Colon, Rectal, and Anal Cancers

June 1, 2007

Despite the existence of excellent screening and preventive strategies, colorectal carcinoma (CRC) remains a major public health problem in Western countries. The American Cancer Society (ACS) estimated that in 2006, 148,610 people were diagnosed with CRC, and 55,170 died of the disease.

COLORECTAL CANCER

Despite the existence of excellent screening and preventive strategies, colorectal carcinoma (CRC) remains a major public health problem in Western countries. The American Cancer Society (ACS) estimated that in 2006, 148,610 people were diagnosed with CRC, and 55,170 died of the disease. CRC is the third most common type of cancer in both sexes (after prostate and lung cancers in men and lung and breast cancers in women) and the second most common cause of cancer death in the United States.

About 72% of new CRCs arise in the colon, and the remaining 28% arise in the rectum. Rectal cancer is defined as cancer arising below the peritoneal reflection, up to approximately 12–15 cm from the anal verge.

The lifetime risk of being diagnosed with CRC in the United States is estimated to be 5.9% for men and 5.5% for women. Despite these daunting statistics, the incidence rates of CRC have been declining in both men and women since 1998, likely reflecting early detection efforts with removal of precancerous polyps.

Epidemiology

Gender Overall the incidence of CRC and mortality rates are higher in men than in women; tumors of the colon are slightly more frequent in women than in men (1.2:1), whereas rectal carcinomas are more common in men than in women (1.7:1).

Age The vast majority, 91%, of all new CRC cases occur in individuals older than age 50. In the United States, the median age at presentation is 72 years.

Race The incidence and mortality rates of CRC are highest among African-American men and women compared with white men and women (15% higher and 40% higher, respectively). The incidence rates among Asian Americans, Hispanics/Latinos, and American Indians/Alaskan natives are lower than those among whites.

Geography The incidence of CRC is higher in industrialized regions (the United States, Canada, the Scandinavian countries, northern and western Europe, New Zealand, Australia) and lower in Asia, Africa (among blacks), and South America (except Argentina and Uruguay).

Survival Five-year survival rates (Table 1) for patients with CRC have improved in recent years. This fact may be due to wider surgical resections, modern anesthetic techniques, and improved supportive care. In addition, better pathologic examination of resected specimens, preoperative staging, and abdominal exploration reveal clinically occult disease and allow treatment to be delivered more accurately. Survival also has improved through the use of adjuvant chemotherapy for colon cancer and adjuvant chemoradiation therapy for rectal cancer.

Etiology and risk factors

The specific causes of CRC are unknown, but environmental, nutritional, genetic, and familial factors, as well as preexisting diseases, have been found to be associated with this cancer. A summary of selected risk factors for CRC is shown in Table 2.

Environment Asians, Africans, and South Americans who emigrate from low-risk areas assume the colon cancer risk for their adopted country, suggesting the importance of environmental factors in CRC. Smoking and alcohol intake (four or more drinks per week) increase the risk of CRC.

Diet Diets rich in fat and cholesterol have been linked to an increased risk of colorectal tumors. Dietary fat causes endogenous production of secondary bile acids and neutral steroids and increases bacterial degradation and excretion of these acids and steroids, thereby promoting colonic carcinogenesis. Historically, diets rich in cereal fiber or bran and yellow and green vegetables are said to have protective effects, although recent studies have failed to prove a risk reduction with increasing dietary fiber intake. A protective role also has been ascribed to calcium salts and calcium-rich foods, because they decrease colon-cell turnover and reduce the cancer-promoting effects of bile acid and fatty acids.

Physical activity Several studies have reported a lower risk of CRC in individuals who participate in regular physical activity. High levels of physical activity may decrease the risk by as much as 50%. Being overweight or obese has been consistently associated with a higher risk of CRC.

Inflammatory bowel disease Patients with inflammatory bowel disease (ulcerative colitis, Crohn’s disease) have a higher incidence of CRC. The risk of CRC in patients with ulcerative colitis is associated with the duration of active disease, extent of colitis, development of mucosal dysplasia, and duration of symptoms.

The risk of CRC increases exponentially with the duration of colitis, from approximately 3% in the first decade to 20% in the second decade to > 30% in the third decade. CRC risk also is increased in patients with Crohn’s disease, although to a lesser extent.

Adenomatous polyps Colorectal tumors develop more often in patients with adenomatous polyps than in those without polyps. There is approximately a 5% probability that carcinoma will be present in an adenoma; the risk correlates with the histology and size of the polyp. The potential for malignant transformation is higher for villous and tubulovillous adenomas than for tubular adenomas. Adenomatous polyps < 1 cm have a slightly greater than 1% chance of being malignant, in comparison with adenomas > 2 cm, which have up to a 40% likelihood of malignant transformation.

Cancer history
Patients with a history of CRC are at increased risk of a second primary colon cancer or other malignancy. The risk of a second CRC is higher if the first diagnosis was made prior to age 60.

Prior surgery Following ureterosigmoidostomy, an increased incidence of colon cancer at or near the suture line has been reported. Cholecystectomy also has been associated with colon cancer in some studies but not in others.

Family history and genetic factors Individuals with a first-degree relative with the disease have an increased risk of developing CRC. Those with two or more relatives with the disease make up about 20% of all people with CRC. The risk of developing CRC is significantly increased in several forms of inherited susceptibility (Table 3). About 5%–10% of all patients with CRC have an inherited susceptibility to the disease. The risks of developing CRC in the subgroups of familial or hereditary CRC vary from 15% in relatives of patients with CRC diagnosed before 45 years of age, through 20% for family members with two first-degree relatives with CRC, to approximately 70%–95% in patients with familial adenomatous polyposis and hereditary nonpolyposis CRC (HNPCC).

Familial adenomatous polyposis (FAP) is inherited as an autosomal-dominant trait with variable penetrance. Patients characteristically develop pancolonic and rectal adenomatous polyps. Approximately 50% of patients with FAP will develop adenomas by 15 years of age and 95% by age 35. Left untreated, 100% of patients with FAP will develop CRC, with an average age at diagnosis ranging from 34 to 43 years. Total colectomy, usually performed on patients in their mid-to-late teens, is the preventive treatment of choice in this group of patients. The familial adenomatous polyposis coli (APC) gene has been localized to chromosome 5q21. Currently, it is possible to detect mutations in the APC gene in up to 82% of families with FAP. Mutations in the APC gene combined with mutational activation of proto-oncogenes, especially K-ras, occur sequentially in the neoplastic transformation of bowel epithelium in patients with FAP. Use of cyclo-oxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex) has been shown to reduce the number of polyps in patients with FAP.

HNPCC is transmitted as an autosomal-dominant trait. It is associated with germline mutations in one of five DNA mismatch repair genes (MSH2, MLH1, PMS1, PMS2, and MSH6). The incidence of a mutated mismatch repair gene is approximately 1 in 1,000 people. The Amsterdam criteria were proposed in 1991 as a way to help identify patients at risk of HNPCC. In 1999, they were revised (Amsterdam II) to recognize extracolonic manifestations as part of the family history. The criteria include the following factors:

  • three or more relatives with a histologically verified HNPCC-associated cancer (colorectal, endometrial, small bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other two (FAP should be excluded)

  • colorectal cancer involving at least two generations

  • CRC involving at least two generations.

