103

ADENOCARCINOMA OF THE COLON AND RECTUM
HOWARD W. BRUCKNER, MD JOHN PITRELLI, MD MARNIN MERRICK, MD

Cancer of the colon and rectum is now the second most common cause of deaths from cancer in the United States. A decline in both incidence and mortality is in progress.1–3 This change is most marked among women and those younger than 55 years of age in both sexes.2,3 Advances in diagnostic and therapeutic colonoscopy, in multimodal adjuvant primary treatment of colorectal cancer, and, occasionally, even curative success with resection and supplementary therapy in treating both regional and distant tumor recurrence4–6 all may have played roles in bringing about the continuing decline in mortality. Broader application of early diagnosis of the premalignant and malignant lesion by systematic endoscopy and removal and adjuvant multimodal management for high-risk patients after primary surgical treatment hold reasonable promise of producing additional benefits. Adjuvant therapy for stage III colon cancer and stage II–III rectal cancer has proven results.6–9 It is cost-effective. Age is not a contraindication to adjuvant therapy. In addition to leucovorin (LV)-fluorouracil (FV) for resected colon cancer and 5-FU radiotherapy for resected rectal cancer, murine monoclonal antibody 17-1A and FU prolonged infusion with radiotherapy are effective options with prospects for further application.10,11 Research will probably define the high-risk stage II colon cancer patient who may also benefit from adjuvant therapy. The past decade has seen major advances in our understanding of the etiology of gastrointestinal (GI) epithelial transformation.12–16 Determination that the adenomatous polyp is the predominant premalignant phenotype for colorectal adenocarcinoma has allowed the epidemiologic study of polyp occurrence and progression, and it has begun to define methods of screening for and treating polyps as an early surrogate end point for the prevention of cancer.17,18 Major categories of genetic changes have been identified involving the acquisition of oncogenes and/or loss of cancer-suppressing genes. These occur in a complex, but predictable and orderly, progression from polyp formation to polyp growth, to polyp dysplasia, and, ultimately, if not removed, to overt carcinoma, not only in the polyposis group of hereditary cancers but in some of the sporadic colorectal neoplasms. Another kind of genetic tumor susceptibility also has been identified (i.e., replication error positivity) conferred by DNA instability in areas of tandem repeat nucleotides (i.e., microsatellites). This occurs in the group of hereditary nonpolyposis cancers and also in some sporadic colon cancers that share the same biologic phenotypes.13,14,19–22 Application of large-bowel screening using both tests for occult blood and periodic endoscopy in known genetic and age-defined highrisk groups gives hope for surgical endoscopic interruption of the carcinogenic process.23–25 Genetic and marker studies seek to define a population “at risk” for epithelial polyp initiation to justify regular colorectal mucosal surveillance to diagnose and remove polyps before they undergo transformation into carcinomas. Screening with and without geneticsguided selection is already cost-effective, as described below. PATHOLOGY Most cancers in the large bowel are adenocarcinomas.26 Twothirds of these cancers are located in the rectum, rectosigmoid, or sigmoid colon with the other third distributed in the remainder of the colon.26 Many of these cancers begin as adenomatous polyps. The progression from adenoma to carcinoma occurs by the sequential accumulation of genetic changes, which many consider to be the leading model for understanding carcinogenesis of a common tumor.27 Dysplasia, adenoma size (2 cm), extent of villous component, multiplicity,

and increasing age are factors associated with a higher potential for malignancy (Plate 21, Figs. 103.1, 103.2).18 It is now clear that multiple mechanisms and great clinical and molecular biologic heterogeneity characterize adenocarcinoma of the colon (see Fig. 6.8). There has been proximal migration in the occurrence of colon cancers. The change has in part been associated with a decrease in the proportion of rectal cancers. The reasons remain unknown. Clearly, early diagnosis is not practiced to an ideal extent, and endoscopic surgical intervention polypectomy is not the whole explanation. Ulcerative colitis has long been implicated as a predisposing condition for colon cancer,28 and increased risk is also seen in Crohn’s disease.29 Duration of disease (i.e., early age of onset) and stricture formation are associated with a higher incidence of dysplastic and subsequent malignant changes (Plate 21, Figs. 103.3, 103.4).29–31 No reliable screening tool or incipient molecular marker exists, however, despite the well-characterized genetic and molecular markers of changes associated with malignant transformation. Squamous carcinoma and adenosquamous carcinoma have been reported infrequently, either alone or metachronously with adenocarcinoma of the colon.32 Carcinoid tumors deriving from hindgut enterochromaffin tissue also uncommonly occur but, unlike foregut carcinoids, have not been reported to secrete vasoactive kinins or to be associated with the carcinoid syndrome. Rectal carcinoid can be highly virulent tumors.33 Some mixed tumors including adenocarcinoid tumors have endocrine biochemical features and possibly produce gastrin or other gastrointestinal hormones that are associated with a poor prognosis. Pseudomyxomas, sarcomas, and lymphomas, as well as tumors extending from the pelvic organs, stomach, and pancreas, all require diagnostic consideration. Although the appearance of adenocarcinoma tends to be straightforward, pathology review is essential for diagnosis, characterization, and staging, as well as for quality control of endoscopic, laparoscopic, and classic surgery. Therapeutic decisions and investigations also increasingly benefit from the optimum information provided by pathology review. STAGING Several leading organizations and specialty groups have recommended that the TNM staging system be applied uniformly to patients with colorectal cancer.34 Unlike other solid tumor TNM classifications, the T in colon and rectal cancer does not relate to the size of the lesion but rather to the depth of penetration by the tumor into or through the bowel wall (Plate 21, Fig. 103.5). The actual TNM classification and its relationship to the most popular modification of the Dukes system (i.e., the Astler/Coller modification of Dukes/Kirklin) are summarized in Table 103.1. The N3 classification is not useful in practice, and external illiac lymph nodes are considered M1 disease. Precise details, millimeters of penetration or invasion, and number of nodes involved and examined allow for useful refinement of prognostication but are not as yet incorporated in formal staging systems. EPIDEMIOLOGY OF COLORECTAL CANCER CANCER STATISTICS The estimated number of new cases of cancer of the colon and rectum for 2000 is 130,200.1 Cancer of the colon and rectum will account for 27,800 male (23,100 colon, 4,700 rectum) and 28,500 female (24,600 colon, 3,900 rectum) deaths.1 The decline in the mortality rate was calculated at 15.4% for the period of 1987 to 1991 compared with the period of 1975 to 1979,2 whereas the actual incidence of colon cancer declined by only 6.6% in the same period.2,35 The decline continues. Overall, 62% of all patients survive, but only 52% of African-Americans survive. Slightly more than onethird of new cases are diagnosed in the localized state, with estimated survival at 5 years upward of 90% for stage I lesions and greater than 70% for stage II lesions. A similar number of cases are diagnosed with regional nodal involvement. Survival falls as depth of penetration into pericolic tissues and serosal involvement increases. Survival falls as tumor grade and age increase; also, males do slightly worse. These are usually independent variables in the prognostic equation. Survival

Table 103.1.

Carcinoma of the Colorectum: Stage Classification and Stage Grouping (AJCC, UICC, Dukes, Astler-Coller)
AJCC 1982 UICC 1978 (3rd ed) Dukes (1932,1935)* Astler-Coller†

Stage 0 Carcinoma in situ Tis, NO,MO Stage I 1A Tumor confined to mucosa or submucosa T1, NO, MO 1B Tumor involves muscularis propria but not beyond T2, NO, MO Stage II Involvement of all layers of bowel wall with or without invasion of immediately adjacent structures T3, NO, MO Stage III Any degree of bowel wall involvement with regional node metastasis Any T, N1-N3; MO Extends beyond contiguous tissue or immediately adjacent organs with no regional lymph node metastasis T4, NO, MO Stage IV Any invasion of bowel wall with or without regional lymph node metastasis but with evidence of distant metastasis Any T, any N, M1

Stage 0 Tis, NO, MO Stage I 1A T1,NO, MO 1B T2, NO, MO Stage II T3, T4 ,NO, MO (T3a with fistula) (T3b without fistula) Stage III Any T, N1, MO A

Stage 0 0 Stage I

A A B

A B1 Stage II B2

C (1932) C1 (1935) C2 (1935)

Stage III C1 C2

Stage IV Any T, any N, M1

Type 4 (so-called D)

Stage IV D

*Dukes: A = Limited to bowel wall; B = spread to extramural tissue; C = involvement of regional nodes (C1: near primary lesion; C2: proximal node involved at point of ligation); type 4 (so-called D) = distant metastasis. † Astler-Coller: A = Limited to mucosa; B1 = same as AJCC stage 1B (T2a): B2 = same as AJCC Stage 1B (T2b); C1 = limited to wall with involved nodes; C2 = through all layers of wall with involved nodes. From American Joint Committee on Cancer Manual for Staging of Cancer, 2nd ed. Hagerstown, MD: Lippincott, 1983. AJCC—American Joint Committee on Cancer.

falls sharply as the number of involved nodes increases. All but single microscopically involved, grossly normal nodes, severely reduces survival chances. The remaining patients are initially diagnosed with distant (i.e., metastatic) disease, for whom the 5-year survival is 10% or less.11 Survival with metastatic disease reflects, in large part, therapeutic intervention. In the United States, the lifetime risk of developing invasive cancer is 1 in 18 (5.64%) for men and 1 in 18 (5,55%) for women.1 The risk is progressive with age and most significant for those over 60 years of age; for those aged 40 to 59 years, the risk is much lower (1 in 108 for men, 1 in 137 for women).1 Women have a lower incidence than men, particularly in the age group under 59 years. A beneficial inhibitory role for female hormones in colon carcinogenesis has been postulated, and the use of hormone replacement therapy in postmenopausal women has been shown to reduce by approximately 50% (relative risk [RR] = 0.54) the risk of colon cancer for up to 10 years after the cessation of treatment.36–38 Early multiparity also may be protective. DIET AND COLORECTAL CANCER Fat and Fiber. Three decades ago, hypotheses were formulated postulating a role of high dietary fat39 in the etiology of colorectal cancer and the protective role of dietary fiber.40 Evidence continues to accumulate that supports these concepts.41,42 Nevertheless, justifiable controversies abound regarding the relative contributions of different kinds of fat 41,43 and fiber,44,45 the specific mechanisms of their effects,41,46,47 and, most of all, the feasibility and value of restructuring dietary patterns.48–52 Skepticism about dietary intervention for cancer prevention should be tempered by the potential for other benefits associated with some of these diets. Diet should not be evaluated in the context of a single end point. Methods used to study the impact of dietary factors on the genesis of colorectal cancer include comparisons of migrant groups showing, for example, lower rates of colon cancer in Chinese native to Asia compared with those born in America; study of special populations with defined dietary patterns, such as Seventh-Day Adventists (i.e., vegetarians) who have lower rates than the general population; and

evaluation of time trends (i.e., reflecting changes in dietary patterns over time) in various regions.53,54 Problems inherent in such studies are the imperfect recall of the subjects under study as well as their inability to quantify components of their diet accurately and scientifically. These difficulties are compounded because the putative causative diet antedated the cancer by many years.55 Also, diet and chemoprevention may have a different impact, or degree of impact, on the risk of sporadic and familial cancers. Although fat intake was early linked to the incidence of colorectal cancer,39 subsequent studies also highlighted total caloric intake.41,52,56,57 Furthermore, a distinction has been made between saturated fat from animal sources, which appeared to enhance the incidence of cancer; vegetable oils, which had no effect; and the highly polyunsaturated omega-3 containing fish oils, which seemed to have a protective effect.41,43,58 Burkitt showed that geographic differences in the incidence of colon cancer, among other malignant and nonmalignant diseases, could relate to differences in dietary fiber.46,50 The broad, inverse relationship between high fiber and low rates of colon cancer generally holds true. Subsequent studies found maximal protective effects associated with natural fibers, particularly of fruit and vegetable origin. There is some benefit from grain, but there is no benefit from artificial or synthetic fibers.44,45,57,59 Dietary composition affects the biochemical composition of fecal content, thereby altering the milieu for colonic mucosal cells and changing both the rate and pattern of their proliferation.41,46,47,60 Increased dietary fat may cause the secretion of increased amounts of secondary bile acids, deoxycholic acid, and lithocholic acid.41,47 Supporting evidence for this change in secretion comes from the higher fecal bile acid levels in high-risk compared with low-risk populations in multiple studies of different demographic groups over two decades.47 These bile acids have the potential to be tumor promoters or co-carcinogens.41,47 Alternatively, they may act as their sodium or potassium salts and raise intraluminal pH, which itself is postulated to be a factor in increased carcinogenic activity.46,47

