Colorectal Cancer: Diagnosis and Management

Molecular Genetics and BiologyEtiology and Risk FactorsPathologyClinical PresentationScreening and DiagnosisStaging and Prognostic FactorsTreatmentConclusionsReferences

In the United States, cancer of the large bowel is the second most common cause of cancer deaths after cancer of the lung [1]. 1995 estimates place large bowel cancer as the third most common malignancy, behind lung and prostate carcinomas in men and behind lung and breast cancers in women. For unknown reasons, overall incidence and mortality rates for colorectal cancer have begun to drop [2-4]. This may be related, at least in part, to better public and professional health education, better primary prevention, including improved diet, and possibly to excision of large bowel adenomas [5]. Mortality rates have begun to decline in whites, remained stable in black women, and risen in black men [6]. Among blacks and Hispanics, there is a trend toward later-stage colorectal cancers at presentation; moreover, these ethnic groups had the worst survival rates at each stage of disease [7], and this trend increased with age. In the United States, the lifetime risk of developing a colorectal cancer is roughly 1 in 20 [8].

The overall incidence of this malignancy is nearly identical in men and women; colon tumors occur slightly more often in women and rectal carcinomas are seen slightly more frequently in men. The risk of developing colorectal cancer usually begins in the fourth decade of life and increases with age; only about 3% of these cancers develop in persons under the age of 40 [9]. The mean patient age at presentation is 60 to 65 years. For persons under 65, the incidence of colorectal cancer is 19.2 per 100,000, and for those 65 or older, 337.1 per 100,000 [3].

The natural history of colorectal carcinoma has changed over the last 3 decades. Colon carcinomas now constitute approximately 70% of all cancers in the large bowel, with the right side of the proximal colon the most common site [10]. This finding may be the result of more frequent use of sigmoidoscopy and polypectomy, which may have lessened the relative incidence of cancers of the rectum and sigmoid colon. The incidence of colon carcinomas in blacks has increased by 30% since 1973 and is now higher than in whites [3]. The reasons for these changes are not known, but dietary and environmental factors may be responsible. Five-year survival rates for patients with Dukes' A, B, and C colon carcinoma (TNM stages I, II, and III, respectively) have improved in recent years (Table 1). This improvement may be due to the wider surgical dissections performed, modern anesthetic techniques and supportive care, better pathologic examination of resected specimens, and preoperative staging and abdominal exploration, which reveal clinically occult disease.

In this review, we will discuss the molecular genetics and biology, etiology and risk factors, pathology, clinical presentation, screening and diagnosis, staging and prognostic factors, and management of carcinomas of the colon and rectum.

Molecular Genetics and Biology

Several articles have been published recently on the molecular biology of tumors of the large bowel. Research in genetic epidemiology found that roughly 10% of large bowel tumors may arise in persons with a genetic susceptibility to them [11]. Molecular genetic information now can be used to screen high-risk populations more aggressively and in the future may have therapeutic applications.

The best characterized conditions that predispose to large bowel cancer are dominantly inherited diseases that can be categorized into one of two groups depending on the presence or absence of a polyposis phenotype. These conditions are the familial adenomatous polyposis (FAP) syndrome and the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, both described below in more detail. The FAP syndrome appears to be due to defects in a single gene, whereas defects in the HPNCC syndrome seem genetically heterogeneous [11].

In 1954, Armitage et al [12] suggested that several types of cancers develop secondary to an accumulation of as many as seven events. Today it is believed that genes are the molecular targets of those events. Colorectal cancer appears to arise as a result of the mutational activation of oncogenes combined with the mutational inactivation of tumor supressor genes, with the latter a predominant action, and a newly described class of mutations, replication errors (RERs)[10].

Activation of Oncogenes: To contribute to carcinogenesis, oncogenes must be activated by mutational changes, which can involve either point mutation or overexpression. Alteration of only one allele is needed to induce malignant changes, an effect called transdominance [13]. The most commonly affected oncogenes in the genesis of large bowel tumors are c-myc and c-Ki-ras; those less frequently affected include c-src, c-myb, and c-erb-b2 [14-16].

The c-Ki-ras oncogene is responsible for synthesis of a protein involved in the transduction of mitogenic messages across the plasmatic membrane of the cell [17]. Point mutations on this oncogene were detected in 39% to 71% of colorectal cancers and in 42% of adenomatous polyps [18-20]. Interestingly, the c-Ki-ras mutation was encountered in more than 40% of the cases involving adenomas larger than 1 cm in diameter, whereas only 10% of adenomas smaller than 1 cm had that mutation. As noted in Figure 1, the mutation of the ras oncogene seems to be involved in the pass from small adenoma to large adenoma, with the latter more likely to progress to cancer than the former [21]. In a study by Sidransky et al [22] of patients whose benign and malignant large bowel tumors contained c-ras mutations, 8 of 9 mutations were found in DNA from stools [22].

FIGURE 1

The c-myc oncogene is activated by its overexpression in colorectal tumors. This oncogene is believed to encode a nuclear phosphoprotein that may be necessary for DNA synthesis [23,24]. In studies of adenoma and colorectal cancer patients, c-myc levels in RNA were increased in 60% to 70% of the cases [25-28] and c-myc expression was greater in tumors from the descending colon than in other tumors.

Inactivation of Tumor-Suppressor Genes: In contrast to the transdominant activity of oncogenes, tumor-suppressor genes exhibit a recessive activity pattern, ie, inactivation of both alleles is necessary, whether by point mutation, deletion, or both [13]. These genes seem to have great importance in the pathogenesis of colorectal tumors.

The FAP syndrome, which confers a susceptibility to large bowel tumors, is the result of point mutations in the adenomatous polyposis coli (APC) tumor-suppressor gene. The APC gene is inherited through the germ line (the first mutational event; cancer develops when the second copy of the gene is deleted or mutated in the somatic tissue) and is localized to chromosome 5 (5q21). This gene encodes a protein whose function is at present poorly understood but that may interact with beta and perhaps alpha catenins. Those proteins together with E-cadherin may be implicated in tumor progression through alteration of the cytoskeleton and cell adhesion systems [29-33]. Disease manifestation depends on the type of mutation occurring in the APC gene; with some types of APC gene mutations (after exon 9), ophthalmologic manifestations of the FAP syndrome are evident, leading to a patchy hyperpigmentation of the retina [34]. Additionally, some types of mutations (in the 5´ region) are associated with attenuated forms of the disease [35-36] rather than with the more virulent form. Inactivation of the APC gene seems to play an important role in sporadic and FAP tumorigenesis and has been detected in 36% to 79% of patients with colorectal tumors and adenomas [37-38].

Deletions and point mutations have been identified in a second gene on the long arm of chromosome 5-the mutated in colon carcinoma (MCC) gene [39-40]; up to 55% of colorectal cancer patients showed deletions involving this gene. MCC function is unknown, but this gene might interact with the APC gene to form a biologically active complex that regulates proliferation and differentiation.

The deleted in colorectal cancer (DCC) gene, a candidate tumor-suppressor gene located on chromosome 18,[41] is activated in 73% of colorectal cancers but in only 11% of adenomas [19]. Preliminary studies suggested that the DCC gene product resembles a cell adhesion molecule and may therefore regulate the interaction of the cell with its enviroment [13]. The loss of chromosome 18q could thus lead to impaired contact between cells and thereby contribute to tumor growth and invasion [42]. Jen et al showed that the status of chromosome 18q has strong prognostic value in patients with stage II colon cancer; the prognosis in patients with stage II disease and 18q allelic loss is similar to that in patients with stage III colon cancer, who are thought to benefit from adjuvant therapy. In contrast, patients with stage II disease who do not have 18q allelic loss in their tumors have a survival rate similar to that of patients with stage I disease and may not require additional therapy.

