Cancer of the large bowel is second only to lung cancer as a cause of cancer death in the United States: 136,830 new cases occurred in 2014, and 50,310 deaths were due to colorectal cancer. The incidence rate has decreased significantly during the past 25 years, likely due to enhanced and more compliantly followed screening practices. Similarly, mortality rates in the United States have decreased by approximately 25%, resulting largely from earlier detection and improved treatment.
POLYPS AND MOLECULAR PATHOGENESIS
Most colorectal cancers, regardless of etiology, arise from adenomatous polyps. A polyp is a grossly visible protrusion from the mucosal surface and may be classified pathologically as a nonneoplastic hamartoma (e.g., juvenile polyp), a hyperplastic mucosal proliferation (hyperplastic polyp), or an adenomatous polyp. Only adenomas are clearly premalignant, and only a minority of adenomatous polyps evolve into cancer. Adenomatous polyps may be found in the colons of ~30% of middle-aged and ~50% of elderly people; however, <1% of polyps ever become malignant. Most polyps produce no symptoms and remain clinically undetected. Occult blood in the stool is found in <5% of patients with polyps.
A number of molecular changes are noted in adenomatous polyps and colorectal cancers that are thought to reflect a multistep process in the evolution of normal colonic mucosa to life-threatening invasive carcinoma. These developmental steps toward carcinogenesis include, but are not restricted to, point mutations in the K-ras protooncogene; hypomethylation of DNA, leading to gene activation; loss of DNA (allelic loss) at the site of a tumor-suppressor gene (the adenomatous polyposis coli [APC] gene) on the long arm of chromosome 5 (5q21); allelic loss at the site of a tumor-suppressor gene located on chromosome 18q (the deleted in colorectal cancer [DCC] gene); and allelic loss at chromosome 17p, associated with mutations in the p53 tumor-suppressor gene (see Fig. 25-2). Thus, the altered proliferative pattern of the colonic mucosa, which results in progression to a polyp and then to carcinoma, may involve the mutational activation of an oncogene followed by and coupled with the loss of genes that normally suppress tumorigenesis. It remains uncertain whether the genetic aberrations always occur in a defined order. Based on this model, however, cancer is believed to develop only in those polyps in which most (if not all) of these mutational events take place.
Clinically, the probability of an adenomatous polyp becoming a cancer depends on the gross appearance of the lesion, its histologic features, and its size. Adenomatous polyps may be pedunculated (stalked) or sessile (flat-based). Invasive cancers develop more frequently in sessile polyps. Histologically, adenomatous polyps may be tubular, villous (i.e., papillary), or tubulovillous. Villous adenomas, most of which are sessile, become malignant more than three times as often as tubular adenomas. The likelihood that any polypoid lesion in the large bowel contains invasive cancer is related to the size of the polyp, being negligible (<2%) in lesions <1.5 cm, intermediate (2–10%) in lesions 1.5–2.5 cm, and substantial (10%) in lesions >2.5 cm in size.
Following the detection of an adenomatous polyp, the entire large bowel should be visualized endoscopically because synchronous lesions are noted in about one-third of cases. Colonoscopy should then be repeated periodically, even in the absence of a previously documented malignancy, because such patients have a 30–50% probability of developing another adenoma and are at a higher-than-average risk for developing a colorectal carcinoma. Adenomatous polyps are thought to require >5 years of growth before becoming clinically significant; colonoscopy need not be carried out more frequently than every 3 years for the vast majority of patients.
ETIOLOGY AND RISK FACTORS
Risk factors for the development of colorectal cancer are listed in Table 40-1.
The etiology for most cases of large-bowel cancer appears to be related to environmental factors. The disease occurs more often in upper socioeconomic populations who live in urban areas. Mortality from colorectal cancer is directly correlated with per capita consumption of calories, meat protein, and dietary fat and oil as well as elevations in the serum cholesterol concentration and mortality from coronary artery disease. Geographic variations in incidence largely are unrelated to genetic differences, since migrant groups tend to assume the large-bowel cancer incidence rates of their adopted countries. Furthermore, population groups such as Mormons and Seventh Day Adventists, whose lifestyle and dietary habits differ somewhat from those of their neighbors, have significantly lower-than-expected incidence and mortality rates for colorectal cancer. The incidence of colorectal cancer has increased in Japan since that nation has adopted a more “Western” diet. At least three hypotheses have been proposed to explain the relationship to diet, none of which is fully satisfactory.