1474 SECTION 29 / Neoplasms of the Alimentary Canal

Dietary fiber may reverse the adverse biochemical consequences that are generated by saturated fat and secondary bile acids by reducing fecal bile acid levels and reducing colonic pH,46,61 which speeds colon transit time,41,62,63 thus decreasing both the effective contact time between putative carcinogens in the fecal content and the colonic mucosa and the available time for gut microflora to act on fecal content to generate additional possible carcinogens. A direct role has been shown for saturated fatty acids in increasing the number of transformed foci in cultured cells that are transfected with a known oncogene, c-ras.63 Similarly, tissue levels of epidermal growth factor (EGF) have been shown to be reduced in rat colonic mucosa by a high-fiber diet.64 This polypeptide hormone, implicated in carcinogenesis on theoretical grounds, has been shown to influence the growth of both normal and cancerous cells, The elevated risk of colon cancer that is noted with obesity, low physical activity, high dietary intake of refined sugars, low dietary fiber intake, and low unsaturated-fat-to-saturated-fat ratio might conceivably be mediated by hyperinsulinemia.65 Caloric restriction by means of a one-third reduction in normally consumed food over a period of 12 weeks in obese subjects (i.e., 130% of ideal body weight) reduced rectal proliferation indices significantly: a 39% reduction in whole crypt labeling index and a 57% reduction in upper crypt labeling. These are probably end points evaluable for susceptibility to carcinogenesis.65 Carcinogens. Fecapentaenes are highly mutagenic ethers of glycerol and various unsaturated alcohols.47 These compounds are found more frequently in populations at high risk for colon cancer than in low-risk groups. They were shown to be derived from the action of Bacteroides species on fecal content and to be the source of the mutagenic activity of organic extracts of feces in the short-term Ames carcinogenic assay.47 Increased colon transit time because of a low-fiber, low-residue diet may predispose to such microfloral activity, resulting in higher levels of fecapentaenes.46,47 The frequently reported elevated risk of colon cancer from various meats has been attributed to the fat content, processing of meats for preservation, and compounds generated by frying and browning the meats.58,66–68 Fried or heavily browned meats contain a carcinogenic heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP).69,70 Varying racial incidence of colorectal cancer may relate to dietary preferences or to genetic variabilities in metabolic activation of procarcinogens.68,71–73 EFFECTS OF INORGANIC IONS Calcium. Dietary calcium may have a protective role, at least partly because of the conversion of fecal bile acids or free fatty acids from the diet to insoluble salts.47,61,74 These findings have not been uniform, however.75 A calcium dependent mechanism that is independent of fat in the diet but related to the cellular biochemical processes involved in proliferation may also be possible74–76 may involve vitamin D metabolism.77 Few of the studies evaluating dietary calcium supplementations over a short-term period (6 months and 1 year)78,79 have shown a positive effect in decreased size of the proliferative compartment in the colonic or change in the proliferative indices.78,79 Randomized studies are in conflict: half have shown a positive effect of calcium, and half have shown no effect.80 Unproven, but theoretically sound, development strategies call for supplementation earlier in life, longer trials, and standardization of study parameters. Potassium, Sodium, and Selenium. Geographic mappings of colorectal cancer rates in the United States show nearly identical distribution for cancers of the colon, rectum, and breast. Studies found significantly lower cancer rates in areas with ground water and soil that had high potassium concentrations.81 Large studies found that high sodium intake was a significant risk factor for rectal cancer in males and a high ratio of potassium-to-sodium intake was a protective factor in females both for colon and rectal cancer.82 Additional suggestive evidence includes the lower cancer rates seen in patients with diseases that are associated with high intracellular potassium (e.g., Addison’s, Parkinson’s, schizophrenia) and the higher cancer rates seen in aging and other conditions associated with low intracellular potassium (e.g., obesity, alcoholism, Crohn’s and Cushing’s diseases).82 Both these and newer studies suggest that any protection attributed to selenium is false.81,83,84

As diets rich in fiber from vegetables and grains inevitably also introduce potassium and possibly promote higher intracellular potassium, and because dietary fat has the opposite effect,81 the independent protective value of a high potassium-to-sodium ratio will continue to be a point of uncertainty. High vegetable intake consistently shows an inverse relationship with risk of colon cancer, and this may be a compound effect of increased soluble fiber, higher potassium intake, and the putative effects of antioxidants or anticarcinogens such as carotenoids, lycophenes, and folic acid.59,85,86 VEGETABLES Less than 50% of the U.S. population currently consumes the recommended five servings per day of fruits and vegetables and six servings of grains (Studies will examine the impact of high dietary fiber and low fat (<30% of total calories) on recurrence rate in patients who are known polyp formers.57 To maximize potential benefits, dietary changes should start as early in life as possible. A dietary change may be most applicable to the teenagers and young adults who seem devoted to fast food (high-fat hamburgers and French fries) and who momentarily are unconcerned about cancer. The applicability to individuals with a familial history of cancer is theoretically possible, but their biggest impact likely will be on the risk of sporadic cancer. Until further results are known, recommendations for colon cancer prevention should include regular, moderate physical activity; avoidance of obesity; caloric reduction in obese states; reduction of fat in the diet to less than 30% of total calories; high intake of grains, fruits, and vegetables; and no more than modest alcohol consumption.57,87 The possible role of synthetic vitamins and nonsteroidals is discussed below. ALCOHOL AND TOBACCO Current alcohol consumption of over two drinks per day and past alcohol consumption double the risk of colon cancer. In those men whose diets also were deficient in methionine and folate, RRs were increased by greater than three-fold.88,89 Abnormalities in methylation of DNA may be the responsible carcinogenic mechanism.88,89 Various reports relate tobacco use to polyp formation. A weak correlation with dose-response relationship exists for carcinoma.89,90 The same carcinogen found in fried meats, PhIP, also is found in tobacco smoke.89,91,92 OCCUPATION AND COLORECTAL CANCER Working in a brewery increased the risks of cancers originating in the rectum, esophagus, pancreas, and lung. Risk may correlate with higher levels of beer consumption.93 An increase in colon cancer was also reported for glass workers, particularly those working in the foundries with crystal glass.94 The mortality rate from colon and rectal cancer in a large cohort of automotive model and pattern makers was twice that of the general population. High-risk workers who did not participate in cancer screening programs suffered four times the mortality from colon cancer compared with the general population.95 Formaldehyde workers, particularly short-term workers and others exposed to particulate compounds, may have an increased incidence of colon cancer.96 Cancer screening assumes increased importance for individuals in these occupations and is not limited to colon cancer. GENETICS OF COLORECTAL CANCER The estimated proportion of colorectal cancers that is attributable to heritable causes has varied between 5 and 20%.97–100 This group of patients has proved to be of great significance to the epidemiologist, the basic scientist, and the clinician. Longitudinal studies have provided information about patterns of inheritance,97,98,101–103 sequence of cancer development from adenomas, and genetic abnormalities leading to cancer. They also have identified a group in which clinical efforts toward early detection can be most rewarding.100,104 The inherited syndromes that predispose the individual for colon cancer may be divided into the polyposis and the nonpolyposis types.100,105 The polyposis type usually manifests at an early age98 and includes familial adenomatous polyposis (FAP), Gardner’s syndrome, Peutz-Jeghers syndrome (all of which display autosomal dominant inheritance), Turcot’s syndrome (which now is known to be genotypically diverse and has been described with both autosomal recessive and autosomal dominant inheritance),106 and juvenile polyposis.97,100,105,106 The polyps may be adenomatous or hamartomas. Adenomatous polyposis occurs in FAP as well as Gardner’s and Turcot’s syndromes,

and hamartomatous polyposis occurs in Peutz-Jeghers and juvenile polyposis.105 Special features include the triad of bone tumors (i.e., osteomas), soft-tissue tumors (i.e., desmoid tumors), and colon polyps (including upper GI polyps) in Gardner’s syndrome.100,105 Congenital hypertrophy of the retinal pigment also has been described in Gardner’s syndrome and in the majority with FAP, thus mandating an eye examination in the proband and the kindred.107 There are many different defects in the APC genes and thus many variant presentations, such as age of onset, heavy involvement of rectum (preventing rectum sparing surgery), and severe Gardner’s syndrome. Surveillance should begin by age 15. Due to the variable defects, DNA assays are not totally predictive, and peripheral blood assays are not available clinically. Truncating assays and denaturing gradient gel electrophoresis are only suitable for evaluations performed by expert users only. Approximately one-third of patients with Gardner’s syndrome do not give a family history of the abnormalities, suggesting a new mutation. Peutz syndrome is associated with mucocutaneous pigmentation.100,105 Both syndromes are infrequent. Reports of familial clustering (two or more first-degree relatives) are common.97,98,100–102 Detailed study of such kindred groups has identified a group of hereditary colonic cancers that are not associated with multiple colonic polyps.101,102,108 Now known as hereditary nonpolyposis colorectal cancer (HNPCC), this entity is divided into a sitespecific type (Lynch syndrome I) and a cancer family syndrome type (Lynch syndrome II). Lynch syndrome I is characterized by autosomal dominant inheritance, early age of onset, predilection to the proximal colon (making sigmoidoscopy an ineffective screening tool), and multiple primary metachronous and synchronous colon cancers.97,101,102,109 In addition to all of the characteristics of syndrome I, Lynch syndrome II includes multiple primary adenocarcinomas in the stomach, colon, endometrium, and ovary as well as adenocarcinoma of the small bowel.97,102,103,109,110 To facilitate the study of these clusters, the International Collaborative Group formulated the Amsterdam criteria: (1) three or more relatives with biopsy verified colorectal cancer, one of whom is a firstdegree relative of the other two; (2) at least two generations involved; and (3) one or more cases diagnosed in a patient younger than 50 years. These are considered to be essential criteria for the diagnosis of HNPCC.111 Their stringency certainly may exclude valid families. This stringency facilitates uniformity between centers and molecular biologic research that is focused on strictly defined familial clusters. Biologically slow disease and improved stage-specific survival compared to the conventional patient may be features of the Lynch syndromes.111 To institute early screening, clinicians may use more eclectic standards than the Amsterdam criteria. Multiple other cancers, including those of endometrium, ovary, stomach, small bowel, bile ducts, and bladder, suggest additional possible patients with Lynch syndrome II for intervention efforts. An association with breast cancer is problematic, at best uncertain. The presence of the Muir-Torre skin syndrome or a pattern of autosomal dominant transmission over several generations should promote a high index of suspicion, warranting an aggressive approach to screening and primary prevention.111 Only the most stringent clinical criteria for undertaking genetic testing are cost-effective, and even with ideal selection the yield only approaches 50%. GENETIC CHANGES IN COLORECTAL CANCER The somatic mutational origin of cancer implies that an alteration occurs in one or more critical genetic loci, leading to the expression of the transformed state or increased cell proliferation and eventually cancer.112,113 These genetic loci, which had a normal physiologic role in early cellular development and proliferation, and are ordinarily quiescent may then have excessive expression. Because of their potential to lead to cancer when they are altered by environmental factors or inherited mutation, they are termed oncogenes or, more correctly, proto-oncogenes.73,112,113 By itself, activation of a gene leading to increased proliferation (i.e., oncogene activation) may be insufficient to lead to a malignant neoplasm.113 A second genetic change involves loss of the normal regulatory controls of proliferation imposed by the product of a gene, loss of tumor suppression. The gene is termed an antioncogene or tumor suppressor gene.112 Loss or mutation of such a gene would, of neces-

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1475

sity, need to occur in both alleles of the gene and therefore could account for the sporadic and inherited forms of the same cancer.112 Thus, cancer can result from oncogene activation, tumor suppressor gene loss or inactivation, or both acting in concert. A third kind of genetic change recently has been described in connection with the HNPCC phenotype, involving microsatellite instability in the region of DNA repair genes. Alteration or mutation in these areas can predispose to the neoplastic state without (either) allelic loss or oncogene activation.13,14,19,20,114,115 A partial list of recognized genes that are involved in colon cancer and their chromosomes includes hMSH2 (2p16), hPMSI (2q31-33), hMLHI (3p21), APC (5q21), MCC (5q21) (role uncertain), hPMS2 (7p22), DRA (7q22-q31), Rb-1 (13q14) (role uncertain), TP53 (17p13), nm23 (17q22), DCC (18q21), Ras-K (12p), N(1p), H(11p), and c-myc (8q24). The proto-oncogene ras has a high frequency of point mutations in colorectal cancers diminishing its affinity for RAF, thus activating a tyrosine phosphorylation pathway and signal transduction.116,117 Evidence suggestive of tumor suppressor gene loss came from the discovery of allelic changes in chromosome 5 in patients with familial polyposis coli118 and in sporadic colon cancer.119 Other investigators have confirmed the allelic deletions of chromosome 5 in both the inherited and the sporadic forms of colorectal cancer.12,120 The deleted region encodes for a genetic locus, termed FAP,121 which behaves as a tumor suppressor gene.122,123 Loss or inactivation of both alleles is required to exert an effect.116 Similar allelic loss of the p53 locus on chromosome 17 and the DCC (deleted in colon cancer) gene on chromosome 18 also have been described.17,27 The normally functioning (wild-type) p53 gene product participates in many important cell-cycle functions, including interaction with DNA to control synthesis of proteins such as p21 that inhibit the cell cycle at the G1-S interface to permit DNA repair, cell differentiation, and programmed cell death (i.e., apoptosis). Loss of this apoptotic function, which normally prevents cells with excessively abnormal DNA from entering the replication cycle, could result in immortalization (i.e., malignant transformation) of the abnormal genome.123,124 All four genetic changes described earlier (i.e., ras gene mutation and allelic changes in chromosomes 5, 17, and 18) were found in a spectrum of tumor states, starting from dysplasia and small adenomas to large adenomas with and without foci of cancer and finally in resected carcinomas.12 Vogelstein and colleagues.12 found that changes accumulated in stepwise fashion. Changes in one or two genes were associated with polyps or early cancer; changes in up to all four loci were associated with manifest invasive cancer. The model is activation of the ras proto-oncogene (acting dominantly at the cellular level) plus hemi- and then homozygous loss of one or more tumor suppressor genes on chromosomes 5 (FAP), 17 (p53), and 18 (DCC), progressing in sequence ultimately to result in colorectal cancer. Additionally, allelic loss of chromosome 18q has independent and strong adverse prognostic impact on survival. Testing for such allelic loss, particularly in stage II colorectal cancer, may assist in identifying a good prognosis group (i.e., no allelic loss), whose survival is similar to that in stage I colon cancer, and a poor prognosis group (i.e., allelic loss present), whose survival is similar to that in stage III disease and who would presumptively benefit from timely and effective adjuvant therapy.125 It is not yet known, however, whether patients with allelic-loss tumors benefit from adjuvant chemotherapy . Deletion of the nm23-H1 gene (for nonmetastatic), another allele on chromosome 17 (at 17q21) distinct and separable from the p53 locus (at 17q13), may involve a late-acting suppressor gene. Its absence in surgical specimens of colon cancer predicted the early occurrence of distant metastases.126 Distinct genetic alterations of tumor DNA are found in regions within repeat elements such as (CA)n or (GT)n. These regions are known as microsatellites; they occur throughout the genome and are stably inherited.127 Differences have been detected between DNA in tumor tissue and that in normal tissue of the same individual because of amplification or deletions of segments of the repeat elements.127