  • one or more CRC diagnosed before the age of 50.


 The Bethesda criteria were developed based upon an analysis of high-risk patients who did not meet the Amsterdam criteria but still demonstrated germline mutations in either the MSH2 or MLH1 gene. These criteria are much less restrictive than the Amsterdam criteria and serve to help identify those individual patients at risk of HNPCC who might benefit from further evaluation. They include the following:

  • individuals with cancer in families who meet the Amsterdam criteria

  • individuals with two HNPCC-related cancers, including synchronous and metachronous CRCs or associated extracolonic cancers; endometrial, ovarian, gastric, hepatobiliary, small bowel, or transitional cell carcinoma of the renal pelvis or ureter

  • individuals with CRC and a first-degree relative with CRC and/or HNPCC-related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed at age younger than 45 years; and the adenoma diagnosed at age younger than 40 years

  • individuals with CRC or endometrial cancer diagnosed at age < 45 years

  • individuals with right-sided CRC with an undifferentiated pattern (solid/cribriform) on histology diagnosed at age < 45 years

  • individuals with signet ring-cell–type CRC diagnosed at age < 45 years

  • individuals with colorectal adenomas diagnosed at age < 40 years.

Mutations in the DNA mismatch repair genes MLH1 or MSH2 can be found in approximately 40% of individuals who meet these criteria. Genetic evaluation for HNPCC should be considered in families that meet the Amsterdam criteria, in affected individuals who meet the Bethesda criteria, and in first-degree relatives of those individuals with known mutations. For situations in which HNPCC is suspected but the first three Bethesda criteria are not met, microsatellite instability (MSI) testing may be considered. Over 90% of HNPCCs will demonstrate MSI, compared with 15%–20% of sporadic CRC, and thus a normal result in the absence of compelling clinical criteria usually excludes the diagnosis of HNPCC. Alternatively, MSH6 may be involved in a substantial proportion of patients in whom HNPCC is suspected and should be considered in those with tumors that are low in MSI.

Chemoprevention

Chemoprevention aims to block the action of carcinogens on cells before the development of cancer.

Antioxidants and calcium Controlled trials of vitamins C and E and calcium have produced mixed results. Clinical trials have shown that calcium supplementation modestly decreases the risk of colorectal adenomas.

Nonsteroidal anti-inflammatory drugs inhibit colorectal carcinogenesis, possibly by reducing endogenous prostaglandin production through COX inhibition. Sulindac (Clinoril) has induced regression of large bowel polyps in patients with FAP. Controlled studies have shown a reduction in the incidence of colorectal polyps with regular, long-term use of aspirin.

Postmenopausal hormones Women who use postmenopausal hormones appear to have a lower rate of CRC than do those who do not.

Signs and symptoms

Early stage During the early stages of CRC, patients may be asymptomatic or complain of vague abdominal pain and flatulence, which may be attributed to gallbladder or peptic ulcer disease. Minor changes in bowel movements, with or without rectal bleeding, are also seen; they are frequently ignored and/or attributed to hemorrhoids or other benign disorders.

Left side of the colon Cancers occurring in the left side of the colon generally cause constipation alternating with diarrhea; abdominal pain; and obstructive symptoms, such as nausea and vomiting.

Right side of the colon Right-sided colon lesions produce vague, abdominal aching, unlike the colicky pain seen with obstructive left-sided lesions. Anemia resulting from chronic blood loss, weakness, weight loss, and/or an abdominal mass may also accompany carcinoma of the right side of the colon.

Rectum Patients with cancer of the rectum may present with a change in bowel movements; rectal fullness, urgency, or bleeding; and tenesmus.

Pelvic pain is seen at later stages of the disease and usually indicates local extension of the tumor to the pelvic nerves.

Screening and diagnosis

Screening

Fecal occult blood testing (FOBT) or fecal immunochemical test (FIT) guaiac-based fecal occult blood tests are, in themselves, inexpensive but have been associated with many false-positive and false-negative results. Almost all colonic polyps and > 50% of all CRCs go undetected because they are not bleeding at the time of the test. The newer FOBTs, including a guaiac-based product called Hemoccult SENSA and immunochemical tests for hemoglobin (HemeSelect), appear to have better sensitivity than the older tests without sacrificing specificity.

Three large randomized controlled clinical trials have demonstrated decreased CRC mortality associated with detection of earlier-stage cancer and adenomas by FOBT. Recently, results from a large trial also showed a decreased incidence of CRC associated with FOBT, largely because of increased use of polypectomy resulting from diagnostic endoscopy following positive tests.

Digital rectal examination is simple to perform and can detect lesions up to 7 cm from the anal verge.

Sigmoidoscopy Flexible proctosigmoidoscopy is safe and more comfortable than examination using a rigid proctoscope. Almost 50% of all colorectal neoplasms are within the reach of a 60-cm sigmoidoscope. Even though flexible sigmoidoscopy visualizes only the distal portion of the colorectum, the identification of adenomas can lead to colonoscopy. When we add the percentage of colorectal neoplasms in the distal 60 cm of the colorectum to the percentage of patients with distal polyps leading to complete colonoscopy, 80% of those individuals with a significant neoplasm anywhere in the colorectum can be identified.

Colonoscopy (optical) provides information on the mucosa of the entire colon, and its sensitivity in detecting tumors is extremely high. Most physicians consider colonoscopy to be the best screening modality for CRC. Colonoscopy can be used to obtain biopsy specimens of adenomas and carcinomas and permits the excision of adenomatous polyps. For this reason, colonoscopy is the only screening modality ever shown to reduce the incidence of cancer in screened individuals. Colonoscopy is the best follow-up strategy for evaluating patients with positive guaiac-based FOBTs and the best screening modality for high-risk patients.

Limitations of colonoscopy include its inability to detect some polyps and small lesions because of blind corners and mucosal folds and the fact that sometimes the cecum cannot be reached. A supplementary double-contrast barium enema may be needed if a colonoscopic exam fails to reach the cecum.

Colonoscopy (CT virtual) Some recent studies have suggested that CT virtual colonoscopy may have sensitivity and specificity for detecting neoplastic polyps that approach those of optical colonoscopy. Unfortunately, other studies have demonstrated clear superiority of optical colonoscopy. Until additional confirmatory studies are available, virtual CT colonoscopy should not replace routine optical colonoscopic screening.

Barium enemas can accurately detect CRC; however, the false-negative rate associated with double-contrast barium enemas ranges from 2% to 61% because of misinterpretation, poor preparation, and difficulties in detecting smaller lesions. A supplementary colonoscopy may be needed if a double-contrast barium enema does not adequately visualize the entire colon or to obtain histopathology or perform polypectomy in the event of abnormal findings.

Recommendations for average-risk individuals Adults at average risk should begin colorectal cancer screening at age 50. The ACS guidelines on screening and surveillance for the early detection of colorectal adenomatous polyps and cancer provide several options for screening average-risk individuals (Table 4).