A deletion on the short arm of the chromosome 17 was associated with point mutations in the p53 allele on the homologous chromosome [43]. In several patients the 17p loss was associated with progression from adenoma to carcinoma and also with poor prognosis. The 17p deletion was observed in 75% to 95% of the colorectal cancers and less commonly in adenomas [44]. Other allelic losses include those from chromosomes 1p, 8q (which also may be associated with poor prognosis), 13q, and 22q [13].

Replication Errors: A newly described class of mutations, called replication errors (RERs) or microsatellite instability, has been described recently [11]. Cells with this phenotype are characterized by genomic instability at simple repeated sequences in DNA [45]. This instability, produced by slippage of DNA strands in the moment of replication, may be secondary to a mutation of genes committed to reparation and/or replication of DNA. Thus, cells with this genetic abnormality accumulate deletions and insertions at repeated sequences [46]. Microsatellite loci are small regions of the genome characterized by mono-, di-, or trinucleotide repetitive sequences and are, in general, noncoding. The two best-known are (A)n and (CA)n, where n = 10–30. Of interest, colorectal tumors having this abnormality are more often located on the right side of the colon, appear to be associated with a good clinical outcome, and may serve as a marker for HNPCC [11]. A candidate for the HNPCC gene has been identified on chromosome 2. This gene, called MSH-2, appears to regulate RERs and is a homolog of the bacterial missmatch repair gene MUT-S [47-48]. Aaltonen et al [49] found RERs in 78% of tumors from patients with HNPCC; RERs also were found in sporadic tumors [42]. The candidate gene on chromosome 2 appears to regulate HNPCC type II (site nonspecific), whereas another gene, on chromosome 3, seems to be involved in HNPCC type I (site specific)[50-51]. The latter gene, hMLH-1, encodes a protein homologous to the bacterial DNA missmatch protein MutL [52]. Recently, two more genes that regulate RERs were discovered: hPMS-1 (homologous to the bacterial PMS-1) on chromosome 2 and hPMS-2 (homologous to the bacterial PMS-2) on chromosome 7 [53].

Adenoma-Carcinoma Sequence

Several trials have suggested that most colorectal tumors arise from adenomas [54]. Tumorigenesis has long been thought to be a multistep process [55]. Recently, the molecular events that underlie tumoral initiation and progression have been identified [56,56a]. Comparison of the frequency with which tumor-suppressor genes and oncogenes are altered in adenomas and carcinomas suggests that there is a preferred order for the occurence of these genes in the adenoma-carcinoma sequence (Figure 1). Fearon et al [21] pointed out, however, that it is the accumulation rather than the order of these mutational events that is essential for carcinogenesis.

Etiology and Risk Factors

The specific causes of colorectal carcinoma are unknown, but environmental, nutritional, genetic, and familial factors and preexisting diseases have been found to be associated with this cancer. The incidence of colorectal carcinoma is higher in industrialized regions, such as the United States, northern and western Europe, New Zealand, Australia, and Canada, whereas a lower rate is observed in Asia, Africa (among blacks), and South America (except Argentina and Uruguay)[57]. Immigrants from low-risk areas assume the colon cancer risk of their adopted country, suggesting the importance of environmental factors [58-59]. Nevertheless, differences in diet within high- or low-risk regions could lead to distinct results. For instance, within the United States, a country with a very high colon cancer risk, a significantly lower risk is noted among Mormons and Seventh Day Adventists, whose diet avoids meat and consists mainly of vegetables, fruits, and whole-grain cereals [60].

Dietary Factors: Diets rich in fat and cholesterol have been linked to an increased risk of tumors of the colon and rectum [8]. The effects of animal fat appear independent of total calorie intake [61]. A sedentary lifestyle [62] and obesity, both linked with dietary fat, also correlate with the incidence of colorectal cancer [63-64]. Dietary fat increases the endogenous production, bacterial degradation, and excretion of bile acids and neutral steroids, which are carcinogens, thereby promoting colonic carcinogenesis [65]. Excess lipids in the colon may lead to an increase in the concentration of secondary bile acids, which may stimulate protein kinase C (PKC), a major cellular communication pathway, resulting in the promotion of cancer [66]. Some authors [67-68] suggested that in colorectal cancer PKC may inhibit growth, while in normal mucosa it may stimulate growth through the action of bile acids. A diet high in fat could lead to a predominance of anaerobic bacteria in the intestinal microflora, and the enzymes in such bacteria may activate carcinogens [69-71]. Nonetheless, prospective trials in Israel, Japan, and the United States failed to find a link between either fat or meat intake and large bowel cancer [72-73]. Interestingly, a protective effect has been suggested for a diet containing fiber and yellow and green vegetables [74]. However, some authors believe that cereal fiber, although beneficial, is not as important as fiber from fresh fruits and vegetables [75]. Possible effects of fiber on colorectal carcinogenesis may include decreased fecal transit time through the bowel, resulting in decreased exposure to fecal carcinogens; reduced carcinogenic microflora in the bowel; and decreased fecal pH, with a consequent decrease in bacterial enzymatic activity and a dilution of carcinogens via an increase in stool bulk [76-78]. In addition, a higher incidence of rectosigmoid tumors in men has been associated with alcohol consumption. A protective role has been ascribed to calcium salts and calcium-rich foods because of their capacity to decrease colon cell turnover rates and reduce the colon cancer-promoting effects of bile and fatty acids [79]. Other diet compounds that may decrease large bowel carcinogenesis are selenium; vitamins C, D, and E; indoles; and beta-carotene [80-82].

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs are known to inhibit the synthesis of prostaglandins. Human tumors have been shown to produce large amounts of prostaglandins, particularly E, which has been implicated in blocking natural killer (NK) cell cytotoxicity [83]. Recent trials suggested that inhibition of prostaglandin synthesis by the NSAID sulindac decreases the development of colonic polyps [84]. Sulindac causes regression of rectal polyps in FAP [84-85]. A phase III randomized trial is planned comparing fluorouracil, levamisole (Ergamisol), and sulindac with fluorouracil and levamisole as adjuvant therapy in patients with resected stage III colon cancer [86]. NSAIDs also may have antiangiogenic effects [87] and may reduce the synthesis of certain growth factors [88].

An American Cancer Society study [89] suggested that aspirin confers a protective effect against colon cancer. In this prospective study in 424 adults, mortality rates from large bowel cancer decreased in both sexes with more frequent aspirin use. Whether this was an overall decrease in colon cancer incidence or just a decrease in the number of deaths from colon cancer was not noted [89].

Familial Factors: Several genetic premalignant polyposis syndromes have been described, including familial adenomatous polyposis (FAP) coli, Gardner syndrome, Oldfield syndrome, Turcot syndrome, Peutz-Jeghers syndrome, juvenile polyposis, and hereditary non-polyposis colorectal cancer (HNPCC).

Even if none of these syndromes is present, patients with family histories of colorectal carcinomas still have an increased risk for the disease [90]. Fuchs et al [91] confirmed this in the first prospective study of 32,085 men and 87,031 women who were first-degree relatives with colorectal cancer and pointed out that the risk was more evident in younger people [91].

Few colon cancer patients have FAP coli (US incidence, 1/6,850) [92]. FAP is inherited as an autosomal dominant trait with more than 90% penetrance. Patients with this disorder develop pancolonic and rectal adenomatous polyposis in the mid-teenage years and may develop colorectal carcinoma if prophylactic total colectomy is not done. The risk of colorectal carcinoma is almost 100% if the patient lives long enough. As stated above, a gene predisposing to FAP was identified; this gene, APC, is linked to a region on the long arm of chromosome 5 (band 5q21)[93-94]. One or more genes on chromosome 5 are involved in the inheritance of FAP as well as in the development of more common sporadic colorectal tumors. This finding may allow genetic identification of FAP family members who will develop colorectal tumors and open the door for studies of genetic events associated with the development of sporadic colorectal cancer.