A 16% reduction in the occurrence of colorectal cancer was observed (and a 34% reduction in the occurrence of prostate cancer) in those males who received α-tocopherol (i. 6..e.151. polyp regressions have also been described.111. it has been possible to alter the transformation properties by introducing the tumor suppressor APC gene. and might be. but at worst it would seem innocuous. the APC genotype (seen in FAP) and the mismatch repair gene “microsatellite instability” genotype (seen in HNPCC). In the area of gene therapy.20.133 and hPMS2. because full-blown neoplasia may take decades to occur. which may contain other prevention molecules as yet unrecognized.g. Antioxidants.138. and colon. such as N-acetyl-L-cysteine.127 Close linkage to two microsatellite areas on chromosomes 2128 and 318 has been documented in colorectal cancer that is associated with HNPCC.131. however.142 In contrast. Other vitamins may also be beneficial. the potential exists to reverse some significant molecular and genomic events leading to development of the neoplastic state. and (3) determination of suitable intermediate clinical end points.153.114. may be the most responsive to acute chemotherapy. repeated DNA sequences not associated with loss of heterozygosity of chromosome 2. controlled clinical trials did not show a statistically significant advantage in susceptible populations.127 Microsatellite instability is found in areas involving genes for DNA repair and indicates defective repair of the genome.21 The biologic behavior of these genetically similar sporadic tumors was consistent with the familial type.148. clinical trials can proceed in suitable populations with elevated susceptibility to the cancer under study.141. can result in the syndrome of multiple colon adenomas and brain tumor.130 hMSH2.136 Two large prospective. A mouse model exhibits an autosomally dominant inherited predisposition to multiple intestinal neoplasia (Min). It is not known if the high-risk. regular use of aspirin (at least 16 days a month for 1 year) was associated with a 40% reduction in the risk of dying from colon cancer.148 Spontaneous.157 The degree and limits of the specific beneficial effects of NSAIDs and cyclooxygenase-2 (COX-2) inhibitors on the occurrence of cancer and on survival remain subjects for investigation. but doses and duration needed to be four to six tablets per week for at least 10 years. They are even inconclusive in patients with high-risk ulcerative colitis where the Tn. The mechanism of action is complex.152 Controlled population studies indicate that a benefit from aspirin and NSAIDs (but not acetaminophen) does exist. and ras markers supplement the finding of severe dysplasia. Similar genetic changes have also been seen in 13% of sporadic cancers.147 and sulindac has induced regression of large bowel polyps in patients with FAP. and completely suppress their ability to form tumors in athymic nude mice.e. which. however. The first randomized trial failed the recognition of obvious balancing risks. and proof of clinical benefit for wide use is inconclusive. Attempts to define a target group should be approached with caution (because of the continued failure to demonstrate a strong association between morphology. liver.140 reduce fecapentaene production.14.111 Awareness of the two different causative genotypes in Turcot’s syndrome should direct screening efforts for additional cancers in the proband and the kindred.153 The Nurses’ Health Study also showed risk reduction by regular use of aspirin. Microsatellite instability as an alternative genetic mechanism leading to neoplasia distinct from either oncogene activation or tumor suppressor gene loss was shown to correlate significantly with proximal colon location. Some multivitamin prevention studies suggest that folates may be operative in chemoprevention. p53. Although none of these tests has more than a 50 to 60% sensitivity. high-proliferative tumors. restitution of the suppressor gene loci) can revert the morphology of the cells. such as piroxicam. In cultured human colon carcinoma cells. and recognition that chemoprevention is ideally multifactorial has prevented clear recommendation for chemoprevention.106.1476 SECTION 29 / Neoplasms of the Alimentary Canal The hypothesis is that these tumors are associated with a genomic instability that may be pronounced at the microsatellites.. increased patient survival. there was an adverse increase in lung cancer in smokers.15 Data show germline alterations in short. Nonsteroidal Anti-inflammatory Drugs.139 (2) determination of evaluable biomarkers of carcinogenesis. The study of ras protein in fecal material or endoscopy effluent may prove to be useful should the methodology become commercially economical. the introduction of normal chromosome 5 or 18 (i. Antioxidants are considered to be agents suitable for chemoprevention trials because they block oxidative damage to DNA resulting from the carcinogen-induced generation of oxygenfree radicals.1 years). even flow cytometry and outcome in rectal cancer). The murine homolog of the APC gene (mAPC) has been found tightly linked to the Min locus and is mutated in the affected lineage. increase the number of early detections where colonoscopy and traditional evaluation of pathologic morphology now fails. an important working hypothesis. with development. they may.133 The combination of genomic instability with loss of normal reparative mechanisms is thought to result in development of the neoplastic state..136 Vitamins C and E have been shown to inhibit nitrosamine formation. have been shown to inhibit experimental colon tumors. vitamin E) compared with those who did not. another prevention study involved randomized daily dietary supplementation of either α-tocopherol (50 mg/d) and/or β-carotene (20 mg/d) versus placebo to male smokers aged 50 to 69 years over a period of 5 to 8 years (mean. but findings are neither consistant nor ideally tested. Indomethacin was shown to reduce the number of experimental tumors induced in rats by a nitrosamine compound.136–138 Essential to the evaluation of potential chemopreventive agents is (1) determination of suitable (safe and effective) doses of agents (e. will require two successful controlled clinical trials in populations susceptible to colon cancer. as described in Turcot’s syndrome.143 This alone is not sufficient to recommend systematic use. the absence of poor prognostic markers makes adjuvant therapy not cost-effective.11. Other antioxidants.146 Nonsteroidal anti-inflammatory drugs (NSAIDs). Other indications for vitamin E possibly allow a general recommendation. there is substantial complexity in using numerous enzymes some considered targets of chemotherapy to predict the outcome of adjuvant therapy with 5-FU. a thiol.13. This is. have been beneficial in reducing the formation of DNA-carcinogen adducts and the occurrence of experimental tumors of the lung.. stage-specific survival noted in the Lynch syndromes for colorectal cancer. however.128 Genealogic tracing of 18 apparently unrelated families in Finland with an HNPCC susceptibility gene on chromosome 3 led back to a common ancestor at least 13 generations before.139 Once these three factors are determined.150 Antiinflammatory drugs are clearly active preclinically and impact polyps (apoptosis).154 Regular use of aspirin or NSAIDs (at least 16 days a month for 3 months) reduced by 50% the risk for cancer of both the colon and rectum154–157. albeit usually temporary. A collateral approach would seek to block the action of carcinogens during the latent period before the appearance of cancer.106 Those cases of glioblastoma multiforme found to have the HNPCC genotype had exceptionally long survival. difluoromethylornithine) that have known anticarcinogenic activity in animals. by analogy to other cancers. reduce their cloning efficiency. actually are the beneficiaries of adjuvant therapy.144. In conjunction with established morphologic criteria.20 The specific genes involved in these areas of microsatellite instability have been identified as hMSH1. and inversely with loss of heterozygosity.135 CHEMOPREVENTION Minimizing exposure to recognized predisposing elements in the diet and environment is one ultimate aim in the prevention of cancer.106 Use of molecular markers to select high-risk patients for surgical treatment remains a promising yet still unproven prospect because of heterogeneity of cancer and lack of sensitivity and specificity of tests. which is consistent with the long.138 Acceptance as a chemopreventive agent in humans. as described below.129 Such areas of “replication error positivity” were found in 77% of colorectal cancers in patients with HNPCC.121 In some colon carcinoma cell lines. Furthermore. Although specific inhibitors demonstrate chemoprevention in the labo- . nevertheless.136 and have a beneficial effect in several experimental colon cancer studies.145 The use of a multivitamin does not substitute for a balanced diet.149 This effect may relate to reduction in endogenous prostaglandin generation.132 hPMS1.134 Both types of germline defects. however.

some colon epithelium adjacent to benign or malignant disease also stained for CEA. presurgical elevated values of higher than the upper limit of normal. Cathepsin B is a lysosomal cysteine protease that can degrade matrix components. 200. ideally operable stages.176 Direct tissue identification of CEA on conventional histopathology-labeled specimens by an immunoperoxidase antibody method showed that CEA can discriminate between normal and malignant tissues. Persistent abnormal assays are not an indication for treatment.ratory. physical examination. Cathepsin B. and in some hereditary syndromes.000) in the periphery of the tumor cell membrane. Within stage III/IV . helps to identify epithelial origin (as in the case of unknown primaries).183. physical examination is useless for early detection and colonoscopy is barely cost-effective . .173.162 CEA is an acid glycoprotein (molecular weight. and cervix. where rise in CEA is not evidence of progression. however. serum CEA levels are not suitable as a screening test for colorectal or other cancer among healthy subjects. large confirmed rises in CEA levels warrant investigation in patients being monitored after prior resection. multiple biochemical targets may be involved.171–173 CEA level may not correlate directly with tumor burden. because this assay is not an accepted criterion of response. not just cyclooxygenase inhibition.172 In contrast.163 Sequence analysis of the CEA gene showed that its nucleotide sequence has homology with members of the immunoglobulin supergene family. Such rewarding outcomes are infrequent. It follows that the use of chemopreventives in no way changes the standard of practice regarding patient history. Rising levels indicate tumor progres- CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1477 sion.167. Residual CEA elevations in the postoperative period and especially rising CEA levels at any time in the follow-up of patients with resected colorectal cancer can be an early sign of recurrent metastatic disease even when the patient is otherwise well. Caution is required. In colon cancer. Its role in monitoring metastatic disease is controversial. CEA is not recommended for screening or for routine office visits for heretofore healthy patients. confirmed. CEA testing is clearly useful for prompting pursuit of suspected recurrence or progressive disease.164 The biologic significance of CEA to the cancer itself is unknown. paraffin-embedded tissues revealed that increased expression of cathepsin B correlated with stage of cancer and inversely with survival (p < . even including occasional sarcomas.181. Tumor markers in actual analyses have proven the single most cost-effective tool for early detection of recurrence and may save a life for as little as $5. Findings must be confirmed.167–169 CEA elevation correlates with the degree of tumor differentiation.001).182 When a tumor does not produce CEA.163 It is most heavily concentrated on the luminal surface and is capable of being easily released into the surrounding body fluids. CA19-9 Antibody and Monoclonal Antibody. in low dosage (81 mg). It is not recommended absent prior cancer or strong current suspicions of cancer because it does not provide conclusive evidence alone.177 Staining was positive in tumors of epithelial origin: carcinomas of the GI bronchus. A potential cause of false-positive test results is a human antibody to the mouse antigen used (HAMA) leading to specious interpretation of isotopic findings. Hydronephrosis and biliary obstruction have been associated with marked elevation of CEA levels. Radiation detectors used intraoperatively can help. enhance the metastatic potential of otherwise weakly metastatic cells. CEA correlates with stage of disease and is elevated most strikingly .151–160 Strong notes of caution remain operative. TUMOR MARKERS CARCINOEMBRYONIC ANTIGEN In 1965.171 It provides an early indication to initiate a thorough search for resectable metastasis at the stage of a potentially resectable hepatic or pulmonary lesion or regional disease amenable to surgery.172 Official guidelines call for serial assays every 3 months. however.172 Levels of CEA also can be used to follow the response of metastatic tumor to treatment. The change in CEA should be large (>10 ng/mL).168.174 Otherwise unexplained. Failure to return to normal after surgery is a useful indication to undertake a search for residual or recurrent tumor. in so doing. Judicious multifactorial diet management remains the best general practice with or without chemopreventives.169.168 and form another unproven basis for expanding the indications regarding need for adjuvant treatment for stage B tumors. Gold and Freedman showed that human colon carcinomas displayed a specific antigen. like other chemopreventives. thus attenuating tissue basement membranes. and the name carcinoembryonic antigen (CEA) was proposed.167.177 Radioactive anti-CEA antibodies are one method of finding recurrent tumors and of staging for resection of recurrent disease.180 The eliciting antigen was termed CA 19-9. and unrelated to change in renal or liver function. and management of human colorectal cancer. CEA elevations of 5 ng/mL or more had a sensitivity of only 43%. False positives must also be considered. Serial CEA testing may decrease the frequency of more expensive tests where a fall in initially elevated CEA appears to correlate with improving CAT scans. Hybridoma technology was used to raise a monoclonal antibody against colon carcinoma cells. 37 U/mL. Several lines of evidence find association between prolonged use of nonsteroidals. and the proper evaluation of symptoms that may be attributable to cancer.175 False-positive values also have been noted during inflammatory liver and biliary disease.165 It may function as an intercellular adhesion molecule166 and. pancreas. and cigarette smoking. as potentially reducing the RR of colon cancer.184 Immunoblot studies of formalin-fixed. CEA testing assay findings must be coordinated with other objective tests. which would support or contraindicate potentially life-saving surgery. Early recognition of failure may now be more important than formerly because there are alternative drugs and other therapeutic approaches. Approximately 20% of patients with documented disease progression nonetheless show a “false” decrease in CEA levels. falling levels indicate response.173.in the plasma of patients with hepatic metastases. Elevated levels in the presence of renal dysfunction must be interpreted with caution. CEA is elevated in the plasma of some patients in the presence of tumors of the colon as well as breast. may have independent prognostic value: patients with the elevated value had a four-fold increase in death from cancer at 3 years compared to patients with lower values. Because of poor sensitivity and nonspecificity. and particularly postoperative.165 Measurement of CEA levels in serum sometimes is important in diagnosis.000 to $10. This method requires an expert user and cautious confirmation of findings. CEA elevations predict for an increased risk of recurrence167. specifically aspirin.171 In general. hepatic injury caused by chemotherapy or anesthesia.167 Smoking cannot explain values above 10 ng/mL. lung. pancreas.174 Some limit assays to those patients with high assays prior to resections and CAT scans to those patients with symptoms clinically suspicious of recurrence or confirmed rise in CEA assays.179 This antibody was shown to react against a monosialoganglioside antigen180 The antibody did not react against a panel of other gangliosides. and liver. None of these seemingly successful demonstrations of an association between aspirin or NSAIDs and a reduced risk of colon cancer mortality are derived from randomized trials. they may provide little protection. the 19-9 assay might serve as a substitute subject to all of the caveats cited relevant to the use of CEA for detecting recurrence and for serial monitoring. CEA tests are also useful in preoperative evaluation since very high values should prompt consideration of further staging. colonoscopy. even less in the early. and helps to identify micrometastases in lymph nodes. but it did react to elements in human meconium. prognosis. and other adenocarcinomas.170 Preoperative. ovary. In patients with identified colorectal cancer evaluated preoperatively.167–169 Measurement of CEA levels in plasma has been used as indirect evidence of tumor presence.177 In general. and a specificity of only 90%. NSAIDs do not provide complete protection.161 The antigen also was detected in embryonic and fetal gut.177 However. The choice of an ideal chemopreventive narrowly targeted is problematic. ovary.000. This results in a higher metastatic potential and a worse prognosis. and patients with poorly differentiated tumors can sometimes have normal tests despite significant tumor volume. CEA positivity in a histologic specimen indicates the presence of malignancy.