For those individuals who elect FOBT/FIT alone, or in combination with flexible sigmoidoscopy, a single test of a stool sample in the clinical setting (as, for instance, is often performed with the stool sample collected on the fingertip during a digital rectal examination) is not an adequate substitute for a full set of samples using the take-home card system. Because combining flexible sigmoidoscopy with FOBT/FIT can substantially increase the benefits of either test alone, the ACS regards annual FOBT/FIT accompanied by flexible sigmoidoscopy every 5 years as a better choice than either FOBT/FIT or flexible sigmoidoscopy alone.

The choice of colonoscopy or double-contrast barium enema for screening may depend on factors such as personal preference, cost, and the local availability of trained clinicians to perform a high-quality examination. For those who elect either colonoscopy or double-contrast barium enema for screening, there is no need for annual FOBT/FIT. Digital rectal examination should be performed at the time of the sigmoidoscopy or colonoscopy.

Recommendations for screening increased-risk and high-risk individuals Risk of CRC is even higher among individuals with hereditary syndromes or a history of inflammatory bowel disease of significant duration.

Those individuals who have been diagnosed as having adenomatous polyps or a personal history of curative-intent resection of CRC should undergo a colonoscopy to remove all polyps from the colorectum, after which a colonoscopic exam should be repeated at an interval to be determined on the basis of the size, multiplicity, and histologic appearance of the adenoma(s) (Table 5). If colonoscopy is not available, or not feasible, flexible sigmoidoscopy followed by double-contrast barium enema may be used for surveillance.

A family history of either CRC or colorectal adenomas increases the risk of developing CRC. Risk is higher for individuals with a family history involving first-degree relatives, those family members with younger age of onset, and those with multiple affected family members. Individuals with a single first-degree relative diagnosed with CRC or an adenomatous polyp after age 60, or with affected relatives who are more distant than first-degree relatives, can be considered to be at “average risk.” In general, colonoscopy is recommended 5–10 years prior to the earliest diagnosis in the family or age 40, whichever is earlier. Subsequent colonoscopy should be repeated at intervals to be determined on the basis of the initial examination. If a colonoscopy is not available or feasible, flexible sigmoidoscopy followed by a double-contrast barium enema can be used.

Individuals at elevated risk due to the known or likely presence of FAP or HNPCC should begin surveillance at an early age with endoscopic examination (Table 5). There is ample evidence to support endoscopic surveillance as a method of early detection. A program of biennial colonoscopy starting at age 20 to 25 years is recommended for HNPCC carriers. For those with FAP, it is recommended that regular sigmoidoscopy start at the age of 12 years and continue at 2-year intervals. DNA testing of at-risk individuals provides the opportunity to identify those who should undergo intensive surveillance and those who are at average risk.

Individuals with a history of extensive inflammatory bowel disease affecting the colon should begin colonoscopic surveillance with biopsy for dysplasia every 1–2 years after 8 years of symptoms. Prophylactic colectomy should be considered in the presence of persistent dysplasia.

Diagnosis

Initial work-up An initial diagnostic work-up for patients suspected of having colorectal tumors should include:

  • digital rectal examination and FOBT

  • colonoscopy

  • biopsy of any detected lesions.

Adequate staging prior to surgical intervention requires:

  • chest x-ray

  • CT scan of the abdomen and pelvis

  • CBC with platelet count

  • liver and renal function tests

  • urinalysis

  • measurement of carcinoembryonic antigen (CEA) level.

FDG-PET scanning FDG (18fluorodeoxyglucose)-PET scanning has emerged as a highly sensitive study for the evaluation of patients who may be candidates for resection of isolated metastases from CRC. Although not usually recommended in the evaluation of primary disease, this modality can aid in the staging of recurrence.

 

Pathology

Adenocarcinomas constitute 90%–95% of all large bowel neoplasms. These tumors consist of cuboidal or columnar epithelium with multiple degrees of differentiation and variable amounts of mucin.

Mucinous adenocarcinoma is a histologic variant characterized by huge amounts of extracellular mucus in the tumor and the tendency to spread within the peritoneum. Approximately 10% of colorectal adenocarcinomas are mucinous. It is more commonly seen in younger patients.

Signet-ring–cell carcinoma is an uncommon variant, comprising 1% of colorectal adenocarcinomas. These tumors contain large quantities of intracellular mucinous elements (causing the cytoplasm to displace the nucleus) and tend to involve the submucosa, making their detection difficult with conventional imaging techniques.

Other tumor types Squamous cell carcinomas, small-cell carcinomas, carcinoid tumors, and adenosquamous and undifferentiated carcinomas also have been found in the colon and rectum. Nonepithelial tumors, such as sarcomas and lymphomas, are exceedingly rare.

Metastatic spread CRC has a tendency toward local invasion by circumferential growth and for lymphatic, hematogenous, transperitoneal, and perineural spread. Longitudinal spread is usually not extensive, with microscopic spread averaging only 1–2 cm from gross disease, but radial spread is common and depends on anatomic location.

The most common site of extralymphatic involvement is the liver, with the lungs the most frequently affected extra-abdominal organ. Other sites of hematogenous spread include the bones, kidneys, adrenal glands, and brain.

Staging and prognosis

The TNM staging classification, which is based on the depth of tumor invasion in the intestinal wall, the number of regional lymph nodes involved, and the presence or absence of distant metastases, has largely replaced the older Dukes’ classification scheme (Table 6).

Pathologic stage is the single most important prognostic factor following surgical resection of colorectal tumors. The prognosis for early stages (I and II) is favorable overall, in contrast to the prognosis for advanced stages (III and IV). However, there appears to be a superior survival for patients with stage III disease whose disease is confined to the bowel wall (ie, ≤ T2, N+).

Histologic grade may be correlated with survival. Five-year survival rates of 56%–100%, 33%–80%, and 11%–58% have been reported for grades 1, 2, and 3 colorectal tumors, respectively.

Other prognostic factors (such as age at diagnosis, presurgical CEA level, gender, presence and duration of symptoms, site of disease, histologic features, obstruction or perforation, perineural invasion, venous or lymphatic invasion, ploidy status, and S-phase fraction) have not consistently been correlated with overall disease recurrence and survival. Furthermore, the size of the primary lesion has had no influence on survival. Elevated expression of thymidylate synthase and allelic loss of chromosome 18 have been correlated with a poor prognosis.

Treatment

PRIMARY TREATMENT OF LOCALIZED DISEASE

Management of colorectal carcinoma relies primarily on resection of the bowel with the adjacent draining lymph nodes. The need for adjuvant systemic or local chemotherapy or immuno therapy, with or without concurrent irradiation, depends on tumor location (colon vs rectum) and stage of disease.

Surgery

Colon The primary therapy for adenocarcinoma of the colon is surgical extirpation of the bowel segment containing the tumor, the adjacent mesentery, and draining lymph nodes. It is recommended that at least 12 lymph nodes be available for examination by a pathologist to confirm the accuracy of a node-negative diagnosis. Surgical resection can be performed by open or laparoscopic approach. The type of resection depends on the anatomic location of the tumor. Right, left, or transverse colectomy is the surgical treatment of choice in patients with right, left, or transverse colonic tumors, respectively. Tumors in the sigmoid colon may be treated with wide sigmoid resection. The length of colon resected depends largely on the requirement for wide mesenteric nodal clearance.

