develops in all FAP patients by

age 40 years if prophylactic colectomy is not performed.

An attenuated form of colonic polyposis has been found and named " attenuated

FAP. " The number of colonic polyps is usually less than 100, and the age of

onset of polyposis and cancer is shifted 1 to 2 decades later.

Duodenal adenomas are common in either form of FAP, and periampullary cancer

is the second leading cause of cancer deaths in this population. Gardner's

syndrome is a phenotypic variant of FAP. In addition to colonic polyposis,

other manifestations may be seen, such as benign soft tissue tumors, osteomas,

supernumerary teeth, desmoid tumors, and congenital hypertrophy of the retinal

pigment epithelium.

Hereditary nonpolyposis colorectal cancer is caused by genetic alterations

in one of the mismatch repair genes. Alterations in these genes prevent

adequate repair of DNA, resulting in an accumulation of mutations in daughter

cells

and leading to carcinogenesis. Germline mutations in one of six genes have

been identified in up to 60% of patients with HNPCC. Colorectal cancer occurs

in up to 80% of those affected, usually by the age of 50, and is often

right-sided. Extracolonic cancers such as endometrial, ovarian, small-bowel,

transitional cell of the ureter or bladder, and gastric often occur in patients

with HNPCC. The risk of endometrial carcinoma has been reported in up to 60%

and

ovarian carcinoma in up to 20% of patients with HNPCC. Therefore, aggressive

gynecologic screening for endometrial and ovarian cancer is recommended in

women in HNPCC kindreds.

Diagnosing families with HNPCC is most often based on clinical criteria. The

strictest criteria are the Amsterdam criteria:

Three or more relatives with colorectal cancer, with one a first-degree

relative of the other two,

At least two successive generations affected,

One cancer diagnosed before age 50 years.

Many researchers have found the Amsterdam criteria neither sufficiently

sensitive nor specific for use as the sole criterion for determining which

families should undergo intensive surveillance or genetic testing.2 The other

criteria include the Amsterdam II and Bethesda criteria. Amsterdam II includes

extracolonic cancers (endometrial, small-bowel, ureter, and renal pelvis) in

addition to colorectal cancer. The Bethesda criteria include young adenomas,

colorectal or endometrial cancers, and individuals with 2 HNPCC-related cancers

(synchronous or metachronous).

The chronic inflammatory colitides, ulcerative colitis and Crohn's disease,

are associated with an increased risk of colorectal cancer. The proximal

extent of colonic involvement and the duration of disease (not activity)

stratify

the level of risk. Risk is highest in patients with pancolitis and

negligible in patients with proctitis. After a decade of disease, the cancer

risk

increases yearly by 1% to 2%.

SIGNS AND SYMPTOMS

Colon polyps and early colon cancer are often asymptomatic until they are

advanced. Gastrointestinal blood loss is the most common sign and may include a

positive FOBT result, iron deficiency anemia, or hematochezia. When tumors

are advanced, unexplained anorexia, weight loss, or symptoms from obstruction

or local invasion, such as a change in bowel habits, abdominal pain, or

obstruction, may occur.

DIAGNOSIS

The diagnosis of colorectal polyps and cancer is most often made during a

colonic evaluation performed for gastrointestinal symptoms, colorectal cancer

screening, or as part of endoscopic surveillance.

Screening

In the past decade, many groups, including the American Cancer Society, the

United States Preventive Service Task Force, and a collaboration of surgical

and gastroenterologic associations under the auspices of the Agency for

Health Care Policy and Research, have established guidelines for colorectal

cancer

screening and surveillance.3,4,5 A variety of options are recommended for

average-risk individuals (Table 3). Colonoscopy was added as a screening option

to guidelines in 1997 and has gained acceptance as the preferred strategy.

One of the first guidelines to recommend colonoscopy as the preferred

screening strategy and annual fecal occult blood testing (FOBT) and flexible

sigmoidoscopy every 5 years as an acceptable alternative is available.5 This

guideline also reviews the advantages and limitations of each screening method.

The evidence to support colonoscopy is derived from data showing a decreased

incidence of colorectal cancer mortality in subjects who have undergone

colonoscopic adenoma removal.6,7 Additionally, colonoscopic screening has been

shown to have favorable cost effectiveness when compared to other screening

strategies.8,9

Patients with symptoms of colorectal cancer and those with greater than

moderate-to-high risk for colorectal cancer should undergo colonoscopy (Table

4).

The American College of Gastroenterology has developed clinical practice

guidelines for subjects with an increased risk of colorectal cancer as well as

surveillance for subjects with adenomas. 5,10 These guidelines put into

perspective the rationale behind differing surveillance intervals based on

adenoma

size, number, histology and family history.

Fecal Occult Blood Test

Randomized trials have found that the use of annual FOBTs have decreased the

mortality from colorectal cancer by up to 33%. The reductions in mortality

are associated with a shift to detection of earlier-stage cancer. In addition,

one study found the incidence of colorectal cancer was reduced by 20% in an

annually screened group. This is likely due to polypectomy in patient's whose

positive FOBT was evaluated by colonoscopy.