Frequent colonoscopy is prudent. The application of various surgical techniques that can remove the large bowel mucosa at risk for malignant transformation without sacrificing the rectal sphincter mechanism should make the surgical preemption of cancer in such patients more acceptable. SCREENING Screening procedures for colon cancer can be divided into two categories. yet physicians are all too often accustomed to discounting it without considering polyps or cancer in their differential diagnosis.116.186 Removal of polyps was found to reduce the incidence of subsequent cancer by 90.204. This predictability relates to population groups only and not to individual patients.02).111. with attention to newly appreciated ethical and psychosocial guidelines. SCREENING HIGH-RISK INDIVIDUALS Patients with Prior Colon Cancer. Thus. the FAP locus on chromosome 5. Annual guaiac testing starting at 45 years and starting at 50 years endoscopy at 3. despite the objective efficacy of diagnostic studies and screening programs for both high-risk and sporadic cases. all will eventually develop colon or rectal cancer.196 Often. severe dysplasia often does not accurately quantify the urgency of intervention or the absolute risk of developing cancer. As described earlier. when the phenotype is first expressed.202 Familial Adenomatous Polyposis. and stage I/II had less elevated levels of cathepsin B than in stage III/IV . there is little or no available surgical opportunity for preempting intestinal epithelial transformation in these patients. the absence of.192 Socioeconomically disadvantaged populations are adverse to appropriate screening and treatment.23 A 3-year colonoscopy interval was just as effective as shorter intervals in detecting recurrence of polyps or a carcinoma.185.1478 SECTION 29 / Neoplasms of the Alimentary Canal low expression correlated with a longer survival compared to high expression (p < . Crohn’s Disease. Removal can prevent cancer and often can be done endoscopically.105.200 It seems prudent to initiate systematic screening at 10 years younger than the youngest affected relative and to repeat it every 5 years or more frequently depending on discovery of a premalignant lesion. . sigmoidoscopy. Prior frequent bleeding caused by the polypoid changes in the intestinal mucosa of patients with FPC creates the possibility that bleeding will be ignored and that cancers will be diagnosed at a late stage in such patients. or mutation of. Once cancer has developed.189 Colonscopic screening should occur at.189 Entry into clinical trials of prevention or prophylactic colonectomy becomes a reasonable topic for expert consideration in individuals who bear the FAP mutation. 78% did not want to know if they had bowel cancer. Despite the presence of inflammatory changes in the small intestine. Patients with ulcerative colitis have a defined increased probability of intestinal epithelial transformation. and (tentatively) colonoscopy. Ideal guaiac testing is not simply random testing but test on several stools accompanied by a 3day meat-free diet.197 The primary rationale for follow-up by interval endoscopy is not to discover the very rare resectable suture line recurrences198 but to find and treat the premalignant polyp. Disordered bowel function on a temporary basis is a protean symptom. Patients with familial polyposis coli (FPC) and their first-degree relatives should be screened.72) for developing colorectal can- cer than the population at large. no matter how conscientious. New molecular biologic techniques can define whether young relatives of patients with FPC have the genetic constitution responsible for FPC.183 Adenomas had low cathepsin activity similar to that of normal mucosa. trial recruitment. advocacy.195 One should not assume. 88.200 Patients who are identified by a high-risk family history may benefit from a screening study of the entire large bowel mucosa. The failures of physicians in dealing with their patients’ clear-cut symptoms. Individual advice usually is based on population statistics. the lack of defined criteria for morphologic assessment of the conversion risk of ulcerative colitic mucosa from severe dysplasia to cancer creates a dilemma for both pathologists and clinicians. about 50% of patients develop metachronous bowel polyps. some patients will die of metastatic colon cancer. Individuals with first-degree relatives who have colorectal cancer are at significantly greater risk (RR = 1. however. probably reflect the fact that adverse beliefs are universal and also affect physicians. 77% were too embarrassed to have a proctoscopic examination.194 and impact (disadvantageously) on a patient’s insurability and employability. and 76% (p < . Consensus recommendations are updated regularly by several gastroenterolgy and oncology specialty groups.183. New issues are arising with the availability of new genetic probes and markers to identify the individual at risk.111. obviating further abdominal surgery.200 Relatives of patients with colon cancer may have the familial polyp syndromes and HNPCC. This suggests that cathepsin B. Removal of the involved bowel (large or small) does not prevent the recurrence of Crohn’s disease. stage for stage. poor compliance. At present.188. it behaves.201 This RR is most pronounced in those with index cases under 45 years of age (RR = 5. and second are for those with no known risk factors other than age.184 Cathepsin B assays have no tested clinical applications as yet. nor does it reduce the potential for subsequent malignant transformation in other parts of the bowel.193. The decision to remove the entire large bowel and rectum often is made subjectively based on the gastroenterologist’s conservatism or aggressiveness and the patient’s choice between fear of a permanent ileostomy and fear of colorectal cancer. cancer is uncommon in the small bowel.189 Consequences may differ in adults and in children189.200. psychosocial. Ulcerative Colitis. that matters are ideal in the advantaged or educated population. adolescence. The latency between diagnosis of polyposis and development of cancer is variable.191. the most stringent clinical criteria are required in order to initiate genetic testing for individual application(s). Issues include the ethics of informed decision-making for genetic testing and the psychological consequences of a test result. New molecular markers may define field changes that can quantify more accurately the progression from dysplasia to transformation in patients with ulcerative colitis. and social work assistance can enhance community education. The earlier literature that cast doubt on the efficacy of screening on the basis of cost. like sporadic colorectal carcinoma. Patients with Crohn’s disease also fall into the high-risk category. and failure to find early cancers has now been replaced by a steady stream of positive reports even for patients with no known risk factors other than age.205 Such proposed markers require clinical trials. is important to the progression from benign/low-grade neoplasm to an invasive/metastatic malignancy. a broader view than the requirements of the Amsterdam criteria is appropriate. Screening is strongly recommended within defined guidelines. but it subjectively underscores a role for systematic endoscopic screening.to 5-year intervals (or more often depending on findings). or just after.186 First are the procedures for patients who fall into highrisk groups. a matrix-degrading protease.118. Histologic identification of conversion from mild to severe dysplasia indicates a need to remove the large bowel before cancer develops. and economic impacts of the testing process. Current screening recommendations include guaiac testing. averaging from 10 to 15 years.111. these lesions are not cancers but are premalignant adenomatous polyps.203 If patients choose to ignore the risk of FPC.192 Appropriate support. relies entirely on colonoscopy and biopsy.to 10-year period of surveillance following primary tumor resection. If the endoscopist.17.193 One must be prepared at both the institutional and individual levels to counsel patients after test results are known. These issues also affect large epidemiologic studies. Patients who have already had colon or rectal cancer carry a significantly increased risk of a metachronous lesion. A family history remains the primary starting point for identifying individuals who are at risk. and post-testing follow-up efforts.37). and 81% cited transportation problems as a barrier to seeking appropriate screening.187–192 Physician responsibility extends to the emotional.195 As many as 70% did not believe that they were at higher risk for bowel cancer.199 Even a 5% risk would probably justify surveillance studies. First-Degree Relatives of Patients. Over a 5. 80% preferred to die rather than have their bowel removed for cancer. however. The segment of bowel involved in the inflammatory process is not predictable. respectively.001) when compared with two unpolypectomized cohorts and to a general population registry.201 In clinical situations.

Screening now has a clear and powerful beneficial impact for low-risk patients. Surgical procedures in which the entire colonic and rectal mucosa are removed.211 Random occult blood screening is not considered to be cost-effective because of false positives from meat.203 Such procedures are not applicable to all patients. Reducing the rate of tests to every 2 years has an adverse effect. Testing after a 3-day meat-free diet is effective when positives are followed by endoscopy. Patients who present with anemia of unknown origin. Some conclusions are based on complex and sometimes controversial CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1479 analyses analyses. however. If there are polyps. most importantly. there are numerous but not identical guidelines. Patient familiarity with blood loss in the stool often prevents this alarming symptom from conveying appropriate warning. Nevertheless. Patients often present with the classic symptoms of right.112 Benefit may result from incidental colonoscopy even without mass screening. in addition to a decreased risk of death.212 These provide additional incentives for earlier diagnosis.218 The story recommendation for colonoscopic surveillance of patients with genetic high-risk characteristics is logical and recommended. investigators will define in detail the genes and gene products involved in regulating intestinal epithelial transformation. In general. Eventually. but not proven. Colonoscopy and polypectomy are in part responsible for the decline in mortality. and whose blood cell indices confirm that chronic blood loss is the likely etiology. did show mortality reductions of one-third or greater.2) These are often symptoms of large tumors that may have been growing for years and too often the result of avoided or omitted rectal exams (occult blood testing. repeat examinations are made every 2 to 3 years when polyps are found. after finding occult blood on systematic stool sampling.219 Patients over the age of 50 years should have regular sigmoidoscopy every 5 years and a fecal occult blood test every year. This may entail genomic investigation of colonic epithelium with a gene chip. practice. In such cases. but treatment of these patients may appear to be technically and practically more difficult. Colonoscopy and virtual colonoscopy have equal sensitivity. polyps) than a control cohort. or colonoscopy). or if an index family member was young or had a right-sided cancer. sigmoidoscomy. Advances in the psychosocial and surgical treatment of patients with ulcerative colitis now may allow better psychologic acceptance of an earlier move to preemptive surgery.The empiric rule is to consider proctocolectomy after 10 years of active ulcerative colitis. The prognosis is no different stage for stage than for sporadic colon cancer. should have both the upper and lower GI epithelium examined. Clinical Presentation. identification of practical molecular markers of early malignancy may resolve much of the debate about time for surgery. and.or left-sided colon cancer or cancer of the rectum (Table 103. colonoscopy has preference over roentgenography and full colonoscopy over sigmoidoscopy. Screening includes rectal examinations. Screening has become an established standard of care. particularly if bleeding is caused by a polyp on a stalk that is easily removed by the endoscopic snare. are more apt to have early bowel cancers or precancers (i. Endoscopic surveillance of the large bowel is significantly more difficult. screening with annual fecal occult blood tests. Otherwise. which could be in part identified by family history.e. preferably by endoscopy. sigmoidoscopy. in patients with ulcerative colitis than in noncolitic subjects because of the extensively diseased colon. screening sigmoidoscopy and colonoscopy surveillance have been proven effective but far from ideal. Colonoscopy at the age of 50 should be repeated every 5 years and more often if polyps are found. unless there is a common step as yet unrecognized. but the main conclusions apply to every clinician almost regardless of specialty. This defined population could then undergo diagnostic and therapeutic endoscopic examination. The risk of such transformation at any instant is limited to a relatively small population. The most efficient method to screen the large bowel mucosa is colonoscopic examination.195 However. and guaiac tests yearly. In contrast. regardless of whether their stool is positive for occult blood at the time of digital examination. Screening is now a highly specialized subject of investigations. of discounting cancer by assuming that the “cause” of rectal . Anemia is one of the few relatively early potential findings.218–225 Future Prospects. however. For ulcerative colitis testing. acuity of the patient’s symptoms. up to 50% of patients with a history of continuing ulcerative colitis for more than 10 years eventually develop bowel cancer. the test is part of the office visit. but patient preference is for fecal occult blood testing.210. The Strang Clinic’s experience supports rectal examination and testing stool for occult blood as an essential part of every complete physical examination. population-screening studies produced conflicting results. It is important to begin earlier.210–212 Despite the complexities in evaluating costeffectiveness. excessive frequency of bowel movements. Colonoscopy allows both necessary diagnostic biopsy and therapeutic intervention. screening fecal occult blood. 10 years before the earliest case in a high-risk family.. there is difficulty in achieving patient and even physician cooperation. Colonoscopy is preferred to fecal testing. and usually less sensitive. Colonoscopy rather than sigmoidoscopy is preferable especially if there is a history of polyps (or cancer) in the family or prior polyp or cancer in the patient. because of co-morbidities. clinically. but the rectal sphincter is preserved. but only colonoscopy provides a tissue diagnosis and polypectomy. Physicians are the most effective in achieving compliance with screening even for educated high-risk patients.206–209 It is no surprise that testing stool samples for occult blood is not aesthetically acceptable to many people.217 Only patients who have appropriate diagnostic work-ups. disruption of children’s scholastic performance. Patients with colitic mucosa therefore are more likely to be diagnosed with later-stage lesions. Initially. and the cost of social support services. especially for those over 40. or a once-ever colonoscopy does have a favorable cost per year of life saved. and increased risk of subsequent surgery for complications. placing undue confidence in a sporadic single negative test for occult fecal blood. which also works provided that the methodology and follow-up are optimum fecal occult blood testing lacks ideal sensitivity. Until then.210 Studies in which a positive fecal occult blood was promptly followed by sigmoidoscopy. the weakest link in the screening process is the lack of a consistent and predictable physician response in ordering a subsequent thorough and appropriate diagnostic work-up. which could be even sharper with greater use of screening practices. colonoscopy should be performed to inspect the entire colon. Ideally. virtual colonoscopy requires a 50% decrease in cost to match colonoscopy. Genetic methods have limited utility and require expert selection and consultation. and they are changing and sometimes require expert application. Methods to reverse the transformation are in development testing both preclinically and clinically. It is important to avoid some of the common errors such as deferring rectal examination and occult blood testing for the specialist.216. Because excisions of early adenomas preempt the eventual development of colon cancer.212–215 Additional societal and financial benefits accrue in terms of fewer workdays lost. and whether recent studies have already been done in the upper or lower GI system. Patients who underwent history and physical examination that did not include digital examination of the rectum and testing of stool for occult blood are more apt to have advanced cancers. it produces considerable cost benefits. In practice. the medicolegal defense of failure to perform the test is difficult and very costly. the standard proctocolectomy with Brooke ileostomy provides preemption of the colon cancer risk and quick rehabilitation without frequent defecation or risk of future surgery for complications. Virtual colonoscopy will not be cost-effective unless the physicians are dealing with a population in which it improves participation by 20%. The cost is trivial when the patient is already in the doctor’s office. the case for timely resection too often ignores the deleterious impact of leaving the patient with a sick organ that produces important consequences other than surgery.213–215 Systematic testing for occult blood can be recommended for patients of appropriate age. improve the psychologic and aesthetic cost benefit ratio in favor of early cancer prevention surgery. and findings demand judicious follow-up steps. Unfortunately. SCREENING IN ASYMPTOMATIC POPULATIONS AT STANDARD RISK Concepts of screening for colorectal cancer in the asymptomatic population not known to be in any high-risk group continue to evolve. The order of examination will depend on the rapidity of the bleeding. spousal and family disruption.

