Epidemiology

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Of the 130,000 cases of colorectal cancer expected in 2000, it was estimated that 93,800 would be classified as colon cancer. Colon cancer ranks fourth in overall cancer incidence and is the third leading cause of cancer-specific mortality in both men and women. Colon cancer has no sex predilection. About 56,000 patients with colon and rectal cancer die of metastatic disease each year (Jemal et al, 2002).

The risk of colon cancer rises with age. The overall risk of colon cancer increases from 1 in 1,600 to 1,900 among individuals aged 39 years or less, to 1 in 120 to 150 among individuals aged 40 to 59 years, to 1 in 30 among individuals aged 60 to 79 years. More than 90% of cases occur in people who are 50 years of age or older.

One of the recognized risk factors for colon cancer is the Western diet high in saturated fat but low in fiber and antioxidants. The protective effects of fiber and calcium have turned out to be not as important as the protective effects of antioxidants. Physical inactivity is a stronger risk factor than obesity in colon cancer. Alcohol use increases colon cancer risk by about twofold, but smoking does not seem to be linked to colon cancer. Patients with a long-standing history of inflammatory bowel disease have an incremental risk of developing colon cancer of 9% at 10 years, 20% at 20 years, and more than 35% at 30 years. Patients with pancolitis are at higher risk than those with segmental colitis. Patients with a history of ulcerative colitis of more than 8 years' duration should undergo surveillance colonoscopy every 6 to 12 months for the detection of dysplastic changes or cancerous polyps, which may be technically challenging owing to the infil-trative nature of the cancer. Detection of precancerous or cancerous lesions should prompt counseling regarding prophylactic total colectomy.

About 15% to 18% of colon cancer patients have an underlying genetic condition that predisposes to colon cancer, such as familial adenomatous polyposis (FAP) (1%) or hereditary nonpolyposis colorectal cancer (15%). FAP is an autosomal-dominant syndrome that occurs in approximately 1 in every 7,500 live births. It is caused by a mutation of the adenomatous polyposis coli (APC) gene, which is located on the long arm of chromosome 5 (region 5q21-q22). Individuals with FAP develop hundreds to thousands of colonic and rectal adenomatous polyps by the third decade of life. Left untreated, virtually every FAP patient will develop invasive adenocarcinoma by age 50 years.

Stage for stage, colorectal cancer patients with FAP have the same prognosis as those with sporadic colorectal cancer except for patients with delayed diagnosis or detection or late secondary complications from desmoid tumors and other secondary malignancies. In contrast, colon cancer patients with microsatellite-unstable tumors (hereditary nonpolyp-osis colorectal cancer) have a better prognosis than do patients with microsatellite-stable cancer. The observed better survival is not due to the effects of adjuvant chemotherapy (Ribic et al, 2003).

Regular use of aspirin has been associated with a significant reduction in the risk of colorectal cancer (hazard ratio, 0.56 to 0.75) in a number of large retrospective analyses. Two large prospective randomized placebo-controlled studies confirmed that daily aspirin use—particularly at a dose of 81 mg daily rather than 325 mg daily—was effective in preventing villous or tubulo-villous polyp formation in patients with a history of adenomatous polyps or colorectal cancer (Baron et al, 2003; Sandler et al, 2003). Specific cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib, which have been shown to cause regression of polyps in patients with FAP, are being studied in patients with sporadic colorectal polyps (Steinbach et al, 2000). The role of estrogen replacement therapy for colon cancer prevention is not well defined.

Colonoscopy is the single most effective measure for colon cancer screening, detection, and prevention. At M. D. Anderson, colonoscopy is routinely performed as the primary mode of screening and follow-up in patients with a history of colorectal cancer. Other potentially cost-effective screening measures include fecal occult blood testing, barium enema, sigmoidoscopy, and computerized tomography colonography ("virtual colonoscopy").

Clinical Presentations

The most common clinical presentations of colon cancer include occult to frank gastrointestinal bleeding with or without evidence of iron-deficiency anemia. Altered bowel habits, fatigue, and unexplained weight loss are uncommon; the presence of unexplained fatigue or gastrointestinal symptoms should prompt clinical evaluation. Right-sided colon cancer tends to be associated with more profound anemia than left-sided colon cancer, as left-sided tumors often present with early warning signs of altered bowel habits and early gastrointestinal bleeding. Patients—even those with advanced colon cancer—may have no clinical symptoms. Jaundice is uncommon unless there is biliary duct obstruction.