Since large polyps and cancers intermittently bleed, the peroxidase activity

of hemoglobin in the stool can be detected by a color change when it

catalyzes the oxidation of guaiac by a peroxide reagent. A special diet (eg, a

meat-free, high-residue diet without vegetables having peroxidase activity,

such

as turnips and horseradish) is recommended for at least 24 hours before three

separate stool specimens are collected at least 1 day apart. Unrehydrated

test sensitivity is low at approximately 80%, with a specificity of up to 98%.

Any positive FOBT should be evaluated by colonoscopy.

Sigmoidoscopy

Results of several case-control studies show a reduction in deaths from

colorectal cancer in subjects who undergo sigmoidoscopic examinations. The

reported reduction in mortality varies between 59% and 80%. The most well-known

study compared the use of rigid sigmoidoscopic screening in 261 patients who

died from cancer of the distal colon or rectum to 868 control subjects.

Screening reduced the rectosigmoid cancer mortality rate by 60%, and the

protective

effect of sigmoidoscopy was noted to last for up to 10 years. This reduction

in mortality may have resulted from earlier detection of cancer and removal of

premalignant polyps. Sigmoidoscopic screening allows the lower third of the

colorectal mucosa to be visualized directly and diagnostic biopsy to be

performed at the time of examination. Both the sensitivity and the specificity

are

high for detection of polyps and cancer in the segment of the bowel

examined. Unfortunately, however, nearly 50% of polyps and cancers are beyond

the

limits of detection of the longest (eg, 60 cm) flexible sigmoidoscope.

Opinions vary regarding the need for colonoscopy for patients in whom a

single, small (< 1 cm) adenoma is found on flexible sigmoidoscopy. Many studies

have shown that the prevalence of advanced proximal neoplasms in patients with

distal adenomas is up to 9%. Therefore, the use of colonoscopy to detect

proximal neoplasia in patients with distal adenomas is strongly recommended.

Sigmoidoscopy Combined with Fecal Occult

Blood Testing

In one controlled trial, 12,479 people underwent annual screening with rigid

sigmoidoscopy or rigid sigmoidoscopy combined with FOBT. A reduction in the

colorectal cancer mortality rate, detection of earlier-stage cancer, and

longer survival were seen in patients undergoing both FOBT and rigid

sigmoidoscopy. Annual FOBT and flexible sigmoidoscopy is the preferred

screening

alternative to colonoscopy screening.5

Barium Enema

Barium enema has the advantage of imaging the entire colon. However, recent

evidence suggests it is inaccurate for detection of polyps and early cancers

and suboptimal for colorectal cancer screening or surveillance. In a

prospective study comparing the use of double-contrast barium enema and

colonoscopy,

the miss rate of barium enema for polyps larger than 1 cm was 52%.11 If

barium enema is the only option for screening or surveillance, it should be

coupled with flexible sigmoidoscopy. The use of flexible sigmoidoscopy allows

visualization of the rectosigmoid, which may not be well seen on barium enema

because of the overlapping loops of bowel. Lesions detected on barium enema

warrant colonoscopic evaluation.

Colonoscopy

Colonoscopy is the " gold standard " for the detection of colonic neoplasms

and the preferred colorectal cancer screening strategy.5 The incidence rate of

colorectal cancer has been shown to be reduced up to 90% in subjects who had

polypectomy versus patients in three reference groups, including two cohorts

in which colonic polyps were not removed and one general-population

registry.6 It can be completed in more than 95% of examinations with negligible

risk.

Colonoscopic screening in individuals with average risk has been found to be

cost-effective, and similar to cervical or breast cancer screening techniques

in cost-effectiveness per life-year saved. Medicare has approved the use of

screening colonoscopy in average-risk beneficiaries. Unfortunately, not all

Americans under the age of 65 have health care benefits that would cover the

charges for colonoscopy which may impact on patient compliance with screening

colonoscopy.

TREATMENT

The stage of colorectal cancer is the most important feature predicting

curability and survival in colorectal cancer. The depth of tumor invasion and

lymph node involvement are the two major components constituting the basis for

colorectal cancer tumor staging. The first colorectal cancer staging system

was developed in 1932 and known as the Dukes' classification. Since then, many

modifications in the Dukes' scheme have been made. This has led to confusion

because most of the schemes utilize the letters A, B, C and D but indicate

different depths of tumor invasion. In an effort to minimize confusion over

which Dukes' stage is implied and to standardize all organ system cancer

staging

the TNM (Tumor, Nodal status and presence of Metastases) system has been

adopted.

The primary treatment of colorectal cancer is surgical resection of the

primary tumor and regional lymph nodes. Surgery is curative for most

early-stage

colorectal tumors (Table 5). For more advanced stages, surgery and adjuvant

therapy are recommended to prevent recurrence and prolong survival.12

Adjuvant Treatment:

Colon Cancer

Studies over the last 10 years have proven the benefit of adjuvant

chemotherapy in prolonging disease-free and overall survival in patients with

stage II

colon cancer compared with patients who received surgery alone.13 Currently,

patients with stage III colon cancer should receive adjuvant therapy with

5-fluorouracil (5-FU) and leucovorin for 6 to 8 months. Patients with stage II

colon cancer should be encouraged to participate in ongoing trials because

adjuvant therapy has not yet proved to offer a survival benefit.