TABLE 40-1Risk Factors for the Development of Colorectal Cancer ||Download (.pdf) TABLE 40-1 Risk Factors for the Development of Colorectal Cancer
|Diet: Animal fat |
|Hereditary syndromes |
| Polyposis coli |
| MYH-associated polyposis |
| Nonpolyposis syndrome (Lynch’s syndrome) |
|Inflammatory bowel disease |
|Streptococcus bovis bacteremia |
|? Tobacco use |
One hypothesis is that the ingestion of animal fats found in red meats and processed meat leads to an increased proportion of anaerobes in the gut microflora, resulting in the conversion of normal bile acids into carcinogens. This provocative hypothesis is supported by several reports of increased amounts of fecal anaerobes in the stools of patients with colorectal cancer. Diets high in animal (but not vegetable) fats are also associated with high serum cholesterol, which is also associated with enhanced risk for the development of colorectal adenomas and carcinomas.
The large number of calories in Western diets coupled with physical inactivity has been associated with a higher prevalence of obesity. Obese persons develop insulin resistance with increased circulating levels of insulin, leading to higher circulating concentrations of insulin-like growth factor type I (IGF-I). This growth factor appears to stimulate proliferation of the intestinal mucosa.
Contrary to prior beliefs, the results of randomized trials and case-controlled studies have failed to show any value for dietary fiber or diets high in fruits and vegetables in preventing the recurrence of colorectal adenomas or the development of colorectal cancer.
The weight of epidemiologic evidence, however, implicates diet as being the major etiologic factor for colorectal cancer, particularly diets high in animal fat and in calories.
HEREDITARY FACTORS AND SYNDROMES
Up to 25% of patients with colorectal cancer have a family history of the disease, suggesting a hereditary predisposition. Inherited large-bowel cancers can be divided into two main groups: the well-studied but uncommon polyposis syndromes and the more common nonpolyposis syndromes (Table 40-2).
Polyposis coli (familial polyposis of the colon) is a rare condition characterized by the appearance of thousands of adenomatous polyps throughout the large bowel. It is transmitted as an autosomal dominant trait; the occasional patient with no family history probably developed the condition due to a spontaneous mutation. Polyposis coli is associated with a deletion in the long arm of chromosome 5 (including the APC gene) in both neoplastic (somatic mutation) and normal (germline mutation) cells. The loss of this genetic material (i.e., allelic loss) results in the absence of tumor-suppressor genes whose protein products would normally inhibit neoplastic growth. The presence of soft tissue and bony tumors, congenital hypertrophy of the retinal pigment epithelium, mesenteric desmoid tumors, and ampullary cancers in addition to the colonic polyps characterizes a subset of polyposis coli known as Gardner’s syndrome. The appearance of malignant tumors of the central nervous system accompanying polyposis coli defines Turcot’s syndrome. The colonic polyps in all these conditions are rarely present before puberty but are generally evident in affected individuals by age 25. If the polyposis is not treated surgically, colorectal cancer will develop in almost all patients before age 40. Polyposis coli results from a defect in the colonic mucosa, leading to an abnormal proliferative pattern and impaired DNA repair mechanisms. Once the multiple polyps are detected, patients should undergo a total colectomy. Medical therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac and selective cyclooxygenase-2 inhibitors such as celecoxib can decrease the number and size of polyps in patients with polyposis coli; however, this effect on polyps is only temporary, and the use of NSAIDs has not been shown to reduce the risk of cancer. Colectomy remains the primary therapy/prevention. The offspring of patients with polyposis coli, who often are prepubertal when the diagnosis is made in the parent, have a 50% risk for developing this premalignant disorder and should be carefully screened by annual flexible sigmoidoscopy until age 35. Proctosigmoidoscopy is a sufficient screening procedure because polyps tend to be evenly distributed from cecum to anus, making more invasive and expensive techniques such as colonoscopy or barium enema unnecessary. Testing for occult blood in the stool is an inadequate screening maneuver. If a causative germline AP C mutation has been identified in an affected family member, an alternative method for identifying carriers is testing DNA from peripheral blood mononuclear cells for the presence of the specific APC mutation. The detection of such a germline mutation can lead to a definitive diagnosis before the development of polyps.