226. Such lesions can be totally resected before the epithelial transformation progresses to malignancy. the patient is inattentive to early change in bowel habits. Such lesions often can be removed with sphincter preservation. LEFT COLON SYMPTOMS The most usual symptom in patients with circumferential adenocarcinomas of the descending colon. Occasionally. or severe and chronic. It is of great concern to screening advocates that patients and physicians alike do not give clearly recognizable bleeding proper attention. Those who commonly present with such symptoms may be quite young. barium studies are a useful complement to define the location of the target bowel and. Tenesmus and pain often reflect ulcerated tumor and may portend the involvement of superficial sphincter muscles in the process of cancer invasion. Colonoscopy and radiologic approaches have been compared in a number of reports. Establishment of any specific risk factor for colorectal cancer in a given patient should increase the suspicion of the examiner. This may be described as unaccustomed or newly appearing constipation or diarrhea or as alternating periods of both. Physical examination of the anus and rectum as a source of bleeding should.229 CLINICAL APPROACH INITIAL WORK-UP An appropriate work-up of any patient begins with a good history and physical examination including a complete family history. Double-contrast roentgenographic examination of the colon largely has replaced a plain barium enema because of increased resolution capacity for small mucosal premalignant or early malignant lesions.2. Presence of a hemorrhoid does not exclude a co-existing.. Comparison of the Five Most Frequent Symptoms in Right Colon. sigmoid. and usually fatal in advanced stages. consist of tenesmus (i. Younger individuals with colorectal cancer have been reported to have a worse prognosis stage for stage. RECTAL SYMPTOMS Patients who have distal rectal carcinomas may present with spotting of blood in their stool. patients present with the classic narrowed-caliber “pencil” or “ribbon” stool. sometimes massive blood loss.228 Numerous benign. tumor often located at ileocecal valve. it is most often found late in the disease. Less frequently. Such verification also provides the opportunity for surveillance of the remainder of the large bowel mucosa. Even physicians seem to find this a difficult diagnosis when they themselves are symptomatic. and the presence of hemorrhoidal bleeding can obfuscate a more proximal source of bleeding. Adapted from Baker (545). mild.227 The lower probability of making the correct diagnosis early in the younger patient make advanced-stage disease more common in the young because of diagnostic delay rather than intrinsically adverse tumor biology. if the physician concludes that the presenting symptoms imply the possibility of GI cancer. and Rectal Cancer Right colon (984 patients) Left colon (99 patients) Rectum and rectosigmoid (258 patients) Abdominal pain—74% Weakness—29% Melena-27% Nausea—24% Abdominal mass—23% Abdominal pain—72% Melena—53% Constipation—42% Nausea—25% Vomiting—23% Variation in symptoms Melena—85% Constipation—46% Tenesmus—30% Diarrhea—30% Abdominal pain—26% Symptom Right colon Left colon Rectum Pain Obstruction Bleeding Weakness‡ Ill-defined Infrequent† Brick red Common Colicky* Common Red. premalignant villous tumor. Even when digital examination is carefully performed. thus. . Verification of a radiologic diagnosis by endoscopic examination and histologic proof of diagnosis by biopsy should be mandatory. inflammatory. The fever is due to pericecal or right paracolic abscess. at minimum. obstruction occurs. The gastroenterology and internal medicine literature strongly favors endoscopic screening of the large bowel and rectum as the initial approach for any patient presenting with symptoms. or middle to upper rectum is an alteration in bowel habits. Abdominal cramps may be absent. More advanced symptoms of distal rectal adenocarcinoma. often curable when treated at early stage.e. endoscopic examination of the rectosigmoid should be part of every initial work-up. or even paradoxic diarrhea from an almost totally constricting distal large bowel adenocarcinoma (see Table 103.229–235 Double-contrast roentgenography is usually cheaper than endoscopy. the first symptoms may be those caused by metastases. the physician often may miss a frond-like. In young patients with virulent familial right-sided tumors. The absence of physical signs noted on the initial examination does not obviate further screening of the entire GI mucosa colonoscopy and. Systematic diagnostic efforts coupled with a high index of suspicion are appropriate to these symptoms because colon cancer is common. Digital and. RIGHT COLON SYMPTOMS Anemia is the most common complication of cecal and right colon cancer and the only common complication leading to early diagnosis. or sooner where family history requires it. mixed with stool Infrequent Steady. An abdominoperineal resection with permanent colostomy is the appropriate primary treatment if appropriate stage and diagnosis is corroborated by rectal ultrasound and full-thickness biopsy. after age 50. in addition to those described for left colon lesions. gnawing Infrequent Bright red. Left Colon. § Accounts for brick red color of stool and persistent. if needed. Nevertheless. when applied together. only if the diagnosis is made before the tumor invades the rectal wall. Often.1480 SECTION 29 / Neoplasms of the Alimentary Canal Table 103. more ominous lesion proximally. and then only if no blood was in the stool and early follow-up confirms that correction of the assigned problem in fact ends the blood loss. unless there are very good alternative explanations such as menorrhagia. If postoperative radiation is contemplated as part of the primary therapeutic regimen. Occasionally. The same may be true for African-American patients who have disproportionately more right-sided tumors. Colonoscopy may also provide one-step definitive therapy. include a digital examination and endoscopy of the anus rectum and sigmoid.2). Even high-grade obstruction often has only vague symptoms. the feeling of having to defecate without stool in the anal canal) or pain on defecation. Unfortunately. to enable accurate delivery of the radiation dose. are better than either alone. ‡ Weakness secondary to anemia. some investigational methods aside. bleeding is due to a benign co-morbid condition such as hemorrhoids.241–246 Roentgenographic and endoscopic techniques. upper endoscopy. with the additional advantage of obtaining histologic proof by biopsy if a lesion is seen. particularly during the initial phases of polyp or malignant tumor development. Iron-deficiency anemia warrants colonoscopy. Hemorrhoids and constipation are common and thus frequently are associated with occult cancers. fever of unknown origin may eventuate in the diagnosis of perforated.227 Vague bowel symptoms commonly lead to alternate diagnostic explanations because such symptoms are common and are associated with many benign conditions. but. patients with cecal or ascending colon cancers present with abdominal pain or even mass lesions evident on physical examination (the consequence of very advanced disease).236–240 The major advantage of endoscopy is increased specificity and sensitivity. and traumatic conditions in the distal rectum and anal canal can produce the same type of fleck-like blood in the stool as that noted by the patient with an early villous tumor or adenocarcinoma. We prefer endoscopy first. coating stool Infrequent Pathophysiology Symptom Right colon Left colon Rectum Caliber of lumen Consistency of stool Proteolytic enzymes † If 6-10 cm Liquid Present§ 1-2 cm Semisolid Absent 5-7 cm Firm Absent *Made worse by ingestion of food. studies of new molecular markers of virulence and of tumor grade and ploidy are beginning to provide explanations as to why some cancers in the young are worse than the average tumor. incorrectly ascribing it to some minor variation in diet. right-sided colonic tumor.

is limited to research and to patients who cannot or will not have colonoscopy or double-contrast studies. These are all investigational. The indication for subsequent bowel resection where penetration is histologically confirmed to be at or through the muscularis mucosa must be made based on the individual patient. Difficult methodology and need for experience limit these applications to expert users. T2 NX M0 polypoid cancers have a 10 to 30% chance of being T2 N1 M0 disease. Early stages are treated primarily by surgery. or fever of unknown origin require appropriate preoperative studies. and sometimes nodes. especially now that there are new. ureters. repeated periods without nutrition unnecessary. Intergroup Adjuvant Therapy Trial for Colon Cancer Dose Duration Patients 5-year at risk relapses % Treatment arm Observation Levamisole 50 mg PO Q8h x 3d Every 2 wk 1 year 315 310 155 144 49 46 Combination Levamisole plus 5-fluorouracil 1 year As above 450 mg/m2 qd x 5d 28 d later. Perhaps the most important consideration is the nihilism of the attending physician despite new data showing that further multi-modality therapy significantly benefits patients who have T2 N1 M0 disease compared with surgery alone (Table 103. that this is due to postresection systemic adjuvant therapy for these high-risk patients. for the management of liver metastases. If at the time of diagnosis regional or distant metastases are discovered. The basic precept justifying a test before surgery should address the question “Will this examination provide information that will alter the therapeutic approach?” Surgeons and internists frequently disagree on which tests meet this criterion. THERAPEUTIC SURGERY: GOALS AND OBJECTIVES Once a colorectal cancer develops. Diagnostic and therapeutic steps to improve cardiac and pulmonary function before surgery often are appropriate. and pathologic definition of free margins. the remainder of the bowel must be thoroughly examined colonoscopically and subject to systematic follow-up. the entire cancer (or precancer) should be removed. subsequent surgery is not required.3). for rectal lesions.253 Also. The importance of prophylactic surgery cannot be overemphasized. isolated lung metastases. It provides complete information on the depth of tumor invasion and the presence or absence of microscopic regional lymph node involvement.249 Nevertheless. Tests that may facilitate a patient’s entry into national adjuvant studies include CT. Intraoperative radio-guided surgery may increase the sensitivity of exploration of the soft tissues and lymph nodes. it is not yet superior to colonoscopy. The indications for single and multiple resections have expanded. Rectal ultrasound may otherwise largely replace CT or MRI. Colorectal surgery. presence or absence of co-morbidity that might militate against the risks of general anesthesia. Five-year survival approaches 50 to 70% in ideal resection candidates. especially when the metastatic tumor is well differentiated. a preoperative CT scan or MRI of the pelvic and perineal region may be required. and complete liver function tests. The resolution of the CT scanner. or diffuse small volume peritoneal carcinomatosis) and even isolated central nervous system metastases. Table 103. sciatica.g. and the overall results appear to be improving.251 Endoscopic removal of polyps. SURGICAL THERAPY OF PRIMARY COLON AND RECTAL CANCER PROPHYLACTIC SURGERY: OBJECTIVES Preventive and therapeutic surgeries are equally important in these diseases. it is essential to establish the extent of disease. Indeed.252 If the endoscopic specimen has been removed piecemeal or has fragmented.3. The role of rectal ultrasound is important for low rectal lesions where sphincter-sparing surgery is an option. Proper preparation of the tissue may facilitate some of these tests.254. in addition to the application of intraoperative ultrasound to the liver. If the symptoms include tenesmus. The decision to proceed to colectomy in such a case depends on the age of the patient. Virtual colonoscopy. excision of lung or pelvic nodules sometimes leads to surgical cures. and colon. and it serves as a baseline for follow-up studies. PREOPERATIVE WORK-UP If a bowel tumor or premalignant lesion cannot be removed endoscopically. a combination of surgical and other therapeutic modalities is indicated. Laparoscopic surgery may bridge the gap only if nodes can be investigated in patients whose endoscopically removed cancers have pathologically free margins and T0 or T1 depth of penetration. magnetic resonance imaging (MRI). low-residue dietary supplements that make long. and available operating room facilities must be prepared to proceed with resection of a solitary hepatic lesion if such is encountered. and positron emission tomography technology can substitute for or supplement other tests.255 Grade is not itself a critreion for other types of resection. Pathologic examination of the removed tumor specimen is the major source of prognostic parameters. or physical examination reveals evidence of carcinoma involving the perirectal space. sequential colonoscopies every 3 to 5 years is a simple surgical approach that decreases the incidence of colorectal cancer. Total colectomy in patients with longstanding premalignant conditions (i. MRI and PET are reserved for times when clinical. or special request highresolution double-phase CT produces suspicion. Surgery for metastatic disease has its particular indications as well (e. universal sporadic and/or familial polyposis and ulcerative colitis) reduces the risk of invasive cancer. CEA assay. additional studies are necessary before surgery. In addition. surgical team.247. either surgery or interval endoscopic follow-up will be necessary. This requires complete pathologic review of the specimen. colonoscopy and computed tomography (CT) with contrast usually provide the most information and the highest specificity. is not an emergency. Specific tests aimed at establishing the presence or absence of coexistent disease should be ordered as indicated.. concerning liver metastases. Biochemical and molecular marker studies may provide additional information. 450 mg/m2 q wk 304 103 34 From Moertel and colleagues9 . especially if the finding will change treatment or lead to attempted resection or hepatic arterial infusion. but no conclusion. Diagnostic tests that starve the patient and contribute to weight loss can and should be avoided. Presenting symptoms of back pain. The results may define the cost-effectiveness of all subsequent diagnostic and therapeutic maneuvers. pending cost reduction. once one polyp has been found. Radiopharmaceutical guided surgery both as part of preoperative evaluation for recurrence and for intraoperative guidance has some role.e. especially analysis of the depth of any carcinoma invasion into the muscularis mucosa. Endoscopic polypectomy CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1481 during regular. Surgery often is necessary to palliate local phenomena caused by the primary tumor.248 In sensitivity and specificity. Intraoperative exploration using visual and tactile staging. laboratory. sonography of the fluid-filled colon.. The exception may be patients with small primary tumors outside the pelvis. provides better staging than any preoperative radiologic or biochemical modality. Together. CT with contrast provides information about the liver. high-quality CT can be cost-effective. or MRI is suboptimal. even the most modern with dynamic imaging.In specialized centers. and acquiescence of the patient to the possibility that microscopic disease will remain undiagnosed without celiotomy. with the exception of complete obstruction. although often obviating formal laparotomy. resection of isolated liver metastases is now widely confirmed associated with prolonged survival in 30% patients or more.250 The ability of the surgeon to define the ureters during a meticulous dissection usually makes general application of screening intravenous pyelograms unnecessary as part of routine staging. It is unproven. such as bleeding and/or obstruction. presence of a flank mass. Localized peritoneal carcinomatosis can often be controlled for years. which may include bone scans and MRI. Thus. The surgeon. but suspected. must still adhere to the major principles of cancer surgery.