Rectal cancer

The major limitation of rectal cancer surgery is the inability to obtain

wide margins because of the confined space of the bony pelvis. Adjuvant

radiation therapy decreases the rate of local recurrence, while the addition of

systemic chemotherapy further enhances local control and improves survival.14 A

1990 NIH Consensus Development Conference recommended that postoperative

5-FU-based chemotherapy combined with irradiation should be the standard

clinical

practice in stage II and III rectal cancer because of its proven decrease in

local recurrence, cancer-related deaths, and overall mortality.12

In the last decade, subsequent randomized trials are challenging that

recommendation. The debate is fueled, in part, by refinements in surgical

techniques. Total mesorectal excision (TME) is one of the most exciting recent

developments in surgical oncology. The sharp dissection follows along the

mesorectal

fascia with removal of the rectum together with all tissue invested by the

adjacent visceral fascia, including fatty tissue, lymph nodes, and lymphatic

vessels. This technique has been associated with a reduction in local

recurrence rates from 39% to below 10%. These low rates have led some

investigators

to question the routine use of adjuvant radiation therapy. A recent study

compared the use of TME with preoperative radiotherapy versus TME alone.15

Short-term survival was no different in the two groups, but the rate of local

recurrence was 2.4% for TME with preoperative radiotherapy versus 8.2% for TME

alone.

There is also controversy over the best timing of radiotherapy. Compared

with postoperative irradiation, preoperative treatment may have less toxicity

and may increase the chance of sphincter preservation. The collected

information from all controlled trials reported so far shows that the proportion

of

local recurrences is reduced to less than one half when radiotherapy up to

moderately high doses is given preoperatively. This reduction is smaller with

postoperative radiotherapy, even if higher doses are used. Improved survival has

been seen in trials using postoperative radiotherapy, but only when combined

with chemotherapy. In one trial, a survival benefit was incurred with

preoperative radiotherapy versus surgery alone. Randomized trials comparing

preoperative and postoperative combined-modality therapy are in progress.

Outside of clinical trials, curative-intent surgery combined with

radiochemotherapy remains the recommended standard for treatment of stage II and

III

rectal cancer.

Chemoprevention:

Epidemiologic studies have found a modest decrease in colorectal cancer in

patients utilizing nonsteroidal anti-inflammatory drugs, particularly aspirin,

and folate.16 Unfortunately, randomized controlled trials of the use of

chemopreventive agents are limited. A 6-month, placebo-controlled trial of a

selective cyclooxygenase (COX)-2 inhibitor, celecoxib, in FAP patients resulted

in a 28% reduction in polyp size and number.17 The US Food and Drug

Administration has approved the use of celecoxib as an adjunct for the

management of

colorectal adenomas in patients with FAP. The value of COX-2 inhibitors in the

sporadic adenoma population is not known. Two randomized, placebo-controlled

trials found a moderate reduction in recurrent adenomas with calcium

supplementation.18,19 These results support the use of calcium for a

moderate-risk

reduction of recurrent colorectal adenomas. The effectiveness and

cost-effectiveness of chemopreventive agents in different risk populations

needs to be

confirmed before widespread recommendations for their use can be given.20

CONCLUSIONS

Colorectal cancer is one of the leading causes of cancer and death from

carcinoma in the United States. Increasing awareness regarding the preventable

nature of this disease, along with widespread use of screening, should

favorably affect the incidence of colorectal cancer. Colorectal cancer

screening and

polyp removal can save lives, and the most exciting area of future research

will be the primary prevention of adenomas and colorectal cancer through

chemoprevention.

Return to Medicine Index

REFERENCES

Jemal A, A, Murray T, Thun M. Cancer Statistics, 2002. CA Cancer J

Clin. 2002;52:23-47.

Giardello FM, Brensinger JD, sen GM. AGA technical review on hereditary

colorectal cancer and genetic testing. Gastroenterology. 2001;121:198-213.

Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and

surveillance: Clinical guidelines and rationale—Update based on new evidence.

Gastroenterology. 2003;124:544-60.

Byers T, Levin B, Rothenberger D, Dodd GD, RA. American Cancer Society

Guidelines for Early Detection of Colorectal Polyps and Cancer. CA Cancer J

Clin. 1997:47:154-160.

Rex D, D, Lieberman D, Burt R, Sonnenber A. Colorectal cancer

prevention 2000: screening recommendations of the American College of

Gastroenterology. Am J Gastro. 2000;95:868-877.

Winawer S, Zauber A, Ho M, et al. Prevention of colorectal cancer by

colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med.

1993;

329:1977-1981.

nsen OD, Kronberg O, Fenger C. The Funen adenoma follow-up study:

Incidence and death from colorectal carcinoma in an adenoma surveillance

program.

Scand J Gastroenterol. 1993;28:869-874.

Sonnenberg A, Delco F, Inadomi J. Cost-effectiveness of colonoscopy in

screening for colorectal cancer. Ann Intern Med. 2000; 133:573-584.

Frazier L, Colditz G, Fuchs C, Kuntz K. Cost-effectiveness of screening for

colorectal cancer in the general population. JAMA. 2000;284:1954-1961.

Bond JH. Polyp guideline: diagnosis, treatment and surveillance for patients

with colorectal polyps. Practice Parameters Committee of the American

College of Gastroenterology. Am J Gastro. 2000;95:3053-3063.

Winawer SJ, ET, Zauber AG, et al. A comparison of colonoscopy and

double-contrast barium enema for surveillance after polypectomy. National Polyp

Study Work Group. N Engl J Med. 2000;342:1766-1772.