TABLE 40-2Hereditable (Autosomal Dominant) Gastrointestinal Polyposis Syndromes ||Download (.pdf) TABLE 40-2 Hereditable (Autosomal Dominant) Gastrointestinal Polyposis Syndromes
|Syndrome ||Distribution of Polyps ||Histologic Type ||Malignant Potential ||Associated Lesions |
|Familial adenomatous polyposis ||Large intestine ||Adenoma ||Common ||None |
|Gardner’s syndrome ||Large and small intestines ||Adenoma ||Common ||Osteomas, fibromas, lipomas, epidermoid cysts, ampullary cancers, congenital hypertrophy of retinal pigment epithelium |
|Turcot’s syndrome ||Large intestine ||Adenoma ||Common ||Brain tumors |
|MYH-associated polyposis ||Large intestine ||Adenoma ||Common ||None |
|Nonpolyposis syndrome (Lynch’s syndrome) ||Large intestine (often proximal) ||Adenoma ||Common ||Endometrial and ovarian tumors (most frequently) gastric, genitourinary, pancreatic, biliary cancers (less frequently) |
|Peutz-Jeghers syndrome ||Small and large intestines, stomach ||Hamartoma ||Rare ||Mucocutaneous pigmentation; tumors of the ovary, breast, pancreas, endometrium |
|Juvenile polyposis ||Large and small intestines, stomach ||Hamartoma, rarely progressing to adenoma ||Rare ||Various congenital abnormalities |
MYH-associated polyposis (MAP) is a rare autosomal recessive syndrome caused by a biallelic mutation in the MUT4H gene. This hereditary condition may have a variable clinical presentation, resembling polyposis coli or colorectal cancer occurring in younger individuals without polyposis. Screening and colectomy guidelines for this syndrome are less clear than for polyposis coli, but annual to biennial colonoscopic surveillance is generally recommended starting at age 25–30.
Hereditary nonpolyposis colon cancer
Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch’s syndrome, is another autosomal dominant trait. It is characterized by the presence of three or more relatives with histologically documented colorectal cancer, one of whom is a first-degree relative of the other two; one or more cases of colorectal cancer diagnosed before age 50 in the family; and colorectal cancer involving at least two generations. In contrast to polyposis coli, HNPCC is associated with an unusually high frequency of cancer arising in the proximal large bowel. The median age for the appearance of an adenocarcinoma is <50 years, 10–15 years younger than the median age for the general population. Despite having a poorly differentiated, mucinous histologic appearance, the proximal colon tumors that characterize HNPCC have a better prognosis than sporadic tumors from patients of similar age. Families with HNPCC often include individuals with multiple primary cancers; the association of colorectal cancer with either ovarian or endometrial carcinomas is especially strong in women, and an increased appearance of gastric, small-bowel, genitourinary, pancreaticobiliary, and sebaceous skin tumors has been reported as well. It has been recommended that members of such families undergo annual or biennial colonoscopy beginning at age 25 years, with intermittent pelvic ultrasonography and endometrial biopsy for afflicted women; such a screening strategy has not yet been validated. HNPCC is associated with germline mutations of several genes, particularly hMSH2 on chromosome 2 and hMLH1 on chromosome 3. These mutations lead to errors in DNA replication and are thought to result in DNA instability because of defective repair of DNA mismatches resulting in abnormal cell growth and tumor development. Testing tumor cells through molecular analysis of DNA or immunohistochemical staining of paraffin-fixed tissue for “microsatellite instability” (sequence changes reflecting defective mismatch repair) in patients with colorectal cancer and a positive family history for colorectal or endometrial cancer may identify probands with HNPCC.
INFLAMMATORY BOWEL DISEASE
Large-bowel cancer is increased in incidence in patients with long-standing inflammatory bowel disease (IBD). Cancers develop more commonly in patients with ulcerative colitis than in those with granulomatous (i.e., Crohn’s) colitis, but this impression may result in part from the occasional difficulty of differentiating these two conditions. The risk of colorectal cancer in a patient with IBD is relatively small during the initial 10 years of the disease, but then appears to increase at a rate of ~0.5–1% per year. Cancer may develop in 8–30% of patients after 25 years. The risk is higher in younger patients with pancolitis.
Cancer surveillance strategies in patients with IBD are unsatisfactory. Symptoms such as bloody diarrhea, abdominal cramping, and obstruction, which may signal the appearance of a tumor, are similar to the complaints caused by a flare-up of the underlying disease. In patients with a history of IBD lasting ≥15 years who continue to experience exacerbations, the surgical removal of the colon can significantly reduce the risk for cancer and also eliminate the target organ for the underlying chronic gastrointestinal disorder. The value of such surveillance techniques as colonoscopy with mucosal biopsies and brushings for less symptomatic individuals with chronic IBD is uncertain. The lack of uniformity regarding the pathologic criteria that characterize dysplasia and the absence of data that such surveillance reduces the development of lethal cancers have made this costly practice an area of controversy.
OTHER HIGH-RISK CONDITIONS
Streptococcus bovis bacteremia
For unknown reasons, individuals who develop endocarditis or septicemia from this fecal bacterium have a high incidence of occult colorectal tumors and, possibly, upper gastrointestinal cancers as well. Endoscopic or radiographic screening appears advisable.
Cigarette smoking is linked to the development of colorectal adenomas, particularly after >35 years of tobacco use. No biologic explanation for this association has yet been proposed.