Gardner syndrome, which occurs 50% less frequently than FAP, is inherited as an autosomal dominant trait [95]. The whole large and small bowel may be affected by adenomatous polyps that may degenerate into cancer.This is accompanied by desmoid tumors of the mesentery and abdominal wall [96], sebaceous cysts, lipomas, fibromas, and osteomas.

Oldfield syndrome, which is related to Gardner syndrome, consists of multiple sebaceous cysts accompanied by polyposis that may degenerate into colorectal carcinoma [97].

Turcot syndrome occurs less frequently than the other syndromes and is possibly inherited as an autosomal recessive condition. This syndrome involves premalignant polyposis of the colon associated with central nervous system tumors [98].

Peutz-Jeghers and juvenile polyposis syndromes are characterized by hamartomatous polyps of the bowel associated with hyperpigmentation of the oral mucosa and skin (in Peutz-Jeghers)[91]. These syndromes carry only a small risk of malignancy (2% to 3%)[99-100].

Some families without a history of adenomatous polyps in the large intestine also have a higher risk of developing colorectal tumors [101-102]. The familial aggregation of these tumors is HNPCC. The cancers that arise from this syndrome differ from the sporadic form by an earlier age of onset (median, 44 years), an increased frequency of right-sided tumors (60% to 70%), an excess of metachronous and synchronous large bowel cancers [103], and an increased frequency of mucinous and poorly differentiated tumors [103].

The clinical diagnosis of HNPCC is made by the Amsterdam Criteria [104-105]. The patient must have (1) three or more relatives with histologically confirmed colorectal cancer, one of whom is a first-degree relative of the other two; (2) familial colorectal cancer affecting at least two generations; and (3) one or more familial colorectal cancer cases diagnosed before age 50. HNPCC is inherited as an autosomal dominant trait with more than 90% penetrance [101]. The two types of HNPCC are A and B, which together currently account for 5% to 15% of all colorectal cancers [106-107]. HNPCC type A, formerly called “Lynch syndrome I,” is a site-specific familial nonpolyposis colon cancer.This syndrome is associated with colon tumors only and with a tumor predilection for the right side. In HNPCC type B, formerly “Lynch syndrome II,” nonpolyposis colon cancer occurs in association with other cancers, such as breast, endometrial, gastric, small bowel, pancreatic, bile duct, urothelial, kidney, and ovarian carcinomas.

Inflammatory Bowel Disease: Patients with inflammatory bowel disease (ulcerative colitis and Crohn's disease) have a higher-than-normal(up to 30-fold) incidence of colorectal carcinoma. The risk of carcinoma in ulcerative colitis patients is associated with the duration of active disease, extent of colitis, development of mucosal dysplasia, and continuity of symptoms [108-111]. The risk of carcinoma increases exponentially with increasing duration of colitis; it is estimated to be approximately 3% in the first decade of disease, 20% in the second decade, and more than 30% in the third decade [112-113]. The risk of developing colorectal cancer also is increased in patients with Crohn's disease, although to a lesser extent than in patients with ulcerative colitis.

Polyps: Colorectal tumors develop more often in patients who have had adenomatous polyps than in those without polyps. There is an approximate 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 [114]. Adenomatous polyps smaller than 1 cm have a less than 1% chance of being malignant compared with adenomas larger than 2 cm, which have up to a 40% likelihood of malignant transformation [114]. In 1993, the National Polyp Study Workgroup concluded that colonoscopy-guided polypectomy lowered the incidence of unexpected colorectal cancer, supporting the view that colorectal adenomas progress to carcinomas [115].

Cancer History: Patients with a history of colorectal carcinoma are at increased risk of developing a second primary colon cancer or other malignancy [116]. Women with a history of breast, endometrial, or ovarian carcinoma also have an increased chance of developing colorectal carcinoma [117]. An increased incidence of colon cancer at or near the suture line following ureterosigmoidostomy has been reported [118]. Cholecystectomy also has been associated with colon cancer in some studies, but others have found no relationship between this procedure and colon cancer [119].

Other Predisposing Factors: Finally, sedentary occupations [120], no or low parity [121], a history of pelvic irradiation for gynecologic cancer [121], and a diet poor in vegetables and grains [122] all have been linked to a higher risk of colon carcinoma.

Pathology

In colorectal carcinoma, the tumor's gross appearance is ulcerating and/or stenosing in about 75% of the cases (left-sided) and fungating in the remaining 25%, which are more frequently located on the right side [123].

With regard to histologic type, adenocarcinomas make up between 90% and 95% of all large bowel neoplasms [124-125]. 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; this tumor variant occurs more often in males and is more frequently diagnosed when the disease is advanced [126-127]. Signet-ring-cell carcinoma is another variant, containing large quantities of intracellular mucin elements that cause the cytoplasm to displace the nucleus. This variant is more common in young females, is frequently diagnosed when the disease is advanced (stage III to IV), and thus tends to have a particularly poor prognosis [127]. Signet-ring-cell tumors tend to spread diffusely through the bowel wall, with relative sparing of the mucosa, producing an appearance of linitis plastica, which could be oligosymptomatic and result in disease-negative biopsies [128]. This tumor shows very little evidence of an association with adenomas [129]. Squamous-cell carcinomas, carcinoid tumors, and adenosquamous and undifferentiated carcinomas all have been reported as colon and rectal cancers [130]. Nonepithelial tumors such as sarcomas [131] and lymphomas [125] are exceedingly rare histologic types in colorectal carcinoma.

Broders and Dukes pioneered the classification of colorectal carcinomas based on their degree of differentiation [132-133]. Broders' system has four grades. Dukes' system, currently the most widely used, considers the arrangement of the cells rather than the percentage of differentiated cells. This system has three grades, with grade 1 the most differentiated tumors and grade 3 the least differentiated [134-135].

Colorectal carcinoma has a tendency for local invasion by circumferential growth (with this type more important in rectal than colon tumors) and for lymphatic, hematogenous, transperitoneal, and perineural spread [136]. The most common site of extralymphatic involvement is the liver, with the lungs the most frequently affected extra-abdominal organ [130]. Other sites of hematogenous spread include the bones, kidneys, adrenal glands, and brain.

Clinical Presentation

Symptoms of colorectal tumors vary depending on the anatomic region involved. During the early stages, patients may be asymptomatic or may 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 also are seen, but these are frequently ignored and/or attributed to hemorrhoids or other benign disorders. Cancers occurring on the left side of the colon generally cause constipation alternating with diarrhea; abdominal pain; a decrease in the caliber of the stools (pencil stools); and obstructive symptoms such as nausea and vomiting. Right-side colon lesions produce vague abdominal aching (unlike the colicky pain seen with obstructive left-side lesions) and also may present as palpable abdominal masses on the physical exam. Anemia resulting from chronic blood loss, weakness, weight loss, and an abdominal mass also may accompany right-side colon carcinoma. Patients with cancer of the rectum may have a change in bowel movements, rectal fullness, urgency, 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.

Many trials tried to identify preoperative clinical findings that will predict patient prognosis. One such finding is rectal bleeding as a presenting symptom. Those patients might have more localized lesions and therefore a better prognosis than the patients who do not bleed [137-138]. Patients presenting with acute symptoms such as obstruction and perforation have a poorer prognosis [139-140]. Age has been implicated as a prognostic factor in very young patients (younger than 20 years old) because of the poor workup usually done in these patients and their high incidence of signet-ring-cell carcinomas [141] and also in very old patients because of their higher incidence of surgical complications. Some authors point out that older patients may have slower-growing tumors than do younger patients [142].