NIH Consensus Conference: Adjuvant therapy for patients with colon and

rectal cancer. JAMA. 1990:264:1444-1450.

Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of adjuvant

chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results

from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies

(C-01, C-02, C-03, and C-04). J Clin Oncol. 1999:17:1349-1355.

Radiation therapy and fluorouracil with or without semustine for the

treatment of patients with surgical adjuvant adenocarcinoma of the rectum.

Gastrointestinal Tumor Study Group. J. Clin Oncol. 1992;10:549-557.

Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy

combined with total mesorectal excision for resectable rectal cancer. N Engl J

Med. 2001;345:638-646.

Janne P, Mayer R. Chemoprevention of colorectal cancer. N Engl J Med.

2000;342:1960-1968.

Steinbach G, Lynch PM, RK, et al. The effect of celecoxib, a

cycloxygenase-2 inhibitor, in familial adenomatous polyopsis. N Engl J Med.

2000;342:1946-1952.

Bonithon-Kopp C, Kronberg O, Giacosa A. Calcium and fibre supplementation in

prevention of colorectal adenoma recurrence: a randomised intervention

trial. European Cancer Prevention Organisation Study Group. Lancet.

2000;356:1300-1306.

Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention

of colorectal adenomas. Calcium Polyp Prevention Group. N Engl J Med.

1999;340:101-107.

Ladabaum U, Chopra CL, Huang G, Scheiman JM, Chernew ME, Fendrick AM.

Aspirin as an adjunct to screening for prevention of sporadic colorectal

cancer. A

cost effectiveness analysis. Ann Intern Med. 2001;135:769-781.

Disclaimer

[Guest guest]

I think the major problem is everyione thinks it will never happen to

me, then it does. What a rude awakening. Love, Ingrid

>

>

> Reviewed June 12, 2003

> Carol A.

> Burke, MD

>

> Department of

> Gastroenterology

> and Hepatology

>

> Print Chapter

> Copyright 2002

> The Cleveland Clinic Foundation

>

>

> Colorectal cancer is one of the few preventable cancers. The

removal of

> precancerous adenomatous polyps during colonoscopy inhibits their

progression to

> cancer. Widely available screening tests such as the fecal occult

blood test

> (FOBT), sigmoidoscopy, and colonoscopy are associated with a

decrease in

> colorectal cancer mortality. Unfortunately, fewer than 50% of

eligible Americans

> have undergone screening, and more than 45% of patients are

diagnosed at a

> time when the cancer is incurable.

> Definition

>

> Prevalence

> Pathophysiology

> Signs and

> Symptoms

> Diagnosis

> Treatment

> Conclusions

> References

> National Guidelines

>

> Colorectal Cancer Screening (AGA)

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

>

> DEFINITION

> The colorectum is the portion of the gastrointestinal tract most

frequently

> affected by tumors. The majority of colonic tumors are benign

epithelial

> polyps. " Polyp " is an inexact term that indicates a protuberance

of tissue into

> the colonic lumen. The most common polyp and the only one that can

become an

> adenocarcinoma is the adenomatous polyp. Both the size and degree

of villous

> features are predictive of the risk of malignancy within the polyp.

> Hyperplastic polyps are the second most common type of polyp,

accounting for

> up to 30% of colonic polyps. Hyperplastic polyps are most often

found in the

> rectosigmoid and are believed to have no clinical significance.

> Unfortunately, hyperplastic polyps and adenomas are

indistinguishable on endoscopy.

> Therefore, all polyps detected in the colon and rectum should be

removed and sent

> for histologic analysis.

> This chapter will focus on the neoplastic epithelial tumors,

including

> adenomatous polyps and adenocarcinoma of the colon and rectum.

> PREVALENCE

> The incidence of colorectal carcinoma has been decreasing on an

average of

> 1.5% annually since the mid-1980s. Research suggests that the

decline may be

> due to an increased use of screening and polyp removal, which

prevents

> progression from polyp to cancer. Adenocarcinoma of the colon and

rectum is the

> third most common cancer and cause of cancer deaths in the United

States. Both

> men and women face a lifetime risk of nearly 6% for the

development of invasive

> colorectal cancer (Table 1).1 It is estimated that approximately

135,000 new

> cases of colorectal cancer will have been diagnosed in 2001, and

that 57,000

> deaths from colorectal cancer will occur. The only known race

predilection

> is in African Americans, who have higher colorectal cancer

incidence and

> mortality rates.

> PATHOPHYSIOLOGY

> In nearly all cases, colorectal carcinoma arises from an

adenomatous polyp.

> Observational studies suggest that the adenoma-to-carcinoma

sequence takes

> approximately 10 years. Although nearly 40% of Americans aged 50

years or older

> harbor adenomatous polyps, it is estimated that only 2% of

adenomas will

> progress to cancer.

> Colorectal cancer arises from a series of histopathologic and

molecular

> changes caused by complex interactions between genetic

susceptibility and

> environmental factors. These molecular changes include multiple,

acquired genetic

> alterations within colonocyte oncogenes (promoting malignant

transformation)

> and tumor suppressor genes (causing loss of the inhibition of

cellular

> proliferation). A newly discovered pathway for carcinogenesis

involves mutations in

> the genes responsible for repair of mismatched DNA base pairs (eg,

mismatch

> repair genes). Mismatch-repair-gene inactivation is present in

approximately

> 15% of sporadic colorectal cancers, but is the major cause of

cancers in

> hereditary nonpolyposis colorectal cancer (HNPCC).