Several orally administered compounds have been assessed as possible inhibitors of colon cancer. The most effective class of chemopreventive agents is aspirin and other NSAIDs, which are thought to suppress cell proliferation by inhibiting prostaglandin synthesis. Regular aspirin use reduces the risk of colon adenomas and carcinomas as well as death from large-bowel cancer; such use also appears to diminish the likelihood for developing additional premalignant adenomas following successful treatment for a prior colon carcinoma. This effect of aspirin on colon carcinogenesis increases with the duration and dosage of drug use. Oral folic acid supplements and oral calcium supplements appear to reduce the risk of adenomatous polyps and colorectal cancers in case-controlled studies. The value of vitamin D as a form of chemoprevention is under study. Antioxidant vitamins such as ascorbic acid, tocopherols, and β-carotene are ineffective at reducing the incidence of subsequent adenomas in patients who have undergone the removal of a colon adenoma. Estrogen replacement therapy has been associated with a reduction in the risk of colorectal cancer in women, conceivably by an effect on bile acid synthesis and composition or by decreasing synthesis of IGF-I.
The rationale for colorectal cancer screening programs is that the removal of adenomatous polyps will prevent colorectal cancer, and that earlier detection of localized, superficial cancers in asymptomatic individuals will increase the surgical cure rate. Such screening programs are particularly important for individuals with a family history of the disease in first-degree relatives. The relative risk for developing colorectal cancer increases to 1.75 in such individuals and may be even higher if the relative was afflicted before age 60. The prior use of proctosigmoidoscopy as a screening tool was based on the observation that 60% of early lesions are located in the rectosigmoid. For unexplained reasons, however, the proportion of large-bowel cancers arising in the rectum has been decreasing during the past several decades, with a corresponding increase in the proportion of cancers in the more proximal descending colon. As such, the potential for proctosigmoidoscopy to detect a sufficient number of occult neoplasms to make the procedure cost-effective has been questioned.
Screening strategies for colorectal cancer that have been examined during the past several decades are listed in Table 40-3.
TABLE 40-3Screening Strategies for Colorectal Cancer ||Download (.pdf) TABLE 40-3 Screening Strategies for Colorectal Cancer
|Digital rectal examination |
|Stool testing |
|• Occult blood |
|• Fecal DNA |
|• Contrast barium enema |
|• Virtual (i.e., computed tomography colonography) |
|• Flexible sigmoidoscopy |
|• Colonoscopy |
Many programs directed at the early detection of colorectal cancers have focused on digital rectal examinations and fecal occult blood (i.e., stool guaiac) testing. The digital examination should be part of any routine physical evaluation in adults older than age 40 years, serving as a screening test for prostate cancer in men, a component of the pelvic examination in women, and an inexpensive maneuver for the detection of masses in the rectum. However, because of the proximal migration of colorectal tumors, its value as an overall screening modality for colorectal cancer has become limited. The development of the fecal occult blood test has greatly facilitated the detection of occult fecal blood. Unfortunately, even when performed optimally, the fecal occult blood test has major limitations as a screening technique. About 50% of patients with documented colorectal cancers have a negative fecal occult blood test, consistent with the intermittent bleeding pattern of these tumors. When random cohorts of asymptomatic persons have been tested, 2–4% have fecal occult blood-positive stools. Colorectal cancers have been found in <10% of these “test-positive” cases, with benign polyps being detected in an additional 20–30%. Thus, a colorectal neoplasm will not be found in most asymptomatic individuals with occult blood in their stool. Nonetheless, persons found to have fecal occult blood-positive stool routinely undergo further medical evaluation, including sigmoidoscopy and/or colonoscopy—procedures that are not only uncomfortable and expensive but also associated with a small risk for significant complications. The added cost of these studies would appear justifiable if the small number of patients found to have occult neoplasms because of fecal occult blood screening could be shown to have an improved prognosis and prolonged survival. Prospectively controlled trials have shown a statistically significant reduction in mortality rate from colorectal cancer for individuals undergoing annual stool guaiac screening. However, this benefit only emerged after >13 years of follow-up and was extremely expensive to achieve, because all positive tests (most of which were falsely positive) were followed by colonoscopy. Moreover, these colonoscopic examinations quite likely provided the opportunity for cancer prevention through the removal of potentially premalignant adenomatous polyps because the eventual development of cancer was reduced by 20% in the cohort undergoing annual screening.
With the appreciation that the carcinogenic process leading to the progression of the normal bowel mucosa to an adenomatous polyp and then to a cancer is the result of a series of molecular changes, investigators have examined fecal DNA for evidence of mutations associated with such molecular changes as evidence of the occult presence of precancerous lesions or actual malignancies. Such a strategy has been tested in more than 4000 asymptomatic individuals whose stool was assessed for occult blood and for 21 possible mutations in fecal DNA; these study subjects also underwent colonoscopy. Although the fecal DNA strategy suggested the presence of more advanced adenomas and cancers than did the fecal occult blood testing approach, the overall sensitivity, using colonoscopic findings as the standard, was less than 50%, diminishing enthusiasm for further pursuit of the fecal DNA screening strategy.