Screening and Diagnosis

Average-Risk Individuals: Currently available screening techniques for populations not at high risk for the development of colorectal cancer are far from ideal.

Many fecal occult blood tests (FOBTs) use guaiac, which detects the peroxidase-like capacity of hemoglobin. Although these guaiac-based FOBTs are inexpensive, easy to perform, and carry no risk for the patient, they have been associated with many false-positive and -negative results. Almost all colonic polyps and more than half of all colorectal carcinomas are undetected by this test because they are not bleeding at the time of testing; the test requires more than 20 mL of blood per day to yield a positive result [143]. The newer FOBTs, including a guaiac-based product called Hemoccult SENSA (SmithKline Diagnostics), immunochemical tests for hemoglobin (HemeSelect; Smith Kline Diagnostics), and HemoQuant (a heme-porphyrin assay specific for fecal heme) appear to have better sensitivity than the older tests without sacrificing specificity [144]. Several trials of FOBTs in Europe and the United States, with a total enrollment of 309,000 patients, failed to conclusively demonstrate a reduction in colorectal cancer mortality, although Winawer et al [145] reported a nonstatistically significant decrease and one European trial reported a trend toward a decrease [146-150]. The latter trial found that when FOBT was done once a year, colorectal cancer mortality decreased by 33%, the first significant reduction in mortality reported. Of note, in this trial testing was done after rehydration of the stool sample.

Digital rectal examination is simple and can detect lesions up to 7 cm from the anal verge. Currently, the American Cancer Society recommends that this procedure be performed annually to screen for rectal and prostate cancers in average-risk populations after age 40.

Flexible proctosigmoidoscopy is safe and more comfortable than examination using a rigid proctoscope. In addition, almost 50% of all colorectal neoplasms are within the reach of a 60-cm sigmoidoscope. Two recent case-control studies support the use of sigmoidoscopy for colorectal screening in average-risk populations after age 50 [151-152].

Colonoscopy provides information on the mucosa of the entire colon, and its sensitivity in detecting tumors is extremely high. Colonoscopy can be used to obtain biopsy specimens of adenomas and carcinomas and allows excision of adenomatous polyps. Limitations of colonoscopy include its inability to detect some polyps and small lesions because of blind corners and mucosal folds and the fact that with colonoscopy the cecum sometimes cannot be reached [153]. Today, most clinical trials use colonoscopy for definitive diagnosis after positive screening tests. Also, colonoscopy may significantly reduce colorectal cancer mortality in high-risk populations [154].

Barium enemas are also accurate in detecting colorectal carcinoma, although double-contrast barium enemas have a false-negative rate of 2% to 18% owing to misreading, poor preparation, and difficulties in detecting smaller lesions [136]. A barium enema should be viewed as complementary to colonoscopy.

The American Cancer Society has recommended that asymptomatic patients with no risk factors should have a digital rectal examination annually beginning at age 40 and should have fecal occult blood tests yearly and flexible sigmoidoscopy every 3 to 5 years starting at age 50 [155]. An analysis of combinations of screening methods found fecal occult blood testing and flexible sigmoidoscopy to be the most cost-effective strategy for reducing mortality from cancer of the rectum and distal colon.

High-Risk Patients: There is no proven screening recommendation for patients at high risk for colorectal cancer, but it is not unreasonable to start screening family members of patients with familial polyposis with annual flexible sigmoidoscopy between the ages of 10 and 12 years [156]. Patients with one or more first-degree relatives who developed colorectal cancer at age 55 years or younger should have an annual FOBT and either a colonoscopy or double-contrast barium enema every 5 years beginning at age 35 to 40 years [155]. Members of families with a history of HNPCC require earlier and more frequent examination with colonoscopy. For patients with a single or several adenomas over 1 cm and/or adenomas with villous changes, surveillance of the entire remaining large intestine has been recommended 1 year after resection and if the initial findings are normal, every 3 to 5 years thereafter. The timing of follow-up colonoscopic examinations after polyp removal has been questioned recently. Winawer and associates of Memorial Sloan-Kettering Cancer Center found that a follow-up colonoscopic examination 3 years after a polypectomy was as effective as were follow-ups at 1 and 3 years. These investigators recommend first follow-up colonoscopy no sooner than 3 years after all polyps are removed [157]. In addition, other investigators have noted that follow-up colonoscopic examinations are warranted in patients with tubulovillous, villous, or large (1 cm) adenomas in the rectosigmoid, particularly if the adenomas are multiple; however, in patients having only a single, small tubular adenoma, surveillance colonoscopy may not have value because the risk of cancer is low [158]. Patients with a longer-than-8-year history of ulcerative colitis with pancolitis who have not undergone proctocolectomy require colonoscopy with multiple random biopsies every 1 to 2 years to detect dysplasia [156]. Individuals with a personal history of colorectal cancer are also at high risk for developing another colorectal cancer and need surveillance of the large bowel as well as regular follow-up for metastatic disease.

Better screening methods for colorectal cancer are needed for both average- and high-risk patients. Stool DNA analysis for mutations of the K-ras gene and other genetic abnormalities may be utilized in the future for early detection of colorectal tumors [159].

Initial Diagnostic Workup: The initial diagnostic workup for patients suspected of having colorectal tumors should include digital rectal examination or an FOBT. An air-contrast barium enema and/or colonoscopy with biopsy of any detected lesions also should be performed prior to surgery in order to detect synchronous polyps or carcinomas. Endoscopic ultrasonography has markedly improved the accuracy of preoperative tumor and node staging in rectal cancers [160]. A chest x-ray, computed tomography (CT) scan of the abdomen and pelvis, complete blood count, platelet count, liver and renal function tests, urinalysis, and preoperative measurement of carcinoembryonic antigen (CEA) level also should be done for adequate staging prior to surgical intervention. Magnetic resonance imaging is under investigation but is not routinely used in the staging of large bowel carcinoma. A CT scan of the abdomen is useful to detect liver metastases larger than 2 cm, but its diagnostic yield drops when the metastases are smaller than 2 cm. Improvement in the detection of liver metastases less than 2 cm in size has been noted using CT arterial portography, which involves insertion of a catheter in the superior mesenteric artery followed by CT scanning of the liver while contrast material is delivered into the artery. This procedure is used in patients with liver metastases from colorectal cancer who may be candidates for surgical resection of the liver [161-162].

Satumomab pendetide (Oncoscint CR/OV) was recently approved as a diagnostic imaging agent indicated for determining the extent and location of extrahepatic malignant disease in colorectal cancer patients [163-164]. This agent is an immunoconjugate of monoclonal antibody B72.3 that has been radiolabeled with (111)In. In a study of 92 patients, these antibody scans were able to detect occult lesions in 11 patients with surgically confirmed adenocarcinoma, and the scans may be particularly useful in detecting extrahepatic disease. In a study of 155 patients with colorectal carcinoma, immunoscintigraphy and CT demonstrated similar sensitivities (69% and 68%, respectively) and specificity (77%). Although CT was able to detect a greater proportion of liver metastases (84% vs 41%), immunoscintigraphy showed greater sensitivity in detecting pelvic tumors and extrahepatic abdominal metastases (84% vs 41%, P < .001)[164].

Staging and Prognostic Factors

The three main staging systems for colorectal cancer are the Dukes, TNM, and modified Astler-Coller (MAC) systems (Table 2)[165]. In the United States, the most widely used clinical and pathologic staging system for colorectal tumors is the modified Astler-Coller Dukes' system, which is based on the depth of tumor invasion into and through the intestinal wall, on the number of regional lymph nodes involved, and on the presence or absence of distant metastases. The 1990 NIH Consensus Conference statement urged a more standard use of the TNM system.