Rectum For rectal carcinoma, the distal surgical margin should be at least 2 cm, although some investigators have suggested that a smaller but still negative margin may be adequate. The resection should include the node-bearing mesorectum surrounding the rectum. This procedure, which is termed total mesorectal excision (TME), is accomplished using a sharp dissection technique (see Figure 1). The use of TME has been associated with a significant reduction in local recurrence rates for patients with rectal cancer.

Posteriorly, the mesorectal dissection is carried out along the presacral fascia. Anteriorly, the dissection follows the posterior vaginal wall in females or Denonvilliers’ fascia in males, either of which may be resected in the presence of an anterior wall rectal cancer. Reported rates of local recurrence following TME for rectal cancer have generally been < 10%, compared with rates of recurrence up to 30% prior to the advent of TME. Selective use of radiation therapy can improve upon the results of TME alone.

Sphincter-sparing approaches Technologies (eg, circular stapling devices) and the application of surgical techniques, such as coloanal anastomosis and creation of intestinal pouches, are employed to maintain anal sphincter function for tumors in the lower one-third of the rectum. If the tumor is located proximally between 6 and 15 cm from the anal verge, a low anterior resection with end-to-end anastomosis may be performed.

Abdominoperineal resection, removing the anus and sphincter muscle with permanent colostomy, may be necessary if the tumor is located in the distal rectum and other characteristics of the tumor (eg, bulky size, proximity to the sphincter musculature) preclude an oncologically adequate sphincter-sparing approach. An alternative procedure for tumors 2–5 cm from the anal verge is to resect the entire rectum, sparing the anoderm and anal sphincter musculature, and to perform a coloanal anastomosis. Either procedure can be performed with autonomic nerve preservation, minimizing bladder and sexual function morbidity.

Local excision alone may be indicated for selected patients who have small (< 3–4 cm), T1, well to moderately differentiated rectal cancers without histologic evidence of lymphovascular involvement, provided that a full-thickness negative margin can be achieved. In most series, transanal excision for these good histology T1 lesions results in excellent long-term control. However, some studies with long-term follow-up demonstrated significant local recurrence rates, even with T1 lesions. For T2 or T3 tumors, the standard therapy remains a transabdominal resection because of the risk of mesorectal nodal spread. Preoperative transrectal ultrasonography is useful in defining lesions that can be resected by local excision alone. A trial sponsored by the CALGB (Cancer and Leukemia Group B) demonstrated reasonable results for patients with T2 rectal cancer undergoing negative margin local excision followed by fluorouracil (5-FU) and external-beam radiation therapy. The locoregional recurrence rate at 6 years was only 14%. Good results with local excision alone following chemoradiotherapy for rectal cancer have been reported. The role of local excision alone in this clinical scenario awaits confirmatory studies.

Laparoscopic colonic resection The use of laparoscopic colonic and rectal resection is becoming an oncologically acceptable method of treating cancers of the colon and rectum. The potential advantages include a shorter hospital stay, reduced postoperative ileus, decreased time away from work, fewer adhesive complications, and a lower risk of hernia formation. The potential disadvantages compared with open transabdominal resection include longer operative time, higher operative costs, and technical considerations related to operative skill.

Patterns of failure

The natural history and patterns of failure following “curative” resection are different for colon and rectal carcinomas. Locoregional failure as the only or major site of recurrence is common in rectal cancer, whereas colon cancer tends to recur in the peritoneum, liver, and other distant sites, with a lower rate of local failure. As a result, local therapy, such as irradiation, may play a significant role in the treatment of rectal tumors but is not used routinely for colon cancers.

ADJUVANT THERAPY FOR COLON CANCER

Approximately 75% of all patients with colorectal carcinoma will present at a stage when all gross carcinoma can be surgically resected. Nevertheless, despite the high resectability rate, almost half of all patients with colorectal adenocarcinoma die of metastatic disease, primarily because of residual disease that is not apparent at the time of surgery. These individuals are candidates for adjuvant local or systemic therapies.

Systemic chemotherapy

Systemic combined chemotherapy is the principal adjuvant therapy for colon cancer (Table 7). When determining the benefit of adjuvant therapy for stage II disease, several factors should be taken into consideration, including the number of lymph nodes analyzed after surgery, the prognostic features (T4 lesion, perforation, peritumoral lymphovascular invasion, poorly differentiated histology), anticipated life expectancy, and comorbid conditions.

5-FU, synthesized by Heidelberger in 1957, remains an important agent in the treatment of advanced colon carcinoma. 5-FU may be administered as a bolus injection either weekly or daily for 5 days, every 4–5 weeks. With these regimens, response rates have been approximately 10%–15%. The development of permanent venous access devices and portable infusion pumps has permitted the continuous infusion of 5-FU on an outpatient basis. Commonly used continuous infusion regimens of 5-FU are 750–1,000 mg/m2/d for 5 days. Protracted infusions have administered 5-FU at 200–400 mg/m2/d for up to 12 weeks.

The pattern of 5-FU toxicity differs depending on whether it is administered as a bolus or continuous infusion than by other methods. Bolus administration has pronounced myelotoxic effects, whereas the dose-limiting toxic effects of continuous infusion 5-FU are mucositis and diarrhea. Palmar-plantar erythrodysesthesia (hand-foot syndrome) has been reported with protracted infusions.

Overall, the incidence of side effects is significantly lower when 5-FU is delivered by continuous infusion. A meta-analysis of more than 1,200 patients treated with either continuous infusion or bolus regimens of 5-FU demonstrated superior response rates and a small survival advantage for the continuous infusion regimens.

Infusional 5-FU is now an important component of therapy when combined with either irinotecan or oxaliplatin.

Biochemical modulation of 5-FU Interest in the biochemical modulation of 5-FU by leucovorin is based on preclinical studies demonstrating that leucovorin raises the level of N5,N10-methylenetetrahydrofolate and, thus, forms a stable tertiary complex of thymidylate synthase (TS), the folate coenzyme, and 5-FU (in the form of 5-fluorodeoxyuridine). The use of 5-FU with leucovorin results in higher response rates than 5-FU alone and may prolong survival.

Although there is no agreement as to the optimal dose of leucovorin, two dosing schedules have been approved by the FDA:

  • “low-dose” leucovorin regimen, consisting of leucovorin, 20 mg/m2/d, immediately followed by 5-FU, 425 mg/m2/d

  • “high-dose” leucovorin regimen, consisting of leucovorin, 200 mg/m2/d, immediately followed by 5-FU, 370 mg/m2/d

With both schedules, leucovorin and 5-FU are administered by rapid IV injections daily for 5 consecutive days. Courses of both schedules are repeated at 4 weeks, 8 weeks, and every 5 weeks thereafter. There is no survival difference between these two regimens.