Diagnosis and Staging

Most colon cancer cases are clinically silent; therefore, colon cancer is often detected on either routine laboratory testing or colonoscopy screening. Once the pathology findings are confirmed, all patients in whom invasive colon cancer is suspected should undergo a thorough history and physical examination as well as laboratory testing including complete blood cell counts; measurement of electrolytes; liver function panels; measurement of prothrombin time, partial thromboplastin time, and carcinoembryonic antigen (CEA); electrocardiography; chest radiography; and a baseline computed tomography scan of the abdomen and pelvis.

More than 95% of colon cancers are adenocarcinoma; rare pathologic subtypes include adenocarcinoma with carcinoid or neuroendocrine features and small cell carcinoma of the large bowel. Pathologic features associated with a poor prognosis include the presence of nodal metastasis (the strongest prognostic factor); poor histologic grade, as determined by the degree of glandular differentiation; the presence of either intracellular mucin (also known as signet ring) or extracellular mucin; and perineural, lymphovascular, or vascular invasion. Adenocarcinoma with mucinous differentiation and lymphocyte infiltration in the tumor is highly suggestive of a microsatellite-unstable tumor. Occasionally, ovarian cancer masquerades as colon cancer or vice versa. The distinction can often be made clinically through histologic examination (orientation of tumor invasion within the colon wall or outside the colon wall). In addition, ovarian cancer is often positive for cytokeratin-7, whereas colon cancers are often positive for cytokeratin-20 but always negative for cytokeratin-7. Mucinous ovarian tumors may also be positive for cytokeratin-20.

Colon cancers are staged surgically. Colon cancer is staged according to the TNM (tumor, nodes, metastasis) staging classification in the 6th edition of the American Joint Commission on Cancer's AJCC Cancer Staging Manual (Greene et al, 2002). The TNM system (see chapter 1, Table 1-6) has replaced the previously used Duke's colon cancer staging system and modified Astler-Coller system and is further simplified by the M. D. Anderson color-matrix cancer staging system.

Half of patients with colon cancer develop distant metastases, and about 25% of patients present with metastases at the time of colon cancer diagnosis. Five-year survival rates in patients with colon cancer correlate with tumor stage. The overall 5-year survival rates for patients with stage I, II, III, and IV colon cancers are 90%, 70% to 80%, 40% to 65%, and less than 10%, respectively.

Tenets of Management

Surgery achieves tumor control through zero-order kinetics; therefore, adequate resection margins and higher number of lymph nodes sampled are associated with improved disease-free and overall survival. Patients with 10 or fewer lymph nodes removed have significantly lower 5-year survival rates than patients with 20 to 40 lymph nodes removed. Hemi-colectomy with regional lymph node dissection is indicated for patients with stage I, II, or III colon cancer; for patients who present with resectable or low-volume synchronous metastatic colon cancer; and for patients with perforation or obstruction.

Resection of liver or lung metastases, anastomotic recurrence, or recurrence in draining lymph nodes is associated with 5-year survival rates of 20% to 40%. Only rarely do patients benefit from resection of peritoneal metastases or retroperitoneal lymph nodes. It is important to note that the surgical series are highly selected retrospective review series in which survival was calculated without inclusion of all stage IV patients in the denominator. Nonetheless, 7 factors are significant and independent predictors of poor long-term outcome after metastasectomy: positive surgical margins, extrahepatic disease, node-positive primary tumor, disease-free interval between diagnosis of primary tumor and diagnosis of metastases of less than 12 months, number of hepatic tumors greater than 1, largest hepatic tumor larger than 5 cm, and CEA level greater than 200ng/ml. Patients with 3, 4, or 5 of these predictors should be considered for experimental trials of adjuvant chemotherapy (Fong et al, 1999). Newer ablative techniques, such as radiofrequency ablation, are increasingly used alone or in conjunction with surgery. In general, 75% of patients with successful metastasectomy have a recurrence within the first 2-3 years.

Twenty percent to 50% of patients with stage II or III disease eventually develop metastatic disease or locally recurrent disease because of occult micrometastases or inadequate resection of tumor. Cytotoxic chemotherapy achieves tumor control through first-order kinetics. Cytotoxic chemotherapy has 3 major roles: (1) To provide effective adjuvant treatment to eliminate or reduce the overall tumor micrometastasis burden. (2) To convert patients with unresectable disease into candidates for surgical resection. The newer combination-chemotherapy regimens are particularly effective in producing tumor response and are therefore more effective in reduction of tumor burden. (3) To palliate tumor-related symptoms or prolong time to tumor progression and overall survival and improve quality of life in patients with metastatic colon cancer.