Pathologic stage is the single most important prognostic factor following surgical resection of colorectal tumors [130]. The prognosis for early stages (I and II) is favorable overall, in contrast to the prognosis for advanced stages (III and IV)(Table 1).

Other, less powerful prognostic factors include the following:

• When adjusted for other factors, age has never been proven an independent prognostic factor for colorectal carcinoma in young people [166]; however, a delay in diagnosis and a higher incidence of mucin-producing tumors may be related to a higher disease stage at presentation. Old patients are prone to have slower-growing tumors, but the incidence of surgical complications in these patients is higher than in younger ones.
• Patients without symptoms tend to have better prognoses, independent of disease stage [130]. However, rectal bleeding has been associated with better survival [167].
• Obstruction and perforation are related to poor prognosis independent of disease stage [168].
• With regard to tumor location, rectal tumors have a poorer prognosis than colon tumors.
• DNA content is an independent factor for survival [130]. The 18q chromosome deletion has been associated with a poorer prognosis (see above).
• Histologic grade also is correlated with survival. Five-year survival rates of 56% to 100%, 33% to 80%, and 11% to 58% have been reported for grades 1, 2, and 3 colorectal tumors, respectively [130].

Other prognostic factors, such as preoperative CEA level, sex, tumor histologic features, perioperative blood transfusions [169], perineural invasion, venous or lymphatic invasion, and S-phase fraction, have not consistently been correlated with overall disease recurrence and survival [159]. Furthermore, the size of the primary lesion has had no influence on survival [170-172].

Treatment

Curative management of colorectal carcinoma relies primarily on surgical resection, possibly accompanied by adjuvant systemic or local chemotherapy and immunotherapy. In rectal cancer, radiation therapy also is used. Palliative treatment is field-of-surgery radiation therapy and chemotherapy, when indicated.

Surgery

Primary Tumor: The primary therapy for adenocarcinoma of the colon and rectum is surgical extirpation of the bowel segment containing the tumor, the adjacent mesentery, and draining lymph nodes. The type of surgical resection depends on the tumor's anatomic location. Right or left hemicolectomy is the surgical treatment of choice in patients with right- or left-side colonic tumors, respectively. Tumors in the sigmoid colon may be treated by wide sigmoid resection [130].

For rectal carcinoma, abdominoperineal resection and permanent colostomy should be performed if the tumor is located in the distal 5 cm of the rectum [173]. However, this treatment sacrifices the rectum and may be associated with urologic dysfunction and impotence. If the tumor is located proximally between 6 and 10 cm, a lower anterior resection with end-to-end anastomosis may be performed. Local excision alone may be indicated for selected rectal cancer patients who have small (less than 3 to 4 cm) [174], exophytic [175], and well-differentiated to moderately differentiated tumors confined to the submucosa and for which a disease-free surgical margin can be achieved [176]. Adam et al showed the importance of the circumferential margin in local recurrence of rectal cancer, reporting a significantly higher recurrence in patients with tumor involvement of the circumferential margin than in those without such involvement [177].

Patients who have low-lying rectal adenocarcinomas and are not candidates for local excision and postoperative radiotherapy may be managed with preoperative radiotherapy (40 to 50 Gy) or preoperative chemoradiotherapy followed by surgery to preserve the sphincter and control local tumor [178-179]. The advantages of this approach include downstaging of the tumor with chemoradiation or radiation, which may allow an adequate surgical margin and sphincter-sparing surgery.

Metastases: Surgical excision is the standard of care in patients with resectable liver and pulmonary metastases from colorectal carcinoma owing to the potential for long-term survival after complete resection in these cases and to the fact that without surgery, such disease remains incurable at present.

Only a small number of patients with large bowel cancer present with lung metastases as the first site of recurrence. One large series demonstrated a 5-year survival rate of 31% [180]. The presence of more than one lung metastasis and an elevated CEA level prior to surgery have been noted as poor-prognosis factors after resection [130].

Twenty-five percent of colorectal cancer patients present with liver metastases (synchronous); about 50% of colorectal cancer patients develop liver metastases after surgical resection of the primary tumor (metachronous) [181]. In six series with more than 100 patients each, 5-year survival rates of from 25% to 39% and a median survival of longer than 2 years were reported after resection of liver metastases [182-187]. In multivariate analyses, the most consistent predictors of long-term survival were stage of the primary tumor, percentage of tumor involvement [185] (with fewer than three metastases and small tumors conferring a better prognosis)[188-189], and disease-negative surgical margins [190].

Of interest, Nordlinger et al concluded that selected patients with liver metastases from colorectal carcinoma can undergo subsequent resection if needed and that a percentage of these patients enjoy long-term survival; this finding emphasizes the need for careful follow-up after hepatectomy for liver metastases [191].

Nonhepatic intra-abdominal recurrence of colon carcinoma frequently is found in patients who have disseminated disease; however, in the presence of localized disease or as treatment of symptomatic disease, surgical resection should be considered with the expectation that some patients will enjoy long-term survival and that many with unresectable disease will be palliated [192].

Adjuvant Therapy for Colon Carcinoma

Approximately 75% of all patients with colorectal carcinoma will present at a stage when all gross carcinoma can be surgically resected [193]. Nevertheless, despite the high resectability rate, almost half of all patients with colorectal adenocarcinoma die of metastatic disease [1], primarily because of residual disease that is not apparent at the time of surgery. These individuals are candidates for adjuvant local or systemic therapies.

The natural history and patterns of failure following “curative” resection for colon cancer differ from those for rectal carcinomas. Local-regional 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, a local therapy such as radiation may have a significant role in the treatment of rectal tumors but is not routinely used for colon cancers. Nonetheless, investigators from Harvard pointed out that certain patients with colon carcinoma, such as those with B3 and C3 lesions (MAC), tumors associated with abscess or fistula formation, and residual disease after subtotal resection, may benefit from postoperative radiotherapy in addition to systemic therapy [194]. Systemic chemotherapy plus levamisole is the principal adjuvant therapy for colon cancer.

Systemic Therapy: The administration of either fluorouracil or floxuridine (FUDR) to patients with Dukes' stage II and III colon tumors following surgical resection has failed to produce a survival advantage over postsurgical observation [195], and a recent meta-analysis did not show any benefit from adjuvant fluorouracil [196-197]. Five trials compared the combination of semustine (methyl-CCNU), vincristine (Oncovin), and fluorouracil with no adjuvant treatment, immunotherapy with bacillus Calmette-Guerin (BCG) or its methanol extraction residue (MER), and fluorouracil alone. Four of these trials, with a total of almost 2,500 patients, failed to demonstrate any effect of adjuvant therapy on overall survival [198-201]. Initial analysis of the fifth trial, which included 1,166 patients and was conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), showed an improvement in disease-free and overall survivals in patients who received combination chemotherapy compared with those in the control arm [202]. Sixty-seven percent of patients treated with adjuvant chemotherapy and 59% of those treated with surgery alone survived for 5 years (P = .05). A recent update of this trial, however, failed to show any survival advantage for the chemotherapy arm, at least from the statistical viewpoint (P = .06)[203]. It is inappropriate to conclude that a regimen containing methyl-CCNU is effective adjuvant therapy, as final analysis of these five trials failed to show any benefit. Furthermore, methyl-CCNU is leukemogenic and nephrotoxic, which may negate the small survival benefit seen in one trial.