The use of imaging studies to screen for colorectal cancers has also been explored. Air contrast barium enemas had been used to identify sources of occult blood in the stool prior to the advent of fiberoptic endoscopy; the cumbersome nature of the procedure and inconvenience to patients limited its widespread adoption. The introduction of computed tomography (CT) scanning led to the development of virtual (i.e., CT) colonography as an alternative to the growing use of endoscopic screening techniques. Virtual colonography was proposed as being equivalent in sensitivity to colonoscopy and being available in a more widespread manner because it did not require the same degree of operator expertise as fiberoptic endoscopy. However, virtual colonography requires the same cathartic preparation that has limited widespread acceptance of endoscopic colonoscopy, is diagnostic but not therapeutic (i.e., patients with suspicious findings must undergo a subsequent endoscopic procedure for polypectomy or biopsy), and, in the setting of general radiology practices, appears to be less sensitive as a screening technique when compared with endoscopic procedures.
With the appreciation of the inadequacy of fecal occult blood testing alone, concerns about the practicality of imaging approaches, and the wider adoption of endoscopic examinations by the primary care community, screening strategies in asymptomatic persons have changed. At present, both the American Cancer Society and the National Comprehensive Cancer Network suggest either fecal occult blood testing annually coupled with flexible sigmoidoscopy every 5 years or colonoscopy every 10 years beginning at age 50 in asymptomatic individuals with no personal or family history of polyps or colorectal cancer. The recommendation for the inclusion of flexible sigmoidoscopy is strongly supported by the recently published results of three randomized trials performed in the United States, the United Kingdom, and Italy, involving more than 350,000 individuals, which consistently showed that periodic (even single) sigmoidoscopic examinations, after more than a decade of median follow-up, lead to an approximate 21% reduction in the development of colorectal cancer and a more than 25% reduction in mortality from the malignant disease. Less than 20% of participants in these studies underwent a subsequent colonoscopy. In contrast to the cathartic preparation required before colonoscopic procedures, which is only performed by highly trained specialists, flexible sigmoidoscopy requires only an enema as preparation and can be accurately performed by nonspecialty physicians or physician-extenders. The randomized screening studies using flexible sigmoidoscopy led to the estimate that approximately 650 individuals needed to be screened to prevent one colorectal cancer death; this contrasts with the data for mammography where the number of women needing to be screened to prevent one breast cancer death is 2500, reinforcing the efficacy of endoscopic surveillance for colorectal cancer screening. Presumably the benefit from the sigmoidoscopic screening is the result of the identification and removal of adenomatous polyps; it is intriguing that this benefit has been achieved using a technique that leaves the proximal half of the large bowel unvisualized.
It remains to be seen whether surveillance colonoscopy, which has gained increasing popularity in the United States for colorectal cancer screening, will prove to be more effective than flexible sigmoidoscopy. Ongoing randomized trials being conducted in Europe are addressing this issue. Although flexible sigmoidoscopy only visualizes the distal half of the large bowel, leading to the assumption that colonoscopy represents a more informative approach, colonoscopy has been reported as being less accurate for screening the proximal rather than the distal colon, perhaps due to technical considerations but also possibly because of a greater frequency of serrated (i.e., “flat”) polyps in the right colon, which are more difficult to identify. At present, colonoscopy performed every 10 years has been offered as an alternative to annual fecal occult blood testing with periodic (every 5 years) flexible sigmoidoscopy. Colonoscopy has been shown to be superior to double-contract barium enema and also to have a higher sensitivity for detecting villous or dysplastic adenomas or cancers than the strategy using occult fecal blood testing and flexible sigmoidoscopy. Whether colonoscopy performed every 10 years beginning at age 50 is medically superior and economically equivalent to flexible sigmoidoscopy remains to be determined.
Symptoms vary with the anatomic location of the tumor. Because stool is relatively liquid as it passes through the ileocecal valve into the right colon, cancers arising in the cecum and ascending colon may become quite large without resulting in any obstructive symptoms or noticeable alterations in bowel habits. Lesions of the right colon commonly ulcerate, leading to chronic, insidious blood loss without a change in the appearance of the stool. Consequently, patients with tumors of the ascending colon often present with symptoms such as fatigue, palpitations, and even angina pectoris and are found to have a hypochromic, microcytic anemia indicative of iron deficiency. Because the cancers may bleed intermittently, a random fecal occult blood test may be negative. As a result, the unexplained presence of iron-deficiency anemia in any adult (with the possible exception of a premenopausal, multiparous woman) mandates a thorough endoscopic and/or radiographic visualization of the entire large bowel (Fig. 40-1).