In line with the above-mentioned therapeutic goals are the 5 following treatment principles: (1) familiarity with agent-specific and regimen-specific toxicity; (2) timely adjustments of dose and schedule as well as institution of treatment breaks or preventative measures to minimize treatment-related side effects; (3) selection of patients for 5-FU monotherapy versus combination chemotherapy or alternating therapy to maximize the duration of tumor control with minimal induction of chemoresistance; (4) appropriate utilization of chemoradiation for palliation and neoadjuvant treatment of metastatic disease; and (5) early identification and timely referral of patients with potentially resectable disease.

Chemotherapy

For decades, 5-FU was the only chemotherapy agent known to be active against colorectal cancer. In recent years, many new chemotherapeutic agents have been introduced, and therapeutic options have been greatly expanded.

Fluorouracil

As an antimetabolite, 5-FU inhibits both the DNA and RNA synthesis pathways in cancer. 5-FU is converted to 5-FUdR by thymidine phosphor-ylase and then to FdUMP through thymidine kinase. FdUMP inhibits DNA synthesis by binding to thymidylate synthase (the process is facilitated by leucovorin) to form a stable ternary complex.

Because for 4 decades 5-FU was the only active agent for the treatment of colon cancer, numerous clinical trials have been conducted of strategies designed to modulate 5-FU activity, either through manipulation of its infusion schedule (continuous infusion, bolus administration, or circa-dian) or through addition of response modifiers such as levamisole, leu-covorin, interferon, and N-(phosphonacetyl)-L-aspartic acid (PALA). The highlights of the study findings are as follows: (1) 5-FU alone produced responses in 15% of patients with metastatic colon cancer, and the addition of levamisole, interferon, or PALA to 5-FU provided no benefits but increased treatment toxicity. (2) Compared with bolus administration of 5-FU, continuous infusion of 5-FU was associated with a modest improvement in the tumor response rate (from 15% to 20%), improvement in tumor control by about 4 weeks, and reduction in the rate of systemic grade 3 and 4 hematologic and nonhematologic side effects (12% vs 35%) except for hand-foot syndrome (34% vs 12%). (3) The addition of leucovorin enhanced 5-FU activity in vitro and in vivo, but the absolute survival benefit of leucovorin was 2% to 4%. (4) A 6-month course of adjuvant 5-FU produced an effect equivalent to that of a 12-month course of 5-FU and leucovorin (O'Dwyer et al, 2001; Rodriguez et al, 2003).

Irinotecan

Irinotecan is a camptothecin derivative that acts as a topoisomerase I inhibitor. Irinotecan was first shown to be active as a single agent in patients in whom treatment with 5-FU failed. Irinotecan in these patients produced a 41% longer median overall survival (9.2 months vs 6.5 months) than best supportive care and was associated with better quality-of-life scores (Cunningham et al, 1998). Compared with infusional 5-FU in patients in whom prior 5-FU failed, irinotecan again produced longer median overall survival (10.8 months vs 8.5 months; P = .02) (Rougier et al, 1998).

Various combinations of irinotecan, 5-FU, and leucovorin were then compared with 5-FU and leucovorin as front-line treatment for metastatic colorectal cancer. The regimens used are described in Table 9-1, and the studies are summarized in Table 9-2. The one U.S. study (Saltz et al, 2000) explored weekly bolus 5-FU and leucovorin plus weekly irinotecan (the so-called IFL regimen), whereas 2 European studies (Douillard et al, 2000; Kohne et al, 2003) explored infusional 5-FU and leucovorin plus irinote-can administered either weekly or biweekly (the so-called FOLFIRI and AIO + irinotecan regimens).

The major findings of these studies were as follows: (1) The combination of irinotecan, 5-FU, and leucovorin consistently produced higher overall tumor response rates (35% to 54.2% vs 18% to 31.5%), longer time to tumor progression (6.7 to 8.5 months vs 4.2 to 6.3 months), and better overall survival (14.8 to 20.1 months vs 12.6 to 16.9 months). (2) The AIO + irinotecan (infusional-5-FU) regimen appeared to be associated with the least treatment-related toxicity and better treatment outcomes (response rate, time to progression, and overall survival) than the respective 5-FU/ leucovorin control arms. Interestingly, the AIO 5-FU/leucovorin regimen was associated with a response rate of 31.5%, time to progression of 6.3 months, and median overall survival of 16.9 months, similar to the outcomes seen with the IFL regimen.

Table 9-1. Commonly Used Chemotherapy Regimens for First- and Second-Line Treatment of Metastatic Colorectal Cancer*

Regimen Name

Drug Doses and Schedules

Incidence of Grade 3 or More Severe Toxic Effects

Reference

AIO + Irinotecan

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