Levamisole is an anthelmintic agent with nonspecific immunostimulating properties in patients with cancer. It enhances fluorouracil's toxicity to human colon cancer cell lines in a dose-dependent manner. This may be caused by levamisole's inhibition of tyrosine phosphatases in tumor cells. Levamisole may also enhance natural-killer lymphocyte activity and may induce expression of HLA-1 molecules in cancer cell membranes [204]. Windle and associates first reported the effectiveness of levamisole plus fluorouracil as adjuvant therapy for colorectal cancer [205]. The North Central Cancer Treatment Group (NCCTG) and Mayo Clinic researchers randomly assigned 401 patients with resectable Dukes' stage II and III colon cancer to receive postsurgical observation alone or postsurgical adjuvant therapy with levamisole alone or levamisole plus fluorouracil for 1 year [207-207]. Levamisole plus fluorouracil significantly reduced the recurrence rate compared with no adjuvant therapy (P = .003), and a benefit from levamisole alone was also suggested (P = .05). In addition, survival advantages were observed in stage III patients treated with levamisole plus fluorouracil (P = .03).

A confirmatory national intergroup trial was implemented using essentially the same methodology, except that patients with stage II tumors were randomly assigned to one of two arms (postsurgical observation or postsurgical levamisole plus fluorouracil) and patients with stage III disease were randomly assigned to one of three arms (observation, levamisole alone, or fluorouracil plus levamisole) [208]. A total of 1,269 patients with resected colon cancer were included in the trial. Among the 929 evaluable patients with stage III tumors, therapy with levamisole plus fluorouracil reduced the risk of cancer recurrence by 41% and the overall death rate by 33%. The 3-year overall survival rate for the levamisole plus fluorouracil arm was estimated at 71% vs 55% for the observation arm (P = .0064). Levamisole alone did not produce a disease-free survival advantage over observation alone. Follow-up of patients with stage II tumors is insufficient to allow analysis at this time. As mentioned previously, stage II colon cancer patients whose tumors have aneuploidy; a high cell-proliferation index on DNA flow cytometric examination; complication by intestinal perforation or colon obstruction; invasion or adherence to adjacent structures; and the 18q chromosome abnormality are noted to have a higher risk of tumor relapse and should be considered for adjuvant therapy. The intergroup trial updated its data on patients with stage III colon carcinoma in 1992, and the final report was published recently [209]. With all 929 stage III colon cancer patients receiving follow-up for 5 years or more (median, 6.5 years), levamisole plus fluorouracil was found to reduce the risk of cancer recurrence by 40% (P < .0001) and the death rate by 33% (P < .0007). Levamisole alone produced no benefit in patients with stage III colon carcinoma. The reported toxicity was mild with no late side effects noted.

Levamisole plus fluorouracil is now considered the standard adjuvant therapy against which future treatments for stage III colon cancer should be compared and the nonprotocol adjuvant therapy of choice for patients with stage III colon cancer when formal clinical trials are not available. However, this opinion is not universally accepted by other investigators for several reasons: levamisole's claimed immunomodulatory effects have been difficult to substantiate, this effect appears more significant at higher doses than those used, single-agent levamisole appears to have no antitumor activity, and the possibility exists of long-term adverse effects such as multifocal leukoencephalopathy. Also, European study findings have raised suspicions about an increase (in a small number of patients) in cancer- and non-cancer-related deaths. Finally, the NCCTG-Intergroup trials lacked a single-agent fluorouracil study arm. In fact, these trials compared the efficacy of fluorouracil plus levamisole with results in historical controls using different doses, schedules, and patient compliance [210].

Based on the encouraging antitumor activity in patients with advanced disease, several investigators reported their results using the combination of fluorouracil and leucovorin in the adjuvant setting. Results of a NSABP C-03 adjuvant colon cancer trial comparing fluorouracil plus leucovorin to MOF (semustine, vincristine, and fluorouracil) suggest that postoperative fluorouracil plus leucovorin results in a 30% reduction in the risk of developing treatment failure and a 32% reduction in mortality compared with patients treated with MOF [211]. This combination also significantly prolongs disease-free and overall survivals [211] based on results 3 years after surgery.

Preliminary results from other studies have also suggested benefits of fluorouracil plus leucovorin in the adjuvant treatment of colon carcinomas [211-213]. Recently, The International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators analyzed the role of adjuvant fluorouracil plus leucovorin for stage II and stage III colon cancer compared with surgery only [213]. These investigators independently undertook three randomized trials done in Italy, Canada, and France and pooled the data for analysis. The dosage was 370 to 400 mg/m² fluorouracil plus 200 mg/m² folinic acid intravenously for 5 days every 28 days for a total of 6 cycles. A total of 1,493 patients were eligible for analysis. The treatment arm showed significant reductions in mortality (by 22%; 95% CI, 3–38; P = . 029) and relapse (by 35%; 95% CI, 22–46; P = .0001). The 3-year relapse-free survival and overall survival rates increased from 62% to 71% and from 78% to 83%, respectively. Toxicity was mild, with less than 3% of the patients experiencing grade 4 toxicity.

Future adjuvant therapy trials for colorectal cancer should determine whether perioperative chemotherapy has a positive effect on survival, the optimal duration of treatment (6 vs 12 months), better chemo-inmunotherapy (ie, the role of alpha interferon [IFN-alfa], high-dose levamisole, leucovorin, combination fluorouracil-leucovorin-levamisole), and the role of adjuvant treatment in stage II disease (Table 3). Currently active cooperative group trials are comparing various combinations of fluorouracil, folinic acid, levamisole, and IFN [214].

Portal Vein Infusion: The liver is the sole site of recurrence in 25% of patients who ultimately develop metastatic colorectal carcinoma. Micrometastatic hepatic disease derives its vascular supply from the portal vein, and delivery of chemotherapeutic agents directly by this route is being investigated. Taylor and associates randomized 244 patients to receive portal vein infusion of fluorouracil and heparin or observation immediately after resection of Dukes' stage A, B, or C colon or rectal tumors [215-216]. The mean duration of follow-up was more than 4 years, and a significant survival advantage and decrease in incidence of liver metastases were observed in treated patients with stage B colon and stage C rectal carcinomas. The 5-year overall survival rates were 77.8% and 57.5% for the treatment and control arms, respectively (P = .002). In a study by the Swiss Group for Clinical Cancer Research (SAKK), 469 patients with Dukes'stage A, B, or C colon or rectal carcinoma were randomly assigned to receive portal vein infusion with fluorouracil, mitomycin (Mutamycin), and heparin or observation following curative resection [217-218]. With a median follow-up of 8 years, the adjuvant therapy arm had a 21% reduction in the risk of recurrence (hazards ratio, .79; 95% CI, .62–1) and a 26% reduction in the risk of death (hazards ratio, .74; 95% CI .57–.97; P = .026). The authors concluded that part of the benefit might result from the systemic effects of the intraportal chemotherapy; in fact, disease recurrence was reduced not only in the liver but also in extrahepatic sites. In contrast, randomized trials conducted by the NCCTG and Mayo Clinic failed to observe a benefit from portal vein infusion of fluorouracil and heparin [219]. These trials included 224 patients with Dukes'stage B2 or C colorectal cancer. The median follow-up was 5.5 years, and the incidence of liver metastases was similar in each group. The 5-year overall survival rate was identical in the treatment and control arms (68%, P = .61).

An NSABP trial randomized 901 eligible Dukes' stage A, B, or C colon cancer patients to receive either portal vein administration of fluorouracil and heparin or no adjuvant therapy [220]. There was a disease-free survival advantage at 4 years for the treatment group (74% vs 64%, P = .02). However, the trial failed to show a reduction in hepatic metastases as the first recurrence in the treated patients. The 4-year overall survival rates were 81% and 73% for the treatment and control arms, respectively (P = .07).