Standard resections are depicted in Figures 103. A right hemicolectomy achieves the desired purpose regardless of the tumor location in the cecum. long-lasting psychologic or functional deficit. The basics of cancer surgery cannot be assumed or taken for granted. Some patients with small tumors may undergo a limited colectomy with curative intent. and principal lymph node groups accompanying the vessels of the colon. Segments of bowel and lymph node containing mesentery to be removed for carcinoma of the cecum (A-A'). and left colic arteries. In the longitudinal axis. specifically the ileocolic. There has always been a steady pattern of reports citing the importance of the surgeon in the outcome of surgery despite the supposedly uniform use of the standardized straightforward operations described above. a standard resection encompassing the lymphatic drainage is sufficient. Considerations include the patient’s age. more experienced surgeons achieve better outcomes. the concepts of wide margins and resection of lymph nodes mandate dissection to both lateral pelvic walls of the mesorectum. . an endoscopic excision with a snare through the polyp base is adequate. with an attempt at cure. favorable impact on outcome. this has become especially clear for rectal cancer surgery where the choice of surgeon and the degree of monitoring and quality control applied appear to have a strong. Transverse colon cancers may be resected with a segmental and/or an extended right or left hemicolectomy.257 Some 20% survive 5 years. but this is not so with the distal margin if sphincter preservation is to be attempted. and now intraoperative ultrasound staging at the time of primary resection. Failure to recognize the presence of involved serosa or nodes.8. There also is reason to ensure adequate coordination with the pathologist.259–263 PRINCIPLES OF COLORECTAL SURGERY The major principles of surgical resection of colon and rectal cancer are (1) removal of the entire cancer with enough bowel proximal and distal to the tumor mass to encompass the possibility that there has been submucosal lymphatic tumor spread. splenic flexure (C-C'). has dire implications in the context of failure to make an optimum choice for adjuvant therapy. In others.256. A tumor in the sigmoid colon can be adequately resected with a segmental resection of the sigmoid only if the sigmoid vessels and/or inferior mesenteric vessels are ligated at their origin. especially patients with biologically less aggressive. (3) adequate visual.258 This allows for anastomosis very close to the dentate line and often accomplishes a potentially curative procedure. intermediate.258 As a consequence. even though the tumor is out. or left hemicolectomy are founded on anatomic structures. In these. and (4) minimization of psychological and functional consequences of surgery without sacrificing any of the first three precepts. defining what is both a convenient anatomic boundary for standard colonic resection and also providing for adequate regional lymph node clearance. ascending colon. If the cancer arises in a pedunculated polyp but without invasion of the muscularis mucosae. hepatic flexure (A-B). The epicolic.6. A tumor in the splenic flexure or descending colon requires a left hemicolectomy. extended resection together with urinary and soft-tissue flap reconstruction. tactile.1482 SECTION 29 / Neoplasms of the Alimentary Canal PREOPERATIVE EVALUATION Overall evaluation of the patient with colorectal cancer is mandatory. Thus. There are Figure 103. Figure 103. middle colic. important progress has been possible with use of the mechanical stapler that allows for sphincter preservation. A particular variation of surgical technique is used for cancers of the rectosigmoid junction and the rectum. As is true for several procedures. but locally extensive cancers. Some patients may effectively be cured. A patient with a locally extensive tumor invading adjacent soft-tissue organs and/or bony structures may benefit from a complex. well-differentiated. Anything less than the standard surgical procedures summarized here is difficult to justify because none of these operations produces a significant.6 through 103. Therapeutic plans should be established before surgery is commenced. paracolic. A biologic understanding of the disease is fundamental to the therapeutic decision.255 If the tumor arises spontaneously without an obvious genetic predisposition or field carcinogenesis. by an exenterative procedure. especially for patients with low-grade tumors. For very low-lying rectal cancers. it is easy to achieve a long proximal margin. and some patients have regional mesenteric involvement without concurrent distant involvement). and descending colon (C-D). Knowledge of the field at risk and routes of dissemination dictate the surgical approach. allowing for sufficient margins and resection of regional lymph nodes in the specimen. the number of abdominoperineal resections has steadily decreased.7. a very extensive local tumor may be treated successfully. Recently.254. (2) removal of regional mesenteric draining lymphatics (there is a predictable lymphatic spread of the disease. with division of the superior and middle hemorrhoidal vessels as distant from the bowel as possible. transverse colectomy.263 because the major draining lymphatics follow these blood vessels in the mesentery. or hepatic flexure. co-morbid conditions. The extent of bowel to be resected depends on the vascular anatomy of the area involved. the right hemicolectomy. omentectomy and adjuvant therapy may extend survival. Similarly. and risk of a given surgical procedure.

A 2.273 PERITONEAL DISEASE Some patients present with a primary cancer and peritoneal carcinomatosis. Earlier comparison based on open selection trials found comparable outcome. surgeons have been placing low anterior reanastomoses closer and closer to the anal verge. Ideally. the availability of standard adjuvant therapy does not offer any rationale for short cuts or limited surgery. which defines the anatomic boundary between the peritoneal cavity and pelvis.CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1483 Figure 103. These issues have become more cogent as the management of mesorectal. have been applied in numerous single-institution settings for many years. and in part because of patient demand. or radial margins. distal adenocarcinomas with little or no chance of microscopic nodal involvement. these trials are inconclusive. but unlikely. which may only add to the patient’s risk of local or distant recurrence.5-cm “wet” margin distal to the tumor has been shown to help prevent submucosal lymphatic or isolated suture-line recurrence of rectal carcinomas. or transanal removal of T1. does not cause increased morbidity. regional. as first standardized by Miles. 5-FU. Extra effort to achieve ideal margins is especially important in surgery for the low sigmoid colon and rectum. one cannot assume acceptable risk from any novel but unproven curative surgical approach. they may benefit from cytoreductive . The most extreme extension of this is the colo-anal reconnection. the risks of local recurrence. the practice of adjuvant use of radiochemotherapy has been. or equivalence to well-tested radiochemotherapy. To provide the same basic precepts of cancer treatment as APR or low anterior resection. seeking to assess safety and survival. staging. Close surveillance and further surgery for local relapse is a critical requirement. but without the need for permanent colostomy as in APR or of celiotomy as in the low anterior resection technique. It remains possible.266–269 Most local treatment modalities have been performed on highly selected patients with severe co-morbid diseases or in expertly selected patients with mobile. Proponents of sleeve resection argue that sacrifice of the superior hemorrhoidal artery as the end vessel of the inferior mesenteric artery is not necessary to achieve control of cancer in most patients. the apex of the sigmoid (A-B). or early T3 distal carcinomas with no obvious perirectal extension has generated several national trials to combine the benefits of external-beam irradiation. and it allows adequate proximal and distal margins and adequate length for an anastomosis without tension. At this time.271 A decisive analysis probably awaits the Dutch Scandinavian randomized “COLOR” trials outcome. One of the limiting factors in the surgical cure of patients with distal rectal carcinoma is the distal margin.to 2. mesenteric. Treatment plans have included multiple coagulation sessions. quality of life. SIGMOID RESECTDION Defining adequacy of sigmoid resection is not easy. Standard techniques for low anterior resection and APR have changed little over the years.258 Interest in new techniques for transsacral. Nevertheless. decreased without proof. unless some well-documented co-morbidity is present that may establish a different cost-benefit evaluation. As the rate of local recurrence has decreased 25 to 30% with mesorectal resection. distal. The success in treating recurrence may determine the as yet unproven acceptability of such colostomy-sparing methods. superficial. The laparoscopy has many of the biologic effects of open laparotomy.270.266 local excision with or without subsequent external-beam radiation. Older standards dictated that any distally located adenocarcinoma of the rectum that could be palpated digitally required abdominoperineal resection. 15 to 20% of laparoscopies were converted to open operations. The most important limiting factor is the radial margins. Until trials have been completed and successful experienced practitioners of limited excision surgery identified. and its success. Port site recurrence is probably uncommon.268 and endocavitary irradiation developed by Papillon. lymph node number. Advanced laparoscopic techniques permit colorectal resections.272 In these trials.264 with the exception of automatic stapling devices.271. but does not eliminate. RECTAL CANCER SURGERY The surgical convention for rectal cancer has been changing steadily. LOCAL TREATMENT OF RECTAL CANCER Alternatives to the classic surgical approaches. The patient must be made formally aware of his or her possibly increased risk. recurring observations that stage-adjusted results are better in expert hands.0. with the possible advantage of easier postoperative recovery. and effectiveness as measured by disease-free survival in patients with open versus laparoscopic colectomy. thus needlessly increasing the probability of regional recurrence. T2. transcoccygeal. The role of chemotherapy alone as a replacement for combined-modality therapy has rarely been tested. costs. Segments of bowel and lymph node containing mesentery to be removed for carcinoma of the transverse colon. a 10 to 70% chance of microscopic nodal spread exists. the choice between an anterior approach. particularly for very distal adenocarcinomas. chemoradiation to potentially involved perirectal nodes and mesorectum is added after pathologically defined complete resection of T2 or T3 cancers. exophytic. although assumed because of the colon adjuvant successes. surgeons in the Cancer and Leukemia Group B (CALGB) are testing the feasibility of sphincter-sparing full-thickness resection for TI tumors and resection plus chemoradiotherapy for T2 tumors.8. unlike the experience with laparoscopic surgery for gallbladder cancer. All patients are closely followed after resection. In patients with T2 or microscopically invasive T3 lesions. and the lower sigmoid or rectosigmoid (A-A'). and limited surgery. particularly in males with low-lying tumors. that early comparable experience with laparoscopy was due to favorable case selection. and assessment of the comparative risk of spread or local recurrence remains inconclusive. it is clear that combined-modality therapy reduces.265 Primary surgical failure excluded 51 of 177 potential patients.269 LAPAROSCOPY Laparoscopic techniques can assist the surgical oncologist in assessing the extent of intra-abdominal disease but is rarely needed because there are few reasons why regional or peritoneal disease would contraindicate palliative resection. Improved local control alone usually does not correspond to improved overall survival. Because of the interest in sphincter sparing for distal rectal cancer now conventionally contraindicated. However. ligation of this vessel. and survival. is not established. or APR should not make a difference in the surgeon’s ability to achieve a satisfactory radial margin. Risk is only reduced by one-third to two-thirds. The availability of adjuvant therapy in theory strongly encourages more extensive surgery including that of metastatic disease. and the major benefit actually may be in the reduced frequency of distant metastases. or chemotherapy267. colo-anal approach. Even without a formalized study. and hepatic extension assumes a greater importance. selectively. Large randomized trials are in progress. Short cuts or technical inadequacies by the surgeon performing a limited resection likely will lead to inadequate proximal. Research programs aside.