5-FU plus leucovorin Studies have demonstrated the benefits of 5-FU plus leucovorin (folinic acid) in the adjuvant treatment of colon carcinomas. Acceptable adjuvant regimens of 5-FU plus leucovorin for colon cancer include:

  • a “low-dose” leucovorin (Mayo Clinic) regimen, consisting of leucovorin (20 mg/m2) immediately followed by 5-FU (425 mg/m2), both given by rapid IV injections daily for 5 consecutive days, with courses repeated every 4 weeks for 6 months

  • a “high-dose” weekly leucovorin regimen, consisting of 5-FU (500 mg/m2) by rapid IV injection given at 1 hour during a 2-hour infusion of leucovorin (500 mg/m2) weekly for 6 weeks, with courses repeated every 8 weeks for 6 cycles. More recently, completed randomized trials by the National Surgical Adjuvant Breast and Bowel Project (NSABP) have used 3 rather than 6 cycles of therapy

An analysis of survival data from patients with stage II or III disease treated in four consecutive NSABP adjuvant chemotherapy trials showed similar relative reductions in disease recurrence and mortality as well as similar improvements in overall survival in patients with stage II and III disease.

5-FU, oxaliplatin (Eloxatin), and leucovorin (FOLFOX) Oxaliplatin has been approved by the FDA for adjuvant therapy for resected stage III CRC. In a phase III trial for resected stages II and III colon cancer from Europe (MOSAIC), the use of FOLFOX compared with the same infusional regimen without oxaliplatin led to a higher 3-year disease-free survival rate (78% vs 73%) in those receiving FOLFOX.

Monoclonal antibody 17-1A (edrecolomab) A randomized study of 17-1A antibody in patients with stage III colon cancer showed it to be inferior to 5-FU and leucovorin. Its addition to 5-FU and leucovorin did not improve disease-free or overall survival. A trial of the antibody in stage II colon cancer recently completed accrual. No results are yet available from this trial.

Irinotecan (CPT-11, Camptosar) Two phase III trials of FOLFIRI (5-FU/irinotecan/leucovorin) compared with the same infusional regimen without irinotecan in either patients with resected stages II and III colon cancer (PETACC3) or high-risk stage III (ACCORD-2) did not show a benefit to the use of irinotecan in the adjuvant setting. Given the results of these two studies, the use of irinotecan currently is not considered a primary option for patients with resected stage II or III colon cancer.

Capecitabine (Xeloda) is an oral fluorinated pyrimidine recently approved by the FDA for adjuvant therapy for patients with stage III colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine was not inferior to bolus 5-FU and low-dose leucovorin for disease-free survival, with a hazard ratio in the capecitabine group of 0.87 (95% confidence interval: 0.75 to 1.00). Capecitabine is an alternative for patients who are unlikely to tolerate 5-FU, leucovorin, and oxaliplatin.

For patients with stage III (T1-4, N1-2, M0) carcinoma, 6 months of 5-FU/leucovorin and capecitabine or 5-FU/leucovorin and oxaliplatin should be considered. Patients with stage IV disease who are candidates for surgery should be considered for neoadjuvant chemotherapy (FOLFIRI or FOLFOX with bevacizumab [Avastin]) followed by synchronous or staged colectomy and hepatic resection.

 

Radiation therapy

Postoperative irradiation to the tumor bed should be considered in patients with T3 node-positive and T4 (B3 or C3) tumors located in retroperitoneal portions of the colon because more than 30% of these patients develop a local recurrence. Retrospective studies suggest improved local control with irradiation, particularly in patients with positive resection margins. If available, intraoperative radiotherapy may be considered for patients with T4 or recurrent cancers as an additional boost.

ADJUVANT THERAPY FOR RECTAL CANCER

Local recurrence alone or in combination with distant metastases occurs in up to 50% of patients with rectal carcinoma. Nodal metastases and deep bowel wall penetration are significant risk factors for locoregional failure.

In the absence of nodal metastases, the rate of local recurrence may be as low as 5%–10% for stage I rectal cancer and 15%–30% for stage II tumors. In stage III disease, the incidence of pelvic failure increases to 50% or more. The use of TME significantly reduces this risk of local recurrence; however, local recurrence remains a concern in patients with stages II and III disease.

Local recurrence in the pelvis is complicated by involvement of contiguous organs, soft and bony tissue, and deep nodal disease. Presenting symptoms vary from vague pelvic fullness to sciatica related to mass effect in the fixed space of the bony pelvis and invasion of the sciatic nerve.

Because local recurrence in the absence of metastatic disease is more common in rectal cancer than in colon cancer, aggressive resections, such as pelvic exenteration (anterior and posterior), sacral resection, and wide soft-tissue and pelvic floor resection, have been employed to treat these recurrences. Modern techniques of pelvic floor reconstruction, creation of continent urinary diversion, and vaginal reconstruction may be required for functional recovery.

The recent findings of the NSABP R-02 trial indicated postoperative adjuvant chemotherapy resulted in similar survival rates to those of postoperative chemoradiation therapy but was associated with a significantly higher rate of locoregional failure.
 

Pre- or postoperative radiation therapy

Radiation therapy has been used to reduce the locoregional recurrence rate of rectal tumors. Preoperative radiation therapy has been demonstrated to reduce local tumor recurrence, even in patients undergoing TME surgery. However, with the exception of one recent study, preoperative therapy has not affected overall survival in patients with stage II or III rectal cancer. An improvement in local control also has been observed with postoperative irradiation, but again with no benefit with regard to disease-free or overall survival. Preoperative radiation therapy reduced local recurrence rates when combined with total mesorectal resection (8% vs 2%; P < .001) in a Dutch phase III trial. In a French study of 762 patients, preoperative chemoradiation therapy compared with preoperative radiotherapy reduced local failure rates in patients with T3–T4 rectal cancers from 16.5% to 8%.

Chemoradiation therapy

Postoperative chemoradiation therapy Clinical trials of surgical adjuvant treatment indicate that postoperative radiation therapy with concurrent chemotherapy (chemoradiation therapy) is superior to postoperative radiation therapy alone or surgery alone. Postoperative chemoradiation therapy is a standard of care for patients with stage II or III rectal cancer based largely on the findings of the North Central Cancer Treatment Group (NCCTG) and Gastrointestinal Tumor Study Group (GITSG) trials. A summary of the 5-year survival results of the Patterns of Care Study (PCS) of the American College of Radiology and the results of the National Cancer Data Base (NCDB), both of which are representative of American national averages, is shown in Table 8.

The most effective combination of drugs, optimal mode of administration, and sequence of irradiation and chemotherapy still need to be determined. Radiation doses of 45–55 Gy are recommended in combination with 5-FU–based chemotherapy. Postoperative bolus 5-FU administration with irradiation is inferior to protracted venous infusion, resulting in lower 3-year rates of both overall survival (68% vs 76%) and disease-free survival (56% vs 67%).