Fielding et al randomized 398 colorectal cancer patients to receive portal vein infusion of fluorouracil and heparin, heparin alone during curative resection and for 7 days thereafter, or resection alone [221]. They found neither reduction in the incidence of liver metastasis nor an increase in overall survival in either active treatment arm. Patients who underwent resection of Dukes' stage C colon tumors and received intraportal infusion of fluorouracil plus heparin demonstrated a significant (P < .03) survival advantage of approximately 16% compared with surgery-only controls.

Results of clinical trials of adjuvant portal vein infusion of chemotherapy for colorectal tumors thus have not consistently shown a benefit for this approach, and it is not recommended outside of clinical research trials.

Hepatic Arterial Infusion (HAI): Adjuvant HAI was evaluated in a single phase II study to administer three courses of floxuridine and mitomycin. Of 38 patients, 50% were alive and free of disease 8 years later [222]. However, HAI has not been compared with less toxic and less expensive delivery approaches such as systemic treatment and should not be recommended outside the context of a clinical trial.

Tumor Vaccine: Autologous and surrogate vaccines also have been utilized as adjuvant therapy for colorectal tumors. Hoover and coworkers randomly assigned 80 patients with Dukes' stage B2 or C colon or rectal carcinomas to receive either vaccination with BCG plus irradiated autologous tumor cells or observation [223-224]. Survival benefits were initially observed in immunized patients [223], but a recent analysis of the control arm has shown similar survival [224]. Further follow-up is needed to reach conclusions about disease-free or overall survival. An Eastern Cooperative Oncology Group (ECOG) trial is currently accruing patients for this purpose.

The major concerns about this treatment modality are that patients must be identified prospectively and that fresh tumor cells must be processed according to specific stringent laboratory guidelines.

Monoclonal Antibodies (MoAbs): A German group [225] evaluated the effect of MoAbs used as adjuvant therapy for resected colorectal cancer in 189 patients with stage III disease who were randomly assigned to either a MoAb treatment arm or a control arm. The MoAb used was 17-1 A, a murine Ig G2A against a cell-surface glycoprotein (adhesion molecule) expressed in malignant and normal epithelial cells. With a median follow-up of 5 years, MoAb therapy reduced the death rate by 30% (P = .05) and the recurrence rate by 27% (P = .05). The toxicity was mild (gastrointestinal and constitutional symptoms).

Adjuvant Therapy for Rectal Cancer

Although some of the factors and issues involved in adjuvant therapy for colon cancer apply also to such therapy for rectal cancer, there are some differences.

• Attaining a tumor-free surgical margin is more difficult in rectal cancers, leading to a higher incidence of local-regional relapses.
• Radiation therapy is a mainstay of treatment in rectal cancer but not in colon cancer.
• Adjuvant therapy for rectal tumors has produced an advantage in stage II and III disease, while such therapy for colon tumors has been advantageous only in stage III disease.
• The standard adjuvant therapy for rectal cancer is fluorouracil given intravenously (IV) by bolus in 2 monthly cycles before and 2 after the radiation therapy (sandwich schedule). Protracted-infusion fluorouracil is given during pelvic irradiation [226-227].

Local recurrence alone or in combination with distant metastases has occurred in 20% to 87% of rectal carcinoma patients in various trials [228-232]. The presence of nodal metastases and deep bowel wall penetration are significant risk factors for local-regional failure. In the absence of nodal metastases, the rate of local recurrence may be as low as 5% to 10% for stage I rectal cancer and 25% to 30% for stage II tumors. In stage III disease, the incidence of pelvic failure increases to 50% or more.

Adjuvant radiation therapy has been used to control the local-regional recurrence of rectal tumors. Preoperative radiation therapy has been demonstrated to reduce local tumor recurrence, albeit without affecting overall survival, in patients with stage II or III rectal cancer [233-234]. An improvement in local control also was observed with postoperative irradiation, but, again, no benefit with regard to disease-free or overall survival was demonstrated [235].

Chemotherapy, alone or combined with radiation therapy, has been prospectively compared with surgical resection alone and with radiation therapy alone in patients with stage II or III rectal cancer (Table 3). The Gastrointestinal Tumor Study Group (GITSG) [231,236] and NCCTG [99] trials have demonstrated that the postsurgical combination of fluorouracil-based chemotherapy and pelvic irradiation reduces local-regional failures [231,237] and increases disease-free [231,237] and overall survivals [236-237] compared with pelvic irradiation or postsurgical chemotherapy alone or with observation following surgery. The NSABP trial of 555 patients with stage II or III rectal carcinoma randomly assigned patients to receive chemotherapy (fluorouracil, methyl-CCNU, and vincristine), irradiation, or observation following curative resection [232]. Disease-free (P = .006) and overall (P = .05) survival advantages were reported in the group that received chemotherapy compared with the group treated by surgery alone. However, this benefit was observed only in men younger than 65 years of age. The rate of local-regional recurrence also was lower in the group that received postoperative radiation than in the control group (16% vs 25%, P = .06).

A combination of fluorouracil chemotherapy and radiation appears to be the best adjuvant therapy for patients with stage II or III rectal cancer [226]. O'Connell et al randomly assigned 660 stage II and III rectal cancer patients to receive bolus injections or protracted venous infusions of fluorouracil during postoperative radiation therapy to the pelvis. The patients also received semustine plus fluorouracil or fluorouracil alone at a higher dose both before and after the radiation. Patients who received the protracted fluorouracil treatment had a significantly increased time to relapse (P = .01) and improvement in survival (P = .005). No benefit was noted with the addition of semustine [226].

The most effective combination of drug, particularly the role of the leucovorin and/or levamisole added to fluorouracil, the optimal mode of administration, and the sequence of radiation and chemotherapy still need to be determined. Ongoing multi-institutional trials of therapy for rectal cancer should help clarify some of these issues [238-240].

Therapy for Advanced Colorectal Cancer

The most effective single agent in the management of advanced colorectal carcinoma is fluorouracil. Recent trials have reported a 10% to 15% objective response rate with standard intermittent intravenous administration of fluorouracil for metastatic colorectal disease [240-242]. Fluorouracil has been administered using various dosage schedules and methods, including both bolus and short-term, continuous intravenous infusion and protracted intravenous infusion via portable, ambulatory infusion pumps. Response rates have increased with increasing doses of fluorouracil [243] and prolonged infusion [244], but fluorouracil alone has failed to improve survival rates in patients with metastatic colorectal disease.

Chloroethylnitrosoureas, mitomycin, and the newly identified agents tauromustine [245], doxifluridine [246], aminothiadiazole [247], 4-deoxydoxorubicin [248], nimustine [249], CPT-11, UFT (uracil-ftorafur)[251], oxaliplatin [250], and Tomudex (ZD 1694) also have shown some activity against advanced colorectal tumors.

CPT-11(Irinotecan) [251a], a semisynthetic derivative of camptothecin that is converted by cellular carboxylestearases to its principal metabolite (SN-38), has powerful topoisomerase I-inhibitory activity [107] and shows promise, particularly in patients with fluorouracil-refractory stage IV disease. Shimada et al showed that 25% of previously treated patients and 36% of patients without prior therapy responded to this drug [252]. The 25% response rate has been reproduced by investigators at San Antonio [253], although other investigators have reported lower response rates (eg, 16%)[254]. CPT-11 also has been evaluated as first-line therapy for patients with advanced colorectal cancer and achieved a response rate of 33% (all partial responses)(The Upjohn Company, unpublished data, 1994).