> Epidemiologic studies have implicated a number of environmental

cofactors in

> the development of colorectal cancer. They include, in order of

strength of

> association, advanced age, high red-meat diet, high fat diet,

smoking,

> alcohol consumption, and obesity. Approximately 70% of newly

diagnosed colorectal

> cancers arise in patients without known risk factors. In

approximately 30% of

> patients with colorectal cancer, risk factors have been identified

(Table 2):

> Table 2:

> Risk Factors for Colorectal Cancer

> Personal history of adenomas or colorectal cancer

> First-degree relative age < 60 yrs with adenoma or colorectal

cancer, or two

> first-degree relatives of any age with colorectal cancer

> Inherited colorectal cancer syndromes

> Hereditary nonpolyposis colorectal cancer

> Familial adenomatous polyposis

> Ulcerative colitis and Crohn's colitis

>

>

>

> A personal history of adenomatous polyps or colorectal cancer

increases the

> risk for metachronous colorectal cancer. First-degree relatives of

patients

> with colorectal cancer have a two- to threefold increased risk for

colorectal

> cancer and adenomatous polyps. Recent work has proven that first-

degree

> family members of patients with adenomatous polyps also have an

increased risk of

> colorectal cancer themselves, particularly when the relative's

adenoma is

> diagnosed before age 60 years.

>

> Patients with the highest risk for colorectal cancer are those who

have one

> of the dominantly inherited colorectal cancer syndromes:

> Familial adenomatous polyposis (FAP) is due to a mutation in the

tumor

> suppressor gene APC on the long arm of chromosome 5. Germline

mutations in APC can

> be detected in approximately 80% of patients with FAP. The APC

mutation

> results in the development of hundreds to thousands of colonic

adenomas, usually

> by the second decade of life. Colon cancer develops in all FAP

patients by

> age 40 years if prophylactic colectomy is not performed.

>

> An attenuated form of colonic polyposis has been found and

named " attenuated

> FAP. " The number of colonic polyps is usually less than 100, and

the age of

> onset of polyposis and cancer is shifted 1 to 2 decades later.

> Duodenal adenomas are common in either form of FAP, and

periampullary cancer

> is the second leading cause of cancer deaths in this population.

Gardner's

> syndrome is a phenotypic variant of FAP. In addition to colonic

polyposis,

> other manifestations may be seen, such as benign soft tissue

tumors, osteomas,

> supernumerary teeth, desmoid tumors, and congenital hypertrophy of

the retinal

> pigment epithelium.

> Hereditary nonpolyposis colorectal cancer is caused by genetic

alterations

> in one of the mismatch repair genes. Alterations in these genes

prevent

> adequate repair of DNA, resulting in an accumulation of mutations

in daughter cells

> and leading to carcinogenesis. Germline mutations in one of six

genes have

> been identified in up to 60% of patients with HNPCC. Colorectal

cancer occurs

> in up to 80% of those affected, usually by the age of 50, and is

often

> right-sided. Extracolonic cancers such as endometrial, ovarian,

small-bowel,

> transitional cell of the ureter or bladder, and gastric often

occur in patients

> with HNPCC. The risk of endometrial carcinoma has been reported in

up to 60% and

> ovarian carcinoma in up to 20% of patients with HNPCC. Therefore,

aggressive

> gynecologic screening for endometrial and ovarian cancer is

recommended in

> women in HNPCC kindreds.

> Diagnosing families with HNPCC is most often based on clinical

criteria. The

> strictest criteria are the Amsterdam criteria:

> Three or more relatives with colorectal cancer, with one a first-

degree

> relative of the other two,

> At least two successive generations affected,

> One cancer diagnosed before age 50 years.

> Many researchers have found the Amsterdam criteria neither

sufficiently

> sensitive nor specific for use as the sole criterion for

determining which

> families should undergo intensive surveillance or genetic testing.2

The other

> criteria include the Amsterdam II and Bethesda criteria. Amsterdam

II includes

> extracolonic cancers (endometrial, small-bowel, ureter, and renal

pelvis) in

> addition to colorectal cancer. The Bethesda criteria include young

adenomas,

> colorectal or endometrial cancers, and individuals with 2 HNPCC-

related cancers

> (synchronous or metachronous).

> The chronic inflammatory colitides, ulcerative colitis and Crohn's

disease,

> are associated with an increased risk of colorectal cancer. The

proximal

> extent of colonic involvement and the duration of disease (not

activity) stratify

> the level of risk. Risk is highest in patients with pancolitis and

> negligible in patients with proctitis. After a decade of disease,

the cancer risk

> increases yearly by 1% to 2%.

> SIGNS AND SYMPTOMS

> Colon polyps and early colon cancer are often asymptomatic until

they are

> advanced. Gastrointestinal blood loss is the most common sign and

may include a

> positive FOBT result, iron deficiency anemia, or hematochezia.

When tumors

> are advanced, unexplained anorexia, weight loss, or symptoms from

obstruction

> or local invasion, such as a change in bowel habits, abdominal

pain, or

> obstruction, may occur.