Double-contrast air-barium enema revealing a sessile tumor of the cecum in a patient with iron-deficiency anemia and guaiac-positive stool. The lesion at surgery was a stage II adenocarcinoma.
Because stool becomes more formed as it passes into the transverse and descending colon, tumors arising there tend to impede the passage of stool, resulting in the development of abdominal cramping, occasional obstruction, and even perforation. Radiographs of the abdomen often reveal characteristic annular, constricting lesions (“apple-core” or “napkin-ring”) (Fig. 40-2).
Annular, constricting adenocarcinoma of the descending colon. This radiographic appearance is referred to as an “apple-core” lesion and is always highly suggestive of malignancy.
Cancers arising in the rectosigmoid are often associated with hematochezia, tenesmus, and narrowing of the caliber of stool; anemia is an infrequent finding. While these symptoms may lead patients and their physicians to suspect the presence of hemorrhoids, the development of rectal bleeding and/or altered bowel habits demands a prompt digital rectal examination and proctosigmoidoscopy.
Staging, prognostic factors, and patterns of spread
The prognosis for individuals having colorectal cancer is related to the depth of tumor penetration into the bowel wall and the presence of both regional lymph node involvement and distant metastases. These variables are incorporated into the staging system introduced by Dukes and subsequently applied to a TNM classification method, in which T represents the depth of tumor penetration, N the presence of lymph node involvement, and M the presence or absence of distant metastases (Fig. 40-3). Superficial lesions that do not involve regional lymph nodes and do not penetrate through the submucosa (T1) or the muscularis (T2) are designated as stage I (T1–2N0M0) disease; tumors that penetrate through the muscularis but have not spread to lymph nodes are stage II disease (T3-4N0M0); regional lymph node involvement defines stage III (TXN1-2M0) disease; and metastatic spread to sites such as liver, lung, or bone indicates stage IV (TXNXM1) disease. Unless gross evidence of metastatic disease is present, disease stage cannot be determined accurately before surgical resection and pathologic analysis of the operative specimens. It is not clear whether the detection of nodal metastases by special immunohistochemical molecular techniques has the same prognostic implications as disease detected by routine light microscopy.
Staging and prognosis for patients with colorectal cancer.
Most recurrences after a surgical resection of a large-bowel cancer occur within the first 4 years, making 5-year survival a fairly reliable indicator of cure. The likelihood for 5-year survival in patients with colorectal cancer is stage-related (Fig. 40-3). That likelihood has improved during the past several decades when similar surgical stages have been compared. The most plausible explanation for this improvement is more thorough intraoperative and pathologic staging. In particular, more exacting attention to pathologic detail has revealed that the prognosis following the resection of a colorectal cancer is not related merely to the presence or absence of regional lymph node involvement; rather, prognosis may be more precisely gauged by the number of involved lymph nodes (one to three lymph nodes [“N1”] vs four or more lymph nodes [“N2”]) and the number of nodes examined. A minimum of 12 sampled lymph nodes is thought necessary to accurately define tumor stage, and the more nodes examined, the better. Other predictors of a poor prognosis after a total surgical resection include tumor penetration through the bowel wall into pericolic fat, poorly differentiated histology, perforation and/or tumor adherence to adjacent organs (increasing the risk for an anatomically adjacent recurrence), and venous invasion by tumor (Table 40-4). Regardless of the clinicopathologic stage, a preoperative elevation of the plasma carcinoembryonic antigen (CEA) level predicts eventual tumor recurrence. The presence of aneuploidy and specific chromosomal deletions, such as a mutation in the b-raf gene in tumor cells, appears to predict for a higher risk for metastatic spread. Conversely, the detection of microsatellite instability in tumor tissue indicates a more favorable outcome. In contrast to most other cancers, the prognosis in colorectal cancer is not influenced by the size of the primary lesion when adjusted for nodal involvement and histologic differentiation.