Given its good activity in this setting, CPT-11 is being evaluated in combination with fluorouracil and leucovorin in patients with advanced colorectal cancer. A recently reported study from Japan [255] discouraged to some extent the simultaneous administration of fluorouracil and CPT-11. As stated above, for optimal antitumor action, CPT-11 needs to be converted to its metabolite SN-38 by the enzyme carboxylestearase. SN-38 is almost 1,000 times more effective in inhibiting topoisomerase I than CPT-11 is. The Japanese investigators suggested that a metabolite of fluorouracil may inhibit carboxylestearase and, therefore, reduce the area under the curve of SN-38. An ongoing multicentric study is evaluating the combination of fluorouracil plus folinic acid with CPT-11 given in an alternating schedule.

UFT, an oral combination of uracil and ftorafur, also has shown some activity against advanced colorectal cancer. Ftorafur is converted to fluorouracil in the liver, and this may lead to a slow but sustained level of fluorouracil in tumor cells. Uracil seems to inhibit the catabolism of fluorouracil, allowing higher fluorouracil levels in the tissues. Pazdur et al tested UFT plus oral leucovorin in stage IV colorectal cancer patients and reported a response rate of 42% [246]. A phase III trial comparing UFT plus oral leucovorin with fluorouracil plus folinic acid has recently begun.

Tomudex (ZD 1694) is a quinazoline folate analog that acts as a pure thymidylate synthase inhibitor. A European phase II trial of this drug reported a 26% response rate in stage IV colorectal cancer patients. The advantage of ZD 1694 over fluorouracil plus leucovorin is the more convenient schedule of the former (one intravenous dose every 21 days compared with a daily × 5 schedule every 28 days for fluorouracil and folinic acid) and possibly its decreased incidence of severe toxicity [257]. Two phase III studies (one in Europe and one in the United States) comparing Tomudex with fluorouracil plus folinic acid in patients with stage IV colorectal cancer recently have been completed.

Oxaliplatin showed a 10% response rate in patients who failed to respond to fluorouracil and folinic acid [250].

Doxorubicin, epirubicin, etoposide, carboplatin, cyclophosphamide, methotrexate, topotecan, CI 980, paclitaxel, docetaxel, and cisplatin are inactive against colorectal adenocarcinomas.

Various combination chemotherapy regimens, including fluorouracil, methyl-CCNU, and vincristine (MOF)[258]; MOF plus streptozocin [259]; cisplatin plus fluorouracil [260]; and methotrexate [261] or N-phosphonacetyl- l-aspartate (PALA)[259] followed by fluorouracil have failed to provide a survival advantage over single-agent fluorouracil.

The combination of folinic acid plus fluorouracil, in various dosages and treatment schedules, has produced higher response rates than fluorouracil alone in previously untreated patients with advanced colorectal cancers (Table 4). Although survival benefits were originally observed in two of these trials [262-263], a recent update of one of these trials comparing fluorouracil plus leucovorin with fluorouracil alone in advanced colorectal carcinoma showed that the survival advantages initially seen were not maintained [263]. The advanced colorectal cancer meta-analysis project included nine randomized trials that compare fluorouracil alone with fluorouracil plus intravenous leucovorin [264]. The investigators observed a highly significant benefit favoring fluorouracil plus leucovorin over single-agent fluorouracil in terms of tumor response rate but no improvement in overall survival. Gastrointestinal effects such as diarrhea and mucositis, rather than myelosuppression, are the dose-limiting toxicities of folinic acid and fluorouracil combinations [265].

In a prospective randomized trial, Buroker et al showed that a regimen of fluorouracil, 425 mg/m², plus folinic acid, 20 mg/m², daily × 5 every 4 to 5 weeks is therapeutically equally effective and has a superior therapeutic index compared with weekly fluorouracil, 600 mg/m², plus folinic acid, 500 mg/m², weekly for 6 weeks with courses repeated every 8 weeks [266].

Although the modulation of fluorouracil by folinic acid has been suggested as a standard of care for patients with metastatic colorectal carcinoma, a recently published Southwest Oncology Group (SWOG) study has noted lower response rates for this combination than had previously been reported [267]. A study to assess the efficacy and toxicity of seven fluorouracil regimens randomized more than 600 stage IV colorectal cancer patients to receive one of the following: fluorouracil IV push; fluorouracil IV push plus low-dose leucovorin; fluorouracil IV push plus high-dose leucovorin; fluorouracil continuous infusion; fluorouracil continuous infusion plus low-dose leucovorin; fluorouracil 24-hour infusion; or fluorouracil 24-hour infusion plus PALA. No regimen produced a higher response rate and/or survival rate than fluorouracil alone. Response rates ranged between 15% and 29%, with a median survival for the entire group of 14 months. Survival ratios showed a positive trend favoring the unmodulated infusion regimens; meanwhile, high-grade toxic effects (neutropenia and diarrhea) were more frequently observed in the fluorouracil bolus arms. The single-agent infusion regimens demonstrated the best results, with a favorable toxicity profile and a 2-month longer survival duration than fluorouracil given by bolus [267].

Fluorouracil in conjunction with recombinant IFN-alfa also has also been utilized in the treatment of advanced colorectal carcinoma. The initial trial of this combination suggested an overall response rate in excess of 50% [268], but subsequent phase II and III studies have reported lower response rates ranging from 19% to 30% [269-272]. A recent multinational randomized trial by the Corfu-A Study Group compared fluorouracil plus IFN-alfa with fluorouracil plus leucovorin in 496 patients with advanced colorectal cancer and reported respective response rates of 21% and 18% [270]. The overall median survival was around 11 months in both treatment arms, but the toxicity profiles differed. Constitutional symptoms and neutropenia were more frequent and severe in the fluorouracil plus IFN-alfa arm, and gastrointestinal toxicity was worse with the fluorouracil plus leucovorin combination. Remarkably, more patients interrupted treatment because of toxicity with fluorouracil plus IFN-alfa with fluorouracil plus leucovorin [270]. Similar results were reported in another recently published phase III study by the Royal Marsden Hospital comparing fluorouracil plus leucovorin with fluorouracil plus IFN-alfa in advanced colorectal cancer patients [272].

Renewed interest in regional delivery of floxuridine into the liver has followed the introduction of effective implantable infusion pumps. These pumps allow delivery of higher concentrations of chemotherapeutic agents directly into the hepatic artery, the blood supply of most hepatic metastases. Using this delivery method, these higher concentrations of drug (floxuridine is the most frequently used) result in more frequent responses in the liver than achieved with systemic chemotherapy [273-277], although toxicity (occasionally irreversible) to the liver and bile ducts is common and gastrointestinal bleeding is possible [278]. Investigators from Memorial Sloan-Kettering Cancer Center studied 62 patients with liver metastases from colorectal cancer, of whom 33 had received prior chemotherapy. In this study, patients were treated with hepatic arterial floxuridine, leucovorin, and dexamethasone, which produced a response rate of 78%; the addition of dexamethasone significantly reduced the incidence of biliary toxicity [279]. Only two randomized trials compared systemic chemotherapy with intrahepatic arterial infusion of chemotherapy, and no differences in survival between the two treatment groups were observed [276-277]. Moreover, hepatic chemotherapy is costly, cumbersome, and associated with gastroduodenal mucosal ulceration hepatitis and sclerosing cholangitis. Thus, there is so far no evidence that this method results in survival improvement in patients with liver metastases from colorectal cancer, and this delivery method should not be used outside the context of a clinical trial.

Laser photoablation also is gaining popularity for the temporary relief of obstructive rectal cancer, especially in the presence of distant metastases or when colostomy is not feasible because of comorbidity.

Conclusions

Fluorouracil and levamisole have produced disease-free and overall survival advantages in patients with stage III colon carcinoma. Chemotherapy combined with pelvic irradiation also has proven beneficial in stage II and III rectal carcinoma patients. Nevertheless, the development of new chemotherapeutic agents or new combinations of existing ones is necessary to further reduce the mortality from colorectal cancer.

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