> DIAGNOSIS

> The diagnosis of colorectal polyps and cancer is most often made

during a

> colonic evaluation performed for gastrointestinal symptoms,

colorectal cancer

> screening, or as part of endoscopic surveillance.

>

> Screening

> In the past decade, many groups, including the American Cancer

Society, the

> United States Preventive Service Task Force, and a collaboration

of surgical

> and gastroenterologic associations under the auspices of the

Agency for

> Health Care Policy and Research, have established guidelines for

colorectal cancer

> screening and surveillance.3,4,5 A variety of options are

recommended for

> average-risk individuals (Table 3). Colonoscopy was added as a

screening option

> to guidelines in 1997 and has gained acceptance as the preferred

strategy.

> One of the first guidelines to recommend colonoscopy as the

preferred

> screening strategy and annual fecal occult blood testing (FOBT)

and flexible

> sigmoidoscopy every 5 years as an acceptable alternative is

available.5 This

> guideline also reviews the advantages and limitations of each

screening method.

> The evidence to support colonoscopy is derived from data showing a

decreased

> incidence of colorectal cancer mortality in subjects who have

undergone

> colonoscopic adenoma removal.6,7 Additionally, colonoscopic

screening has been

> shown to have favorable cost effectiveness when compared to other

screening

> strategies.8,9

> Patients with symptoms of colorectal cancer and those with greater

than

> moderate-to-high risk for colorectal cancer should undergo

colonoscopy (Table 4).

> The American College of Gastroenterology has developed clinical

practice

> guidelines for subjects with an increased risk of colorectal

cancer as well as

> surveillance for subjects with adenomas. 5,10 These guidelines put

into

> perspective the rationale behind differing surveillance intervals

based on adenoma

> size, number, histology and family history.

> Fecal Occult Blood Test

> Randomized trials have found that the use of annual FOBTs have

decreased the

> mortality from colorectal cancer by up to 33%. The reductions in

mortality

> are associated with a shift to detection of earlier-stage cancer.

In addition,

> one study found the incidence of colorectal cancer was reduced by

20% in an

> annually screened group. This is likely due to polypectomy in

patient's whose

> positive FOBT was evaluated by colonoscopy.

> Since large polyps and cancers intermittently bleed, the

peroxidase activity

> of hemoglobin in the stool can be detected by a color change when

it

> catalyzes the oxidation of guaiac by a peroxide reagent. A special

diet (eg, a

> meat-free, high-residue diet without vegetables having peroxidase

activity, such

> as turnips and horseradish) is recommended for at least 24 hours

before three

> separate stool specimens are collected at least 1 day apart.

Unrehydrated

> test sensitivity is low at approximately 80%, with a specificity

of up to 98%.

> Any positive FOBT should be evaluated by colonoscopy.

> Sigmoidoscopy

> Results of several case-control studies show a reduction in deaths

from

> colorectal cancer in subjects who undergo sigmoidoscopic

examinations. The

> reported reduction in mortality varies between 59% and 80%. The

most well-known

> study compared the use of rigid sigmoidoscopic screening in 261

patients who

> died from cancer of the distal colon or rectum to 868 control

subjects.

> Screening reduced the rectosigmoid cancer mortality rate by 60%,

and the protective

> effect of sigmoidoscopy was noted to last for up to 10 years. This

reduction

> in mortality may have resulted from earlier detection of cancer

and removal of

> premalignant polyps. Sigmoidoscopic screening allows the lower

third of the

> colorectal mucosa to be visualized directly and diagnostic biopsy

to be

> performed at the time of examination. Both the sensitivity and the

specificity are

> high for detection of polyps and cancer in the segment of the

bowel

> examined. Unfortunately, however, nearly 50% of polyps and cancers

are beyond the

> limits of detection of the longest (eg, 60 cm) flexible

sigmoidoscope.

> Opinions vary regarding the need for colonoscopy for patients in

whom a

> single, small (< 1 cm) adenoma is found on flexible sigmoidoscopy.

Many studies

> have shown that the prevalence of advanced proximal neoplasms in

patients with

> distal adenomas is up to 9%. Therefore, the use of colonoscopy to

detect

> proximal neoplasia in patients with distal adenomas is strongly

recommended.

> Sigmoidoscopy Combined with Fecal Occult

> Blood Testing

> In one controlled trial, 12,479 people underwent annual screening

with rigid

> sigmoidoscopy or rigid sigmoidoscopy combined with FOBT. A

reduction in the

> colorectal cancer mortality rate, detection of earlier-stage

cancer, and

> longer survival were seen in patients undergoing both FOBT and

rigid

> sigmoidoscopy. Annual FOBT and flexible sigmoidoscopy is the

preferred screening

> alternative to colonoscopy screening.5

> Barium Enema

> Barium enema has the advantage of imaging the entire colon.

However, recent

> evidence suggests it is inaccurate for detection of polyps and

early cancers

> and suboptimal for colorectal cancer screening or surveillance. In

a

> prospective study comparing the use of double-contrast barium enema

and colonoscopy,

> the miss rate of barium enema for polyps larger than 1 cm was

52%.11 If

> barium enema is the only option for screening or surveillance, it

should be

> coupled with flexible sigmoidoscopy. The use of flexible

sigmoidoscopy allows

> visualization of the rectosigmoid, which may not be well seen on

barium enema

> because of the overlapping loops of bowel. Lesions detected on

barium enema

> warrant colonoscopic evaluation.