20%. Synchronous discovery of a primary and resectable metastatic disease carries an even better relative prognosis than late recurrent disease. This aggressive practice is supported by the availability of adjuvant therapy. the availability of potentially effective adjuvant therapy should in theory dictate increased demands for optimum surgery and rigorous pathologic assessment of prognosis to facilitate application of these treatments. youngest (right side) and oldest. Complete resection is critical to subsequent adjuvant therapy.281 These have been selectively combined with tumor embolization prior to hepatic resection. Morbidity rates (mainly thromboembolic. do worse over several months and several years.278 Five-year survival in selected series exceeds 20%. Anesthetic and operative mortalities have been reduced. T1 N0 (A) patients have a 97% 5-year disease-free survival. one half are amenable to resection when intraoperative ultrasound confirms the localization of metastases. stage II T2 N0 (B2) patients have a 90 to 78% rate. or regionally extensive carcinomas suffer a high rate of recurrence. and alcohol injection. obstructing. and extensive resections now may be performed with relative safety. The acute morbidity and mortality from surgery for colorectal carcinoma should be low. Even if such patients who have T4 or B3 or C3 lesions usually cannot be cured. Second resections are feasible and sometimes successful. Thus.275 Radical resection of all peritoneal disease followed by intraperitoneal hyperthermic chemotherapy is sometimes followed by prolonged disease-free survival. Indeed. and stage of the tumor and its biologic behavior. The scope of regional resection and resection of metastases in liver. When metastases in the liver are widespread or nonresectable because of size and/or anatomic location. Significant. Surgical cure of colorectal cancer is determined by the size. PELVIC RECURRENCE Patients with isolated perineal or pelvic recurrences after an unsuccessful (or inappropriate) low anterior resection of rectal cancer represent a special case. and although encouraging results have been reported. In the case of patients operated on for acutely obstructed carcinomas where adequate bowel preparation . and cryoablation. This helps to justify such large surgical procedures as legitimate palliative attempts when performed by experienced practitioners of these methods. Age by itself is not a short-term prognostic factor but the extremes of age. number of metastases. Smaller. Marked progress has been made in perioperative management. despite bigger. A single metastatic node adjacent to the tumor is compatible with more than a 50% chance of cure. 5-year survival remains about 30%. number of lesions (five. In addition to the long-term survivors. with complete resection. and stage III T2-3 N1 M0 (C) patients have only a 50 to 20% rate if no other therapies are used. The presence of other pathologic and molecular markers of virulence increases the risk. Patients with perforating. The potential contribution of standard or intraperitoneal adjuvant therapy remains to be proven. HEPATIC RESECTION The most frequent site of colorectal cancer metastasis is the liver. other patients have enjoyed 2. and more difficult resections. and extent of surgery.277 One-third of resected patients achieve 5-year survival if the resection margins are pathologically free from tumor and intraoperative ultrasound and careful examination by sight and frozen section demonstrate a technically ideal resection.278 Survival approaches 50% in some good prognostic groups. ulcerated tumors invading into the pericolonic fat and/or vessels and lymphatics are less likely to be cured by surgery alone. and lymphatic invasion are also ominous but prognostically complex findings. or whatever else is necessary. size (greater than 5 cm).254. followed by intraperitoneal chemotherapy. extent. but best outcome is rapidly becoming the standard measure of ideal surgery and staging. Approximately one-third of colon cancer metastases occur solely in the liver.279 Each of these approaches remains investigational. different locoregional modalities of treatment have been investigated: intra-arterial hepatic chemotherapy by catheter or via implanted pump.276 Many patients still prove ineligible on careful work-up because of extrahepatic disease (21%) and occult lymph node disease (19%).255. Thus. In contrast. Curative-attempt exenterative approaches (including extended sacral resection) appear to produce an important minority. to ensure pathologically free margins. lung.275 Large tumors with direct extension can be resected en bloc. deeper.274. patients with larger. Poor differentiation of the tumor or vascular. more frequent. Neither age nor sex normally justifies changes from best standard practice. which do not necessarily represent independent markers of prognoses. Surgical Prognosis.280 as well as by neoadjuvant systemic chemotherapy methods that produce substantial responses prior to attempting hepatic resection. alcohol intratumoral injections. Resection of metastases is increasing in frequency. neural. None of the prognostic factors such as site of primary (rectum). of long-term disease-free patients. an attempt to prevent systemic and regional recurrence is often justified. cured.284 The direction of practice is to do more than resect the primary tumor ehen one discovers regional or metastatic disease. infectious. ureteral reconstruction. size of metastasis.282 Improved techniques. electrode diathermy. even if the resection is apparently complete and has clear margins. time to recurrence.254. have led to a shortened length of hospital stay and quicker rehabilitation. Several studies confirm a worse prognosis in males. The surgeon must remove the contiguous organ. extent of margin. a substantial increase in the cure rate can be achieved.274. The same good outcome of the stage II patients has not been found in all cooperative groups. nonetheless. yielding opportunities for adjuvant radiotherapy and chemotherapy. Overall. in fact. pelvis. Eligibility for and long-term success of hepatic resection may have been expanded by adjuvant systemic and additional hepatic artery infusion. CEA (> 200). stage I. randomized trials and further follow-up are necessary to determine their objective value. and anastomotic problems) should be less than 10%. including the use of unilateral or bilateral posterior thigh myocutaneous pedicle flaps to fill the perineal space. some of these patients are. A number of selection criteria define the likelihood of successful hepatic resection: primary tumor B versus C.283 SURGICAL CONSIDERATIONS IN ADJUVANT THERAPY The primary surgical approach must be the cornerstone of any appropriate therapy combination. presurgical radiation therapy. Removal of adjacent soft tissue or contiguous organ structures must be undertaken without compromise or complacency generated by plans for adjuvant treatment. particularly in patients with co-morbidity.to 3-year periods of disease-free survival and surprisingly good rehabilitation before re-recurrence in the region of initial bulk disease. respectively. Increased rates of response and improved local control may not improve quality of life or survival for unselected patients. satellitosis. Another approach is external radiotherapy with or without chemotherapy followed by resection with or without intraoperative radiotherapy.281 Preoperative embolization may also render metastasis more resectable and trigger the compensatory function of the remaining liver.276 Surgical excision of isolated or anatomically confined liver metastases is the primary standard against which other treatments for hepatic metastasis must be compared. or short interval less than 12 months after initial surgery clearly exclude attempting resection. compared to that defined by conventional surgical staging alone. and staging of major operative procedures. others have unresectable locations. such as cryotherapy. and even peritoneum has increased. as are multi-step resections of liver and lung metastases. of these. CEA level. prospective. superficial tumors without vascular or lymphatic invasion can be easily resected with a high chance of cure. This is a group of patients for whom investigators also describe possible advantages of regional radiotherapy and combined-modality therapy significantly benefiting 20 to 40% of patients compared with historical controls given standard (adjuvant) therapy. especially if the tumor is of a low microscopic grade and does not distort the lymphatic architecture of the involved lymph node. CONTIGUOUS SPREAD Patients with contiguous spread of tumor into peritoneal surfaces or adjacent organs do not necessarily have other widespread regional or distant disease spread.255. and the surgery is increasingly the province of the specialty of surgical oncology. co-existent disease increases both mortality and morbidity. however. Resection must be macroscopically complete and the microscopic tumor burden in theory must be made as small as possible if adjuvant therapy is to achieve its maximum potential.1484 SECTION 29 / Neoplasms of the Alimentary Canal surgery by resecting most of the bulky disease.

Go-Lytely (Braintree Laboratories. These trials evaluated the role of pelvic radiation. This trial had several limitations. over 90% of patients who recurred were noted to have either local or regional nodal failure as a component of their recurrent disease. nor is it exclusively a function of improved surgery. by imaging studies. isolated local failures. especially its effects on survival. or combination radiotherapy/chemotherapy in patients with Dukes’ stage B2 and C rectal cancers who had undergone APR or low anterior resections. TNM stage T3-4 N0 M0 and T1-4. Local recurrences. Outcome is further improved by earlier diagnosis attributable to testing for occult blood. so that for any discussion. laterally on the pelvic sidewall. the most appropriate bowel cleansing consists of a copious oral solution of polyethylene glycol with sodium sulfate. Local failure also can be defined clinically by symptomatic failure with far different sensitivity and clinical implications. The study was terminated before completion of the targeted accrual goal. chemotherapy. and possibly reduced use of blood transfusions during surgery. Preventing local failure in these patients.288. mitomycin C and nitrosoureas. and more proximal location of the primary tumors. radiotherapy alone. Biology probably plays some role in the high local failure and poor survival rates after a potentially curative resection because. including those associated with distant metastases. and therapy create the need for prospective controlled trials in order to test any further. or total local failure. or combination treatment with chemotherapy and radiotherapy. N1-3 M0) who remain at significant risk of local failure despite having an APR or low anterior resection. C2. by surgical exploration. benefit from adjuvant therapy. it also may result from technical limitations on the ability of the surgeon to achieve wide radial margins in the primary resection of rectal carcinoma. At present. once clinically well established. There is some doubt that new. monoclonal antibodies. are not easily or effectively treated and often are associated with progressive severe morbidity and decreased quality of life. These patients (MAC stage A and B1. and C3. the decision to perform intraoperative bowel preparation or. Chemotherapy treatment continued for 18 months. pathology.290 Females have better biology and better anatomy for resection. Depth of bowel-wall invasion and nodal status are the two most important factors in predicting risk of local failure. It is these patients (MAC stage B2. In studies analyzing radial margins after radical surgery.cannot occur. TNM stage T1-2 N0 M0) are appropriately treated by surgery alone. perhaps. There are several established forms of adjuvant therapy for colon cancer using:chemotherapy with biochemical modulation and supplementary regional therapy. Addition of either oral preparative antibiotics or parenteral antibiotics perioperatively decreases the wound infection rate.294.287a For practical clinical purposes. smaller size.5 weeks.289 rectal cancer has been estimated at 50%. Influence of Stage of Disease on Postoperative Prognosis 5-Year survival (%) Surgical stage 1940s and 1950s 1960s and 1970s A1 B1 B2 C 80 60 45 15-30 >90 85 70-75 45-60 Adapted from Higgins and colleagues. blood transfusion is thought to affect adversely the rates of infection and complications and actual survival.289 This improvement is not exclusively a function of a change in disease biology. The dose of 5-FU was 375 mg/m2 when given alone. multi-institution prospective randomized trials were conducted to assess the role of adjuvant therapy. It decreases with lower T stage. In most national trials. Others are problematic and probably too toxic—for example.8 The GITSG 7175 study was a four-arm study comparing surgery without adjuvant therapy to surgery followed by chemotherapy alone. Not all are applicable or tested for rectal cancers. These important changes in practice. The B2 rectal cancer patients. it includes the effects of stage migration because of better pathologic staging. However. absent vascular invasion and with female patients. Given the high local failure rate for rectal cancers that invade through the bowel wall and/or involve regional lymph nodes despite undergoing complete radical resection. where the margins posteriorly on the sacrum. is an important goal.8 cm. These tumors often are located deep in the pelvis. The Gastrointestinal Tumor Study Group (GITSG) published the first modern trials.287 The prognosis has progressingly improved in recent decades (Table 103.400 CGy over 4. Local failure can be defined in various ways. RADIATION THERAPY Radiation therapy is used in a variety of settings for the treatment of patients with rectal cancer.286 Although improving. Failure to convince physicians is the dominant reason for the poor use of these new practice opportunities.4.5 and 0. rectal cancer has a worse prognosis than colon cancer. This underestimates the true risk to the patient of developing a later local recurrence and suffering from its consequences. but implementation remains inadequate. Risk of local failure can be even higher if the tumor is adherent to or invades adjacent organs and structures.289 Surveys conflict as to the actual impact of these practice changes. Only 202 patients were eligible . the risk of local recurrence of CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1485 Table 103.000 to 4. Thus. If one examines a greater denominator of lymph nodes. More likely. or anteriorly on the prostate often limit the surgeon’s ability to obtain wide radial margins around the primary rectal tumor mass. ADJUVANT RADIATION THERAPY OF RECTAL CANCER Adjuvant radiation therapy benefits those patients who remain at high risk for locoregional failure despite complete resection of the rectal tumor. Risk of local failure can refer to first site of failure. screening. decreasing numbers and architectural damage of node metastasis. Unlike colon cancer. stage for stage. local failure was determined clinically and defined as the first site of failure. or at autopsy. it is important to fully define the term. with dose prescribed to mid-plane at the central axis. These additional prognostic factors are currently only of use for trial analysis investigational direction of treatment choice. Inc. The numerous early failures of 5-FU alone and in combination and of immune therapy illustrate the need for complex and rigorous trials to achieve a successful demonstration of adjuvant therapy. even if not always associated with improved overall survival.1). Radiation therapy consisted of parallel opposed fields. the risk of local failure increases to approximately 25 to 50%. more and better trained surgeons. When patterns of failure of rectal cancer after curative surgery were analyzed in a University of Minnesota reoperation series.4). increased awareness.295 It also decreases with the expertise of the surgeon.285. Opportunities to improve outcome for patients with rectal cancer are especially recognizable. Patients whose tumors have not penetrated through the bowel wall and are without metastatic disease to regional lymph nodes have an 80% or better overall survival and less than 10% locoregional failure. fiberoptic endoscopy. proven practices are being applied with adequate frequency to impact national health statistics. the median distance is unsatisfactory between 0. bicarbonat and potassium chloride. staging in colorectal cancer is not complete until pathologic examination of the removed specimen has been performed (see Table 103.5 to 5. as a group. which improves the outcome of both the N0 and N1 groups. Rectal stents remain investigational but when selectively used avoid some colostomies and two-stage procedures.). the B2 rectal cancer patient is clearly at high risk of recurrence and is a candidate for adjuvant therapy. the dose was 4. which is reflected in a modestly improved stage-adjusted survival well demonstrated in NSABP adjuvant trials. new candidate therapy. a temporary colostomy may obviate the increased risk of a leak if primary anastomosis is performed. Local relapse is often scored at 30 to 40% in patients treated with surgery alone in cooperative group studies but may be as low as 10 to 15% in best reports where mesorectal resection is possible. Chemotherapy consisted of semustine and 5-FU. When tumor invades through the rectal wall or involves lymph nodes. Currently. and levamisole (LEV). but not the actual rate of relapse. patients who normally would have been staged as TX N0 now are being staged as TX N1.7. B3. operative staging is imperfect. When radiotherapy was given with chemotherapy.