An adjuvant treatment combining chemotherapy and pelvic irradiation in patients with stage II or III disease used the following regimen: 5-FU, 500 mg/m2/d administered as a rapid IV infusion on days 1–5 and 450 mg/m2/d on days 134–138 and days 169–173. Patients received a protracted IV infusion of 5-FU, 225 mg/m2/d, by portable ambulatory infusion pump during the entire period of pelvic irradiation. Pelvic radiation therapy began on day 64 with a multiple-field technique to the tumor bed and nodal groups. A total of 4,500 cGy in 180-cGy fractions was administered over a 5-week period. Patients received a minimal boost dose of 540 cGy to the entire tumor bed, adjacent nodes, and 2 cm of adjacent tissue. A second boost dose of 360 cGy was allowed in selected patients with excellent displacement of the small bowel.

Neoadjuvant therapy For rectal cancers approaching the anal sphincter, preoperative (neoadjuvant) irradiation or the combination of chemotherapy and irradiation will significantly reduce the size of the majority of tumors. This approach allows for sphincter-preserving surgery in many patients. In addition, the long-term morbidity of radiation therapy for rectal cancer may be reduced if it is administered prior to surgery. The use of preoperative chemotherapy and radiation therapy is particularly important for patients presenting with locally advanced, unresectable rectal cancer, as the disease of the majority will be rendered resectable following neoadjuvant therapy. One additional role of neoadjuvant therapy may be in facilitating transanal excision of T2 and T3 rectal cancers in poor surgical risk patients. A number of investigators have reported good results with transanal excision of T2 and T3 tumors following a complete response to neoadjuvant therapy. However, this approach cannot be considered the current standard of care.

Preoperative vs postoperative chemoradiation therapy Preoperative chemoradiation therapy may be preferred to postoperative adjuvant treatment, particularly in patients with T3 or T4 lesions. Such treatment may enhance resectability and may be associated with a lower frequency of complications compared with postoperative treatment. In a report of a randomized trial conducted by the German Rectal Cancer Study, Sauer et al found that compared with postoperative chemoradiotherapy, preoperative chemoradiotherapy significantly decreased local failure (7% vs 11%; P = .02) and sphincter preservation in low-lying tumors (39% vs 19%; P < .004). In addition, the incidence of chronic anastomotic recurrence was also lowest in the preoperative chemoradiotherapy group (2.7% vs 8.5%; P = .001).

TREATMENT OF ADVANCED AND METASTATIC COLON CANCER

Surgery

Local recurrences from colon cancers usually occur at the site of anastomosis, in the resection bed, or in the contiguous and retroperitoneal (para-aortic, paracaval) lymph nodes. Anastomotic recurrences heralded by symptoms are the most curable, followed by local soft-tissue recurrences. Regional and retroperitoneal lymph node recurrences portend a poor prognosis and systemic disease.

Metastasectomy Metastases to the liver and lungs account for most cases of non-nodal systemic disease in CRC. Resection of metastases, or metastasectomy, has gained recognition as a viable treatment. Resection of liver metastases results in cure rates of 5%–60%, depending on the number of metastases and stage of disease. Resection of solitary metastases in patients with stage I or II disease results in a 5-year survival rate of ~40%.

Adjuvant therapy after resection of hepatic metastases has been assessed in several randomized trials. Intra-arterial administration of floxuridine, using a hepatic artery catheter, alternating with systemic 5-FU and leucovorin, improves overall survival and reduces the risk of recurrence within the liver.

Chemotherapy The development of chemotherapy for advanced CRC has become a very active field (Table 9). After decades of 5-FU–based treatment, and of little clinical gains, the arrival of new, effective agents has significantly changed the way this cancer is treated. Although 5-FU remains the backbone of most regimens, the new agents irinotecan and oxaliplatin are rapidly becoming an important part of front-line treatment of this disease in the United States and abroad. The rapid development of newer agents, such as the molecular-targeted agents, holds the promise that progress will continue in chemotherapy for CRC.

5-FU, leucovorin, and oxaliplatin Oxaliplatin combined with infusional 5-FU and leucovorin was approved by the FDA in 2004 as first-line therapy. Oxaliplatin has demonstrated activity in patients with pretreated, 5-FU–resistant CRC when used alone (10% response rate) or in combination with 5-FU (45% response rate). In patients with untreated metastatic colon cancer, response rates of 27% have been reported with oxaliplatin alone, and rates as high as 57% have been noted when the drug is combined with 5-FU. Patients receiving oxaliplatin, infusional 5-FU, and leucovorin have achieved overall survivals of > 20 months in several reported trials. However, many of these patients have received second- and even third-line therapies at the time of disease progression. Oxaliplatin’s toxicity profile includes nausea/vomiting and cumulative, reversible peripheral neuropathy. Patients may also develop a reversible, cold-induced, acute pharyngolaryngeal neuropathy.

A multicenter, randomized phase III study (ASCO 2002, 2003) showed improved outcome with regard to response rate, time to disease progression, and overall survival for patients receiving first-line therapy for metastatic CRC with oxaliplatin, infusional 5-FU, and leucovorin, compared with IFL. At the time of the 2003 presentation, the time to disease progression for the oxaliplatin combination was 8.7 months, compared with 6.9 months for the irinotecan combination. The oxaliplatin regimen also had a significantly better overall survival (19.5 vs 14.8 months) and response rate (45% vs 31%).

Irinotecan has significant clinical activity in patients with metastatic CRC whose disease has recurred or spread after standard chemotherapy. Its FDA approval was based on two phase III trials showing that irinotecan (350 mg/m2 once every 3 weeks) significantly increased survival, compared with best supportive care and infusional 5-FU, respectively, in patients with recurrent or progressive cancer following first-line 5-FU therapy. Irinotecan increased the median survival by 27% and 41%, respectively, in the two trials.

Irinotecan is active in patients whose disease progressed while receiving 5-FU. Reproducible 15%–20% response rates in this patient population led to the approval of irinotecan for use in patients with 5-FU–refractory disease. The dosage schedules most commonly used are 125 mg/m2 weekly for 4 weeks, followed by a 2-week rest period (United States), and 350 mg/m2 every 3 weeks (Europe).

The primary toxicities of irinotecan are diarrhea and neutropenia. Intensive loperamide is important in the management of the former complication. An initial 4-mg loading dose is given at the first sign of diarrhea, followed by 2-mg doses every 2 hours until diarrhea abates for at least a 12-hour period.

5-FU, leucovorin, and irinotecan (FOLFIRI) Several randomized trials have shown improved response rates and overall survival when irinotecan is added to an infusional regimen of 5-FU and leucovorin. However, more severe toxicity (grade 3/4, primarily diarrhea and neutropenia) occurs with the addition of irinotecan. The infusional regimen, however, appears to be better tolerated than a similar bolus regimen (IFL). Although there has not been a direct comparison of these regimens, the bolus regimen may cause severe and life-threatening diarrhea and neutropenia shortly after the initiation of therapy.