TABLE 40-4Predictors of Poor Outcome Following total Surgical Resection of Colorectal Cancer ||Download (.pdf) TABLE 40-4 Predictors of Poor Outcome Following total Surgical Resection of Colorectal Cancer
|Tumor spread to regional lymph nodes |
|Number of regional lymph nodes involved |
|Tumor penetration through the bowel wall |
|Poorly differentiated histology |
|Tumor adherence to adjacent organs |
|Venous invasion |
|Preoperative elevation of CEA titer (>5 ng/mL) |
|Specific chromosomal deletion (e.g., mutation in the b-raf gene) |
Cancers of the large bowel generally spread to regional lymph nodes or to the liver via the portal venous circulation. The liver represents the most frequent visceral site of metastasis; it is the initial site of distant spread in one-third of recurring colorectal cancers and is involved in more than two-thirds of such patients at the time of death. In general, colorectal cancer rarely spreads to the lungs, supraclavicular lymph nodes, bone, or brain without prior spread to the liver. A major exception to this rule occurs in patients having primary tumors in the distal rectum, from which tumor cells may spread through the paravertebral venous plexus, escaping the portal venous system and thereby reaching the lungs or supraclavicular lymph nodes without hepatic involvement. The median survival after the detection of distant metastases has ranged in the past from 6–9 months (hepatomegaly, abnormal liver chemistries) to 24–30 months (small liver nodule initially identified by elevated CEA level and subsequent CT scan), but effective systemic therapy is significantly improving this prognosis.
Efforts to use gene expression profiles to identify patients at risk of recurrence or those particularly likely to benefit from adjuvant therapy have not yet yielded practice-changing results. Despite a burgeoning literature examining a host of prognostic factors, pathologic stage at diagnosis remains the best predictor of long-term prognosis. Patients with lymphovascular invasion and high preoperative CEA levels are likely to have a more aggressive clinical course.
TREATMENT Colorectal Cancer
Total resection of tumor is the optimal treatment when a malignant lesion is detected in the large bowel. An evaluation for the presence of metastatic disease, including a thorough physical examination, biochemical assessment of liver function, measurement of the plasma CEA level, and a CT scan of the chest, abdomen, and pelvis, should be performed before surgery. When possible, a colonoscopy of the entire large bowel should be performed to identify synchronous neoplasms and/or polyps. The detection of metastases should not preclude surgery in patients with tumor-related symptoms such as gastrointestinal bleeding or obstruction, but it often prompts the use of a less radical operative procedure. The necessity for a primary tumor resection in asymptomatic individuals with metastatic disease is an area of controversy. At the time of laparotomy, the entire peritoneal cavity should be examined, with thorough inspection of the liver, pelvis, and hemidiaphragm and careful palpation of the full length of the large bowel. Following recovery from a complete resection, patients should be observed carefully for 5 years by semiannual physical examinations and blood chemistry measurements. If a complete colonoscopy was not performed preoperatively, it should be carried out within the first several postoperative months. Some authorities favor measuring plasma CEA levels at 3-month intervals because of the sensitivity of this test as a marker for otherwise undetectable tumor recurrence. Subsequent endoscopic surveillance of the large bowel, probably at triennial intervals, is indicated, because patients who have been cured of one colorectal cancer have a 3–5% probability of developing an additional bowel cancer during their lifetime and a >15% risk for the development of adenomatous polyps. Anastomotic (“suture-line”) recurrences are infrequent in colorectal cancer patients, provided the surgical resection margins are adequate and free of tumor. The value of periodic CT scans of the abdomen, assessing for an early, asymptomatic indication of tumor recurrence, is an area of uncertainty, with some experts recommending the test be performed annually for the first 3 postoperative years.
Radiation therapy to the pelvis is recommended for patients with rectal cancer because it reduces the 20–25% probability of regional recurrences following complete surgical resection of stage II or III tumors, especially if they have penetrated through the serosa. This alarmingly high rate of local disease recurrence is believed to be due to the fact that the contained anatomic space within the pelvis limits the extent of the resection and because the rich lymphatic network of the pelvic side wall immediately adjacent to the rectum facilitates the early spread of malignant cells into surgically inaccessible tissue. The use of sharp rather than blunt dissection of rectal cancers (total mesorectal excision) appears to reduce the likelihood of local disease recurrence to ~10%. Radiation therapy, either pre- or postoperatively, further reduces the likelihood of pelvic recurrences but does not appear to prolong survival. Combining radiation therapy with 5-fluorouracil (5-FU)-based chemotherapy, preferably prior to surgical resection, lowers local recurrence rates and improves overall survival. Preoperative radiotherapy is indicated for patients with large, potentially unresectable rectal cancers; such lesions may shrink enough to permit subsequent surgical removal. Radiation therapy is not effective as the primary treatment of colon cancer.
Systemic therapy for patients with colorectal cancer has become more effective. 5-FU remains the backbone of treatment for this disease. Partial responses are obtained in 15–20% of patients. The probability of tumor response appears to be somewhat greater for patients with liver metastases when chemotherapy is infused directly into the hepatic artery, but intraarterial treatment is costly and toxic and does not appear to appreciably prolong survival. The concomitant administration of folinic acid (leucovorin) improves the efficacy of 5-FU in patients with advanced colorectal cancer, presumably by enhancing the binding of 5-FU to its target enzyme, thymidylate synthase. A threefold improvement in the partial response rate is noted when folinic acid is combined with 5-FU; however, the effect on survival is marginal, and the optimal dose schedule remains to be defined. 5-FU is generally administered intravenously but may also be given orally in the form of capecitabine (Xeloda) with seemingly similar efficacy.