> Colonoscopy

> Colonoscopy is the " gold standard " for the detection of colonic

neoplasms

> and the preferred colorectal cancer screening strategy.5 The

incidence rate of

> colorectal cancer has been shown to be reduced up to 90% in

subjects who had

> polypectomy versus patients in three reference groups, including

two cohorts

> in which colonic polyps were not removed and one general-

population

> registry.6 It can be completed in more than 95% of examinations

with negligible risk.

> Colonoscopic screening in individuals with average risk has been

found to be

> cost-effective, and similar to cervical or breast cancer screening

techniques

> in cost-effectiveness per life-year saved. Medicare has approved

the use of

> screening colonoscopy in average-risk beneficiaries. Unfortunately,

not all

> Americans under the age of 65 have health care benefits that would

cover the

> charges for colonoscopy which may impact on patient compliance with

screening

> colonoscopy.

> TREATMENT

> The stage of colorectal cancer is the most important feature

predicting

> curability and survival in colorectal cancer. The depth of tumor

invasion and

> lymph node involvement are the two major components constituting

the basis for

> colorectal cancer tumor staging. The first colorectal cancer

staging system

> was developed in 1932 and known as the Dukes' classification.

Since then, many

> modifications in the Dukes' scheme have been made. This has led to

confusion

> because most of the schemes utilize the letters A, B, C and D but

indicate

> different depths of tumor invasion. In an effort to minimize

confusion over

> which Dukes' stage is implied and to standardize all organ system

cancer staging

> the TNM (Tumor, Nodal status and presence of Metastases) system

has been

> adopted.

> The primary treatment of colorectal cancer is surgical resection

of the

> primary tumor and regional lymph nodes. Surgery is curative for

most early-stage

> colorectal tumors (Table 5). For more advanced stages, surgery and

adjuvant

> therapy are recommended to prevent recurrence and prolong

survival.12

>

> Adjuvant Treatment:

> Colon Cancer

> Studies over the last 10 years have proven the benefit of adjuvant

> chemotherapy in prolonging disease-free and overall survival in

patients with stage II

> colon cancer compared with patients who received surgery alone.13

Currently,

> patients with stage III colon cancer should receive adjuvant

therapy with

> 5-fluorouracil (5-FU) and leucovorin for 6 to 8 months. Patients

with stage II

> colon cancer should be encouraged to participate in ongoing trials

because

> adjuvant therapy has not yet proved to offer a survival benefit.

> Rectal cancer

> The major limitation of rectal cancer surgery is the inability to

obtain

> wide margins because of the confined space of the bony pelvis.

Adjuvant

> radiation therapy decreases the rate of local recurrence, while the

addition of

> systemic chemotherapy further enhances local control and improves

survival.14 A

> 1990 NIH Consensus Development Conference recommended that

postoperative

> 5-FU-based chemotherapy combined with irradiation should be the

standard clinical

> practice in stage II and III rectal cancer because of its proven

decrease in

> local recurrence, cancer-related deaths, and overall mortality.12

> In the last decade, subsequent randomized trials are challenging

that

> recommendation. The debate is fueled, in part, by refinements in

surgical

> techniques. Total mesorectal excision (TME) is one of the most

exciting recent

> developments in surgical oncology. The sharp dissection follows

along the mesorectal

> fascia with removal of the rectum together with all tissue

invested by the

> adjacent visceral fascia, including fatty tissue, lymph nodes, and

lymphatic

> vessels. This technique has been associated with a reduction in

local

> recurrence rates from 39% to below 10%. These low rates have led

some investigators

> to question the routine use of adjuvant radiation therapy. A

recent study

> compared the use of TME with preoperative radiotherapy versus TME

alone.15

> Short-term survival was no different in the two groups, but the

rate of local

> recurrence was 2.4% for TME with preoperative radiotherapy versus

8.2% for TME

> alone.

> There is also controversy over the best timing of radiotherapy.

Compared

> with postoperative irradiation, preoperative treatment may have

less toxicity

> and may increase the chance of sphincter preservation. The

collected

> information from all controlled trials reported so far shows that

the proportion of

> local recurrences is reduced to less than one half when

radiotherapy up to

> moderately high doses is given preoperatively. This reduction is

smaller with

> postoperative radiotherapy, even if higher doses are used. Improved

survival has

> been seen in trials using postoperative radiotherapy, but only when

combined

> with chemotherapy. In one trial, a survival benefit was incurred

with

> preoperative radiotherapy versus surgery alone. Randomized trials

comparing

> preoperative and postoperative combined-modality therapy are in

progress.

> Outside of clinical trials, curative-intent surgery combined with

> radiochemotherapy remains the recommended standard for treatment of

stage II and III

> rectal cancer.