In a phase III trial comparing the sequence of FOLFIRI followed by FOLFOX or the reverse sequence for patients with metastatic colorectal cancer, no difference in median survival was seen. Grade 3 or 4 mucositis, nausea, and vomiting occurred more frequently with FOLFIRI, whereas grade 3 or 4 neutropenia and neurosensory toxicity were more frequent with FOLFOX. Response rates were similar between the two groups. However, there did appear to be a higher proportion of patients with liver metastases responding to FOLFOX than FOLFIRI. The results of this clinical trial and others stress the importance of using all available agents in the treatment of metastatic colorectal cancer, and the sequence of their use appears to be less important.

Capecitabine In a phase III trial of previously untreated patients with metastatic colon cancer, capecitabine produced higher response rates than 5-FU and leucovorin. Overall survival and time to disease progression were similar (noninferior) to those with 5-FU and leucovorin. The recommended dose of capecitabine is 2,500 mg/m2 each day, given as a twice-daily dose, for 14 days followed by a 1-week rest period. The side effects of capecitabine tend to be similar to those seen with prolonged infusion of 5-FU, with hand-foot syndrome being the most common.

Molecular-targeted agents A variety of monoclonal antibodies and small molecules are being evaluated in clinical trials and preclinical studies. Three of these agents (cetuximab [Erbitux], bevacizumab, and panitumumab [Vectibix]) have been FDA approved for use.

Cetuximab is a human/mouse chimeric antibody directed against the epithelial growth factor receptor (EGFR). In a randomized trial of patients with CRC refractory to irinotecan, patients were randomized to receive either cetuximab and irinotecan or cetuximab alone. The addition of cetuximab to irinotecan led to a significantly higher response rate compared with cetuximab alone. The median survival for those receiving cetuximab and irinotecan was also longer. Based on the results of this study, cetuximab has been approved by the FDA for use in patients whose disease is refractory to irinotecan with tumors expressing EGFR.

Bevacizumab is a humanized monoclonal antibody that binds circulating vascular endothelial growth factor (VEGF). When given with either 5-FU and leucovorin or IFL as first-line therapy in patients with metastatic CRC, bevacizumab led to improved outcome. The addition of bevacizumab to 5-FU and leucovorin resulted in significant improvement in disease progression-free survival. Even better results were seen with IFL. The addition of bevacizumab to IFL resulted in significant improvement in overall survival and response rate. These studies led to FDA approval of bevacizumab. It is indicated for use in first-line therapy for metastatic CRC when combined with 5-FU–based chemotherapy, such as FOLFOX.

Panitumumab is a monoclonal antibody that targets the epidermal growth factor receptor (EGFR). In a pivotal phase III trial, 463 patients with metastatic colorectal cancer who had failed previous standard therapy were randomized between panitumumab (6 mg/kg q2wk) plus best supportive care (BSC) vs BSC alone. Patients in the panitumumab arm achieved a significantly improved time to disease progression (96 d vs 60 d, P = .000000001) and objective response rate (8% vs 0%). On the basis of the results of this trial, the FDA approved panitumumba for the treatment of patients with colorectal cancer that has metastasized following standard chemotherapy.

Intrahepatic floxuridine administration Renewed interest in regional delivery of floxuridine into the liver has followed the introduction of effective implantable infusion pumps. These pumps allow chemotherapeutic agents to be delivered in higher concentration directly into the hepatic artery.

Randomized trials have shown a considerably higher therapeutic response rate with intrahepatic administration (IA) of floxuridine than with systemic therapy. A meta-analysis of studies comparing IV vs IA fluorinated pyrimidines in patients with unresectable, liver-confined, metastatic disease has indicated a small advantage for IA therapy.

Intrahepatic chemotherapy is costly and associated with gastroduodenal mucosal ulceration, hepatitis, and sclerosing cholangitis. The addition of dexamethasone to floxuridine infusions appears to decrease biliary sclerosis.

TREATMENT OF ADVANCED RECTAL CANCER

Radiation therapy

Radiation therapy is moderately effective in palliating the symptoms of advanced rectal cancer. Pain is decreased in 80% of irradiated patients, although only 20% report complete relief. Bleeding can be controlled in more than 70% of patients. Obstruction cannot be reliably relieved by irradiation, and diverting colostomy is recommended. Only 15% of patients with recurrent rectal cancers achieve local disease control with irradiation, and median survival is < 2 years.

Chemoradiation therapy may be useful to convert fixed unresectable lesions into resectable lesions. These regimens have generally used protracted infusions of 5-FU (200–250 mg/m2/d) delivered via a portable infusion pump during pelvic radiation therapy (450 cGy over 5 weeks).

Intraoperative radiotherapy (localized irradiation given to the tumor or tumor bed at the time of resection) is under active investigation in advanced and locoregionally recurrent rectal cancer.

Laser photoablation

Laser photoablation is occasionally employed for temporary relief of obstructive rectal cancer in patients who are not surgical candidates because of the presence of distant metastases, surgical comorbidity, or extensive intra-abdominal disease.

Follow-up of long-term survivors

Patients who have completed therapy for CRC require monitoring for potential treatment-related complications, recurrent disease, and new metachronous cancers. Specific follow-up recommendations for these patients are controversial. Guidelines for post-treatment surveillance/monitoring adopted by the National Comprehensive Cancer Network (NCCN), a consortium of 19 American cancer centers, are shown in Table 10.

ANAL CANAL CARCINOMA

 

Epidemiology, etiology, and risk factors

In the United States, about 3,990 new cases of anal canal carcinoma are diagnosed each year. Overall, it is slightly more common in women than men. More than 80% of anal canal tumors occur in individuals > 60 years of age. Recent epidemiologic studies suggest that receptive anal intercourse is strongly related to anal cancer.

The incidence rate of anal cancer for single men is reported to be six times that for married men. In people < 35 years old, anal carcinoma is more common in men than women. A history of genital warts has been observed, suggesting that papillomavirus may be an etiologic factor.

Signs and symptoms

The diagnosis of anal canal carcinoma is usually delayed because the symptoms (bleeding, pain, and sensation of mass) are so often attributed to benign anorectal disorders, such as hemorrhoids or anal fissures.

Diagnosis

Evaluation should include a careful rectal examination, endoscopic examination with description of lesion size, and assessment of whether there is invasion of disease into adjacent organs (vagina, urethra, or bladder). Reexamination under general anesthesia may be necessary. A diagnostic incisional biopsy is required.

Pelvic CT is suggested to evaluate pelvic nodes. Although distant metastases are uncommon at diagnosis, a chest x-ray and liver function tests are recommended. Suspicious inguinal nodes discovered on physical examination must be assessed pathologically. The incidence of inguinal nodal metastases at diagnosis varies from 13% to 25%. The presence of perirectal, inguinal, and pelvic lymph node involvement correlates with tumor size and is unusual for tumors < 2 cm in diameter. Formal groin dissection is not advised; needle aspiration should be performed, with limited surgical biopsy if results of aspiration are inconclusive.

Pathology

Squamous cell carcinomas Most anal canal malignancies are squamous cell carcinomas. They have been classified as cloacogenic carcinomas, basaloid carcinomas, transitional cell carcinomas, or mucoepidermoid carcinomas. However, there is little difference in the natural history of these various types.

Unusual tumors arising in the anal canal include small-cell carcinomas, anal melanomas, and adenocarcinomas.