Irinotecan (CPT-11), a topoisomerase 1 inhibitor, prolongs survival when compared to supportive care in patients whose disease has progressed on 5-FU. Furthermore, the addition of irinotecan to 5-FU and leucovorin (LV) (e.g., FOLFIRI) improves response rates and survival of patients with metastatic disease. The FOLFIRI regimen is as follows: irinotecan, 180 mg/m2 as a 90-min infusion on day 1; LV, 400 mg/m2 as a 2-h infusion during irinotecan administration; immediately followed by 5-FU bolus, 400 mg/m2, and 46-h continuous infusion of 2.4–3 g/m2 every 2 weeks. Diarrhea is the major side effect from irinotecan. Oxaliplatin, a platinum analogue, also improves the response rate when added to 5-FU and LV (FOLFOX) as initial treatment of patients with metastatic disease. The FOLFOX regimen is as follows: 2-h infusion of LV (400 mg/m2 per day) followed by a 5-FU bolus (400 mg/m2 per day) and 22-h infusion (1200 mg/m2) every 2 weeks, together with oxaliplatin, 85 mg/m2 as a 2-h infusion on day 1. Oxaliplatin frequently causes a dose-dependent sensory neuropathy that often but not always resolves following the cessation of therapy. FOLFIRI and FOLFOX are equal in efficacy. In metastatic disease, these regimens may produce median survivals of 2 years.
Monoclonal antibodies are also effective in patients with advanced colorectal cancer. Cetuximab (Erbitux) and panitumumab (Vectibix) are directed against the epidermal growth factor receptor (EGFR), a transmembrane glycoprotein involved in signaling pathways affecting growth and proliferation of tumor cells. Both cetuximab and panitumumab, when given alone, have been shown to benefit a small proportion of previously treated patients, and cetuximab appears to have therapeutic synergy with such chemotherapeutic agents as irinotecan, even in patients previously resistant to this drug; this suggests that cetuximab can reverse cellular resistance to cytotoxic chemotherapy. The antibodies are not effective in the approximate 40% subset of colon tumors that contain mutated K-ras. The use of both cetuximab and panitumumab can lead to an acne-like rash, with the development and severity of the rash being correlated with the likelihood of antitumor efficacy. Inhibitors of the EGFR tyrosine kinase such as erlotinib (Tarceva) or sunitinib (Sutent) do not appear to be effective in colorectal cancer.
Bevacizumab (Avastin) is a monoclonal antibody directed against the vascular endothelial growth factor (VEGF) and is thought to act as an antiangiogenesis agent. The addition of bevacizumab to irinotecan-containing combinations and to FOLFOX initially appeared to significantly improve the outcome observed with chemotherapy alone, but subsequent studies have suggested a lesser degree of benefit. The use of bevacizumab can lead to hypertension, proteinuria, and an increased likelihood of thromboembolic events.
Patients with solitary hepatic metastases without clinical or radiographic evidence of additional tumor involvement should be considered for partial liver resection, because such procedures are associated with 5-year survival rates of 25–30% when performed on selected individuals by experienced surgeons.
The administration of 5-FU and LV for 6 months after resection of tumor in patients with stage III disease leads to a 40% decrease in recurrence rates and 30% improvement in survival. The likelihood of recurrence has been further reduced when oxaliplatin has been combined with 5-FU and LV (e.g., FOLFOX); unexpectedly, the addition of irinotecan to 5-FU and LV as well as the addition of either bevacizumab or cetuximab to FOLFOX did not significantly enhance outcome. Patients with stage II tumors do not appear to benefit appreciably from adjuvant therapy, with the use of such treatment generally restricted to those patients having biologic characteristics (e.g., perforated tumors, T4 lesions, lymphovascular invasion) that place them at higher likelihood for recurrence. The addition of oxaliplatin to adjuvant treatment for patients older than age 70 and those with stage II disease does not appear to provide any therapeutic benefit.
In rectal cancer, the delivery of preoperative or postoperative combined-modality therapy (5-FU plus radiation therapy) reduces the risk of recurrence and increases the chance of cure for patients with stage II and III tumors, with the preoperative approach being better tolerated. The 5-FU acts as a radiosensitizer when delivered together with radiation therapy. Life-extending adjuvant therapy is used in only about half of patients older than age 65 years. This age bias is unfortunate because the benefits and likely the tolerance of adjuvant therapy in patients age ≥65 years appear similar to those seen in younger individuals.