>

> Chemoprevention:

> Epidemiologic studies have found a modest decrease in colorectal

cancer in

> patients utilizing nonsteroidal anti-inflammatory drugs,

particularly aspirin,

> and folate.16 Unfortunately, randomized controlled trials of the

use of

> chemopreventive agents are limited. A 6-month, placebo-controlled

trial of a

> selective cyclooxygenase (COX)-2 inhibitor, celecoxib, in FAP

patients resulted

> in a 28% reduction in polyp size and number.17 The US Food and

Drug

> Administration has approved the use of celecoxib as an adjunct for

the management of

> colorectal adenomas in patients with FAP. The value of COX-2

inhibitors in the

> sporadic adenoma population is not known. Two randomized, placebo-

controlled

> trials found a moderate reduction in recurrent adenomas with

calcium

> supplementation.18,19 These results support the use of calcium for

a moderate-risk

> reduction of recurrent colorectal adenomas. The effectiveness and

> cost-effectiveness of chemopreventive agents in different risk

populations needs to be

> confirmed before widespread recommendations for their use can be

given.20

>

> CONCLUSIONS

> Colorectal cancer is one of the leading causes of cancer and death

from

> carcinoma in the United States. Increasing awareness regarding the

preventable

> nature of this disease, along with widespread use of screening,

should

> favorably affect the incidence of colorectal cancer. Colorectal

cancer screening and

> polyp removal can save lives, and the most exciting area of future

research

> will be the primary prevention of adenomas and colorectal cancer

through

> chemoprevention.

> Return to Medicine Index

> REFERENCES

> Jemal A, A, Murray T, Thun M. Cancer Statistics, 2002. CA

Cancer J

> Clin. 2002;52:23-47.

>

>

> Giardello FM, Brensinger JD, sen GM. AGA technical review on

hereditary

> colorectal cancer and genetic testing. Gastroenterology.

2001;121:198-213.

>

>

> Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening

and

> surveillance: Clinical guidelines and rationale†" Update based on

new evidence.

> Gastroenterology. 2003;124:544-60.

>

>

> Byers T, Levin B, Rothenberger D, Dodd GD, RA. American

Cancer Society

> Guidelines for Early Detection of Colorectal Polyps and Cancer. CA

Cancer J

> Clin. 1997:47:154-160.

>

>

> Rex D, D, Lieberman D, Burt R, Sonnenber A. Colorectal

cancer

> prevention 2000: screening recommendations of the American College

of

> Gastroenterology. Am J Gastro. 2000;95:868-877.

>

>

> Winawer S, Zauber A, Ho M, et al. Prevention of colorectal cancer

by

> colonoscopic polypectomy. The National Polyp Study Workgroup. N

Engl J Med. 1993;

> 329:1977-1981.

>

>

> nsen OD, Kronberg O, Fenger C. The Funen adenoma follow-up

study:

> Incidence and death from colorectal carcinoma in an adenoma

surveillance program.

> Scand J Gastroenterol. 1993;28:869-874.

>

>

> Sonnenberg A, Delco F, Inadomi J. Cost-effectiveness of

colonoscopy in

> screening for colorectal cancer. Ann Intern Med. 2000; 133:573-584.

>

>

> Frazier L, Colditz G, Fuchs C, Kuntz K. Cost-effectiveness of

screening for

> colorectal cancer in the general population. JAMA. 2000;284:1954-

1961.

>

>

> Bond JH. Polyp guideline: diagnosis, treatment and surveillance

for patients

> with colorectal polyps. Practice Parameters Committee of the

American

> College of Gastroenterology. Am J Gastro. 2000;95:3053-3063.

>

>

> Winawer SJ, ET, Zauber AG, et al. A comparison of

colonoscopy and

> double-contrast barium enema for surveillance after polypectomy.

National Polyp

> Study Work Group. N Engl J Med. 2000;342:1766-1772.

> NIH Consensus Conference: Adjuvant therapy for patients with colon

and

> rectal cancer. JAMA. 1990:264:1444-1450.

>

>

> Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of

adjuvant

> chemotherapy in patients with Dukes' B versus Dukes' C colon

cancer: results

> from four National Surgical Adjuvant Breast and Bowel Project

adjuvant studies

> (C-01, C-02, C-03, and C-04). J Clin Oncol. 1999:17:1349-1355.

>

>

> Radiation therapy and fluorouracil with or without semustine for

the

> treatment of patients with surgical adjuvant adenocarcinoma of the

rectum.

> Gastrointestinal Tumor Study Group. J. Clin Oncol. 1992;10:549-557.

>

>

> Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative

radiotherapy

> combined with total mesorectal excision for resectable rectal

cancer. N Engl J

> Med. 2001;345:638-646.

>

>

> Janne P, Mayer R. Chemoprevention of colorectal cancer. N Engl J

Med.

> 2000;342:1960-1968.

>

>

> Steinbach G, Lynch PM, RK, et al. The effect of

celecoxib, a

> cycloxygenase-2 inhibitor, in familial adenomatous polyopsis. N

Engl J Med.

> 2000;342:1946-1952.

>

>

> Bonithon-Kopp C, Kronberg O, Giacosa A. Calcium and fibre

supplementation in

> prevention of colorectal adenoma recurrence: a randomised

intervention

> trial. European Cancer Prevention Organisation Study Group.

Lancet.

> 2000;356:1300-1306.

>

>

> Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the

prevention

> of colorectal adenomas. Calcium Polyp Prevention Group. N Engl J

Med.

> 1999;340:101-107.

>

>

> Ladabaum U, Chopra CL, Huang G, Scheiman JM, Chernew ME, Fendrick

AM.

> Aspirin as an adjunct to screening for prevention of sporadic

colorectal cancer. A

> cost effectiveness analysis. Ann Intern Med. 2001;135:769-781.

>

> Disclaimer

>