Small-cell carcinomas of the anal canal are aggressive neoplasms similar in natural history to bronchogenic small-cell carcinomas. If such a histology is identified, the clinician should be alerted to the possibility of early distant metastases, and treatment should include chemotherapeutic regimens used in bronchogenic small-cell carcinomas.

Anal melanomas Although advanced anal melanomas generally are associated with a dismal survival, prognosis may be related to the depth of disease penetration. Early anal melanomas < 2.0 mm in depth can be cured with wide excision. More advanced disease can be treated with local excision and external-beam irradiation with excellent local control. Abdominoperineal resection is indicated only rarely in the management of anal melanoma, because lesions large enough to require radical surgery are almost always associated with distant spread of disease.

Adenocarcinomas are uncommon cancers associated with a poor prognosis. Treatment should be aggressive and based on a multimodality approach. The rarity of this tumor precludes the development of specific clinical trials.

Staging

Size of the primary tumor is the most important clinical predictor of survival for patients with anal carcinomas. Both the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) have agreed on a unified staging system (Table 11). The TNM classification distinguishes between anal canal carcinoma and anal margin tumors, since the latter exhibit biologic behavior similar to that of other skin cancers and are staged as skin cancers.

Treatment

Surgery

In selected individuals with small superficial T1 tumors, local excision has achieved adequate local control and survival. However, most studies of local excision have been retrospective, with small numbers of patients. Prior to the advent of primary radiotherapy and combined-modality treatment (see later in this chapter), abdominoperineal resection was considered to be the conventional treatment for patients with invasive anal canal cancer. Unfortunately, even with radical surgical procedures, local recurrences are frequent. Currently, radical extirpative surgery is indicated only after the failure of combined-modality treatment.

Radiation therapy

Trials of primary external-beam radiotherapy in patients with anal canal carcinomas have used doses varying between 4,500 and 7,550 cGy. Local control rates of 60%–90%, with 5-year survival rates of 32%–90%, are similar to the results of surgical series when the trials are controlled for tumor size.

Interstitial radiation therapy alone has been used primarily in Europe for early-stage lesions. A relatively high radiation dose is delivered to a small volume. This modality carries a high potential for radiation necrosis and fails to incorporate treatment of the inguinal nodes.

Combined-modality treatment

Chemotherapy given concurrently with irradiation is the preferred therapy for most patients with anal canal cancer (Table 12). Investigators from Wayne State University pioneered the use of simultaneous pelvic irradiation and chemotherapy in the treatment of patients with anal canal carcinomas. They demonstrated that the majority of such patients could be treated with this combination, obviating the need for an abdominoperineal resection. The original study design used 3,000 cGy over 3 weeks with 5-FU (1,000 mg/m2/d) as a continuous infusion on days 1–4 and then repeated on days 29–32. Mitomycin (Mutamycin), 15 mg/m2, was administered as an IV bolus on day 1. A total of 4 to 6 weeks after the completion of therapy, patients had a deep muscle biopsy of the anal canal scar.

An updated analysis of this experience demonstrated that 38 of 45 patients (84%) were rendered disease free after chemotherapy and irradiation. Individuals who had positive results on biopsy underwent an abdominoperineal resection.

Because of the success of this experience, other investigators have attempted to implement infusional 5-FU and mitomycin with irradiation as definitive therapy. Most studies have used similar schedules of 5-FU and mitomycin but have used higher doses of pelvic irradiation (4,500–5,700 cGy). Five-year survival rates > 70% have been reported.

A randomized trial from the Radiation Therapy Oncology Group (RTOG) showed that the use of mitomycin with irradiation and 5-FU increased complete tumor regression and improved colostomy-free survival over irradiation and 5-FU alone. At 4 years, the colostomy-free survival rate was higher in the mitomycin arm than in the 5-FU–alone arm (71% vs 59%), as was the disease-free survival rate (73% vs 51%). Current studies are examining the role of cisplatinum versus mitomycin along with radiation therapy and 5-FU.

Several investigators have compared the results of irradiation alone vs irradiation plus chemotherapy. Cummings et al found that with identical irradiation doses and techniques, the local control rate for cancers > 2 cm rose from 49% with radiation therapy alone to 85% when 5-FU and mitomycin were combined with irradiation. Papillon and Montbarbon found an increase in the rate of local control with a combined-modality approach compared with pelvic irradiation alone (81% vs 66%). Two recent randomized studies have shown improved local control with chemoradiation therapy over irradiation.

A complete response to combined chemotherapy and radiation therapy is expected in 80%–90% of patients with anal cancer. It is important to evaluate the response of therapy with a careful examination of the anal canal after treatment. Anal canal cancers can continue to regress for up to 3 or more months after completion of treatment. For this reason, it is recommended that a biopsy be performed no sooner than 3 months after the completion of treatment, unless there is evidence of progression or other evidence to suggest early recurrence. If pathologic evidence of recurrence is diagnosed, abdominoperineal resection is expected to yield long-term disease control and survival in 40%–60% of patients.

Chemotherapy

Reports of other chemotherapeutic agents in anal cancer have been relatively anecdotal, with limited phase II studies. Because of the activity of cisplatin in other squamous cell carcinomas, this agent has been employed as a single agent or combined with infusional 5-FU in advanced disease.

SUGGESTED READING

ON COLORECTAL CARCINOMA Andre T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351, 2004.

Benson AB III, Goldberg RM: Optimal use of the combination of irinotecan and 5-fluorouracil. Semin Oncol 30(3 suppl 6):68–77, 2003.

Bentrem DJ, Okabe S, Wong WD, et al: T1 adenocarcinoma of the rectum: Transanal excision or radical surgery? Ann Surg 242:472–477, 2005. 

Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345, 2005.

Clinical Outcomes of Surgical Therapy Study Group: A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 350:2050–2059, 2004.

Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30, 2004.

Kapiteijn E, Marijnen CA, Nagtegaal ID, et al; Dutch Colorectal Cancer Group: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638–646, 2001.

Leung KL, Kwok SP, Lam SC, et al: Laparoscopic resection of rectosigmoid carcinoma: Prospective randomised trial. Lancet 363:1187–1192, 2004.

Le Voyer TE, Sigurdson ER, Hanlon AL, et al: Colon cancer survival is associated with increasing number of lymph nodes analyzed: A secondary survey of intergroup trial INT-0089. J Clin Oncol 21:2912–2919, 2003.

Poynter JN, Gruber SB, Higgins PD, et al: Statins and the risk of colorectal cancer. N Engl J Med 352:2184–2192, 2005.

Sauer R, Becker H, Hohenberger W, et al; German Rectal Cancer Study Group: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740, 2004.

Swanson RS, Compton CC, Stewart AK, et al: The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 10:65–71, 2003.

Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229–237, 2004.

Twelves C, Wong A, Nowacki MP, et al: Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352:2696–2704, 2005.

ON ANAL CANAL CARCINOMAGhouti L, Houvenaeghel G, Moutardier V, et al: Salvage abdominoperineal resection after failure of conservative treatment in anal epidermoid cancer. Dis Colon Rectum 48:16–22, 2005.