500 mg/m2/d for 5 consecutive days during weeks 1 and 5. where no significant survival benefit was seen with adjuvant chemotherapy alone. perhaps due to the weak statistical power of the GITSG trial. These trials can be . have been unsuccessful as yet. improved surgical resectability. by use of transrectal ultrasound to evaluate the extent of transmural penetration by the tumor. The three-arm postoperative adjuvant rectal cancer trial (INT-0144) is comparing prolonged venous infusion (PVI) 5-FU to bolus 5-FU plus LV plus LEV to bolus 5-FU alone. initially recurred with locoregional disease. Surgery or secondary adhesions that inadvertently fixed a portion of bowel in the radiation fields can prohibitively increase radiation treatment related enteritis.1486 SECTION 29 / Neoplasms of the Alimentary Canal for analysis. this toxicity manifests by loose bowel movements or diarrhea that is self-limited or managed by antidiarrheal medication. only two trials also showed a benefit in overall survival. and found no harm in the moderate delay of the radiotherapy element. Retrospective studies have shown a benefit with preoperative radiation therapy both in local control. the systematic application to resectable cancer compared to primary resection and postoperative adjuvant therapy remains unproven. In addition. All four trial arms received pelvic radiation therapy. In stage II and stage III rectal cancer.8 Local or regional failure was assessed only if it was the site of initial recurrence. the improved control rate with chemoirradiation over radiation alone suggests a synergistic effect between the two modalities. fewer than expected. followed by two more cycles of 5-FU. and 11% in the chemoirradiation arm. B3) and III (Dukes’ C) rectal cancer. The benefit of combined-modality therapy was confirmed by the Mayo/North Central Cancer Treatment Group (NCCTG). and increased chance of sphincter preservation. 5-FU and LEV . If preoperative radiation is given in the adjuvant setting. Transrectal ultrasound is approximately 90% accurate in determining the extent of tumor invasion of the bowel wall. thereby decreasing tumor cell seeding from surgical manipulation.11 Issues that remain in adjuvant treatment of rectal cancer include the optimal chemotherapeutic regimen to be used in conjunction with radiation therapy and the optimal sequencing of chemotherapy and radiotherapy alone or in combination and before or after in relationship to surgery. Proof of principal remains elusive. there are potential advantages to delivering radiation therapy before surgery. patients with early-stage disease and a small risk of local failure might be treated unnecessarily. patients on the combined chemoirradiation arm had the best outcome: the chemoirradiation arm showed a benefit in disease-free survival. attempts have often failed and only rarely and inconsistently succeeded. results with single-agent 5FU in appropriately high doses (450–500 mg/m2) were as good as those with semustine combined with lower doses of 5-FU (300–400 mg/m2). also confirming the GITSC outcome. Despite these limitations.299 The bolus given with radiotherapy was replaced by 5-FU infusion. Occasionally. The Mayo trials examined starting with chemotherapy. and only 65% completed the prescribed chemotherapy in the combined-modality arm. in the radiation and chemotherapy arm. No survival advantage was noted in the NSABP radiotherapy arm. PREOPERATIVE VERSUS POSTOPERATIVE ADJUVANT RADIATION THERAPY Although recently successful randomized adjuvant rectal cancer trials in the United States evaluated only postoperative radiation therapy. Initial local recurrence was reduced to 13. There was a modest survival advantage in the adjuvant chemotherapy arm (53% vs. allowing more time for recovery from surgery before starting radiotherapy. The disadvantages of preoperative radiation include delayed definitive excision of the tumor. In fact.292 It was a three-arm trial of surgery alone versus surgery plus either adjuvant chemotherapy or radiotherapy and enrolled a total of 555 patients. This contrasts with the GITSG study. hemorrhage.”288 The contribution of adjuvant chemotherapy by itself was the subject of the NSABP R-01 study.4 to 54.291 Standard postoperative adjuvant therapy initially consisted of rapid intravenous injection of 5-FU. compared to 25% with radiation alone. which is clearly superior to 5-FU bolus. GITSG 7180 showed that semustine (MeCCNU) was not required in the adjuvant treatment of rectal cancer. 5-FU and LV . chemotherapy consisted of 5FU given as an intravenous bolus injection and semustine. There are now numerous demonstrations of such downstaging for unresectable cancers. DNA damage is more readily repaired under hypoxic conditions. 24% of patients. compared with 21. As in the GITSG study. Recent American attempts to test this in randomized trials have failed because of poor accrual. followed on week 9 by radiation therapy of 50 to 54 Gy with concurrent 5-FU. substantially reduce local recurrence. 43%) at 5 years. The results show no survival advantage of any treatment regime over 5-FU alone in combination with radiation therapy.11 Attempts to improve on the chemotherapy component. Additional trials followed with and without semustine given its nephrotoxicity and leukemogenicity. 500 mg/m2/d for 3 consecutive days during weeks 1 and 5 of radiation. small bowel toxicity is more severe. In the observation arm. however. Because chemotherapy alone had no influence on loco-regional failure.7. By causing tumor shrinkage.291 This was a two-arm study comparing postoperative radiation with radiation plus chemotherapy. and prolong patient survival. This compares to 27% in the chemotherapy arm. Protracted infusion of low-dose 5-FU for the duration of the 42 days of radiation (as tolerated) was preferable to bolus injections during the same period at spaced intervals.3% of the adjuvant radiotherapy arms. These include decreased toxicity. However.293 These results were confirmed in an NCCTG study. although the trial findings encourage continued investigation of preoperative therapy. or fistula formation. Preoperative radiation may also permit a patient who otherwise would need an APR and colostomy to undergo a sphincter-sparing operation. Overall survival in the combined-modality therapy adjuvant arm was improved by 29%.5%. 20% in the radiotherapy arm. 450 mg/m2/d for ideally 5 days. Usually. Radiation therapy given preoperatively may be more effective than an equivalent dose given postoperatively. Oxygen is a strong radiation sensitizer. Another potential advantage of preoperative radiation therapy is sterilization of tumor cells in the perirectal tissues. 5-FU alone. These trials formed the basis of the National Institutes of Health Consensus Development Conference and a National Cancer Institute Clinical announcement concluding that “5-FU based chemotherapy and radiation therapy can reduce overall rectal cancer recurrence rates. All three arms receive identical radiation therapy to a total dose of 50. this risk of overtreatment can be reduced. This also argues for preoperative treatment but alone is not persuasive. multiple randomized studies with preoperative radiation therapy have been conducted. The most common and severe morbidity related to pelvic radiation is that associated with small bowel toxicity. Toxicity from radiation may be greater after surgical intervention because fibrotic adhesions from surgery tend to limit bowel motility. and lack of pathologic staging. however. The radiation therapy that was delivered was suboptimal because of its low dose and lack of multi-field planning to maximally exclude small bowel from the field. The twofold improvement in local control with chemoirradiation over radiation alone is consistent with the GITSG trial results.0 Gy. significantly. Current trials examine the complete replacement of 5-FU bolus courses with 5-FU infusions. increased biologic effectiveness. Such a regimen (now without semustine) may be recommended as therapy for individuals with resected TNM stage II (Dukes’ B2. potential for increased surgical complications and delayed wound healing. Despite the improvement in local control. either alone or in combination with distant metastases. 39% of patients did not receive their radiation per protocol specifications.5% of the surgery-only arm. This limited the trial’s statistical power to detect significant differences between the study arms. and 5-FU with both LV and LEV. and also showed improvement in overall survival compared with the surgery-only arm. such as an obstruction requiring surgical intervention. First site of treatment failure was locoregional in 24. It is probable that fibrosis and altered vascularity from surgery limit the oxygen supply to the tumor bed.4% of the adjuvant chemotherapy and 16. radiation given preoperatively can convert unresectable disease into a situation that is amenable to surgical excision. Given the potential advantages of preoperative radiation therapy and the results from retrospective studies. Intergroup (INT) trial 0114 was a four-arm trial for patients with TNM stage II and III rectal cancer evaluating 5-FU.

The goal is to resect the tumor completely while attempting to minimize functional impairment. In three of four trials using 2. One trial using three 500-cGy fractions over 5 days showed a benefit in local control only. There is no standardization of what is considered to be resectable disease.004). The incidence of perineal wound sepsis was higher in the preoperative arm. which can be successfully treated by surgery alone. postoperative radiotherapy did not produce the expected low rate of local recurrence in the treatment group. If incomplete surgery can be anticipated.001) and improved 5-year survival from 48 to 58% (p . In one series.168 patients were randomized. radionecrosis of bone with fractures. especially for high-risk patients. Pelvic control and survival were 86 and 68% in the partially fixed group and 80 and 60% in the completely fixed group. Early initiation of systemic therapy compared with waiting and delay until surgical healing.500–4. 134 patients with either tethered or completely fixed tumors received 45-cGy pelvic radiation therapy followed by a 4. The rate of small bowel complications also was lower among the patients receiving preoperative radiation therapy. Adjuvant preoperative radiotherapy also produced adverse effects documented during long-term follow-up of two randomized trials. remains high (25–50%). not surprisingly. local control was significantly improved over that with surgery alone. patients treated with preoperative radiation had a higher compliance rate and less toxicity than those in the postoperative radiation trials. Local control was 91% in patients receiving 50 Gy but only 67% in those receiving . If an incomplete resection is performed. All had initially resectable rectal cancer. and late intestinal obstruction. Attempts to test preoperative chemoirradiation have proven difficult although the dosage of 5-FU for such trials has been defined. The preoperative trials are not. The experience using combined chemoirradiation preoperatively has been more limited. Both the patient populations treated and the technical delivery of radiation therapy differed. improving local control. MRI. has too little practical benefit. Some trials tested accelerated schedules of radiotherapy. p < 02). The preoperative trials also used large fraction sizes and radiation fields extending beyond the pelvis to include para-aortic lymph nodes and made no attempt to limit small bowel from the irradiated field. the NSABP R03 trial was also closed prematurely because of poor patient accrual. The risk of local failure was unacceptably higher than anticipated in controls. Standard preoperative therapy alone continues to fail. p . For those given 25 Gy over 5 days. acting both as a radiation sensitizer and on subclinical disease outside the radiation field. patients with locally advanced rectal cancer constitute a diverse and heterogeneous population. although it comes close in analysis of several disease-free survival end points. respectively. LOCALLY ADVANCED RECTAL CANCER Although often analyzed as a group.and postoperative radiotherapy remains to be defined as much as does the therapeutic benefit. In the five trials using higher doses. the local relapse rate was 11% (63 of 553) versus 27% (150 of 557. cervix. Some evidence-based recommendations may yet be anticipated. 5-FU–based chemotherapy can be used to enhance tumoricidal activity. especially with doses above or below 40 to 45 Gy. Few trials have directly compared preoperative with postoperative radiation therapy. Complete tumor resection may require extending a standard APR to include a posterior vaginectomy or it may require total pelvic exenteration. In patients with advanced but resectable disease. Too many physicians will not randomize. allows for earlier treatment of potential micrometastatic disease. when evaluated for impact on overall survival. however.6-Gy boost. Five-year survival in locally advanced rectal cancer has ranged from 18 to 69%.000 cGy) and those that used intermediate doses (2. The first Swedish multicenter trial randomized patients in the preoperative arm to 2. A historically parallel study of postoperative radiation therapy by the Medical Research Council (MRC) illustrates some of the problems of evaluating the practical benefits of preoperative radiotherapy. which are consistent failures. when the tumor burden is presumably smaller. adjunctive treatment is recommended. without simultaneous chemotherapy. 21%. and advanced-stage patients with distant metastases may obscure any potential benefit of local control on survival. Tumors may be fixed to the pelvic sidewall or sacrum.8.000 cGy. postoperative radiotherapy may have fewer CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1487 complications. The preoperative trials contained a heterogeneous patient population staged without benefit of imaging modalities such as CT. preoperative radiation may allow for a less radical surgical procedure or a sphincter-saving approach. The preoperative randomized trials used lower doses of radiation than those delivered in the postoperative trials. postoperatively. In one important exception after 10 failures of what seemed similar trials. In patients with unresectable disease at presentation. but it may have practical advantages over postoperative treatment. Resectability depends on the skill or aggressiveness of the surgeon and whether the assessment is made clinically or intraoperatively. These results compare favorably with those of adjuvant postoperative radiation. but the comparative quality of life impact of pre. external radiation therapy precedes surgery and IORT or brachytherapy. the risk of pelvic recurrences. Preoperative radiotherapy has significant side effects: thromboembolism. directly comparable to the postoperative adjuvant trials. Despite complete resections.divided into those that used low doses of radiation (500–2. There appears to be a dose-response relationship. no benefit was seen either in local control or overall survival. Despite this poorer technique. over 75% were able to undergo sphincter-sparing surgery. Advantages of preoperative radiation therapy may in theory be further potentiated by addition of a radiation sensitizer like 5-FU. It is uncertain if these best results are comparable to best repeatedly confirmed results achieved with postoperative combined-modality therapy. Postoperative radiotherapy. 79 of 235 controls and 48 of 234 in the treatment group suffered local failure. they either believe or do not believe in preoperative radiotherapy. Pelvic bone destruction can occur from direct invasion.000 cGy preoperative radiation therapy or less. This trial needs to be confirmed in view of the numerous earlier failed attempts to improve overall survival and also considered in the context of other trials. Despite the higher postoperative dose. A German trial comparing pre. The overall benefit is possibly real but modest and difficult to demonstrate with current eligibility and staging criteria. The relative merit of preoperative versus postoperative combined modality will not be defined in American trials. or transrectal ultrasound and often included patients with stage I disease and also patients with clinically unrecognized unresectable tumors or distant metastases. uterus. or prostate. bladder.54).550 cGy and in the postoperative arm to 6. the rate of local failure was lower in the preoperative arm (12 vs. In spite of its favorable impact.000 cGy). preoperative radiation may cause sufficient tumor shrinkage to allow resectability in half. 1.and postoperative neoadjuvant radiotherapy is in progress with satisfactory ongoing accruals of patients with resectable rectal cancer. In a Swedish trial conducted between March 1987 and February 1990. Although 86% of patients had tumors located in the low rectum (6 cm from the anal-rectal junction). but this may relate to the large (510 cGy) fraction size used. Q-Twist methods support combined-modality therapy versus radiation therapy alone for adjuvant therapy of rectal cancer. In the postoperative adjuvant trials. Because a surgical approach alone will often leave behind gross or microscopic residual disease or produce functional deficits. In theory. Overall survival at 9 years was 74 versus 65% for ideally resected patients. a rapid course of preoperative radiation therapy improved both local control and survival. Although it works. Patients with locally advanced disease can benefit from aggressive local treatment. Including early-stage patients with a good prognosis. local control and overall survival were best among those patients treated with both 5-FU–based chemotherapy and radiotherapy. Locally advanced tumors include those that are tethered or have limited mobility and those with complete fixation to contiguous pelvic organs such as the vagina. Of interest and some surprise. then intraoperative radiotherapy (IORT) or a brachytherapy implant can potentially sterilize the remaining tumor cells. There is a wide institutional variation in risk of local failure. In addition to INT-0147. reducing local recurrence (RR = 0. Pelvic Radiation.to 9. Advanced fixation can lead to a completely frozen pelvis.

IORT can also be delivered with a high-doserate remote afterloader. stage II. plastic catheters placed against the high-risk area are afterloaded to allow optimal dose distribution based on computer-derived dosimetry. and perhaps all low distal tumors in men are considered high risk in spite of their small size.. higher doses than can be given safely with external-beam therapy. C nodes. either alone or with the addition of postoperative radiation therapy. Particularly for patients with early rectal cancers. with the aid of a special applicator placed directly over the target area and then lined up in the treatment machine. In appropriately selected patients (i. Radiation therapy in the management of favorable or early rectal cancer has been used both as the primary treatment modality and as adjunctive therapy with local excision and other sphincter-sparing surgery. Either preoperative radiation therapy is given in conjunction with sphincter-sparing surgery or postoperative radiation is given after local excision based on pathologic factors finding high risk of recurrence. It is clear that there is also a role for second salvage surgery to minimize the consequences of local failure and thereby perhaps spare the majority of selected patients an APR. compared to a local failure rate of 8% with 55 Gy given preoperatively. Early-stage tumors with high-grade architecture or vascular invasion. APR has become the standard treatment because high local failure rates have been observed with more conservative surgery.4 Gy followed by either low anterior resection or coloanal anastomosis.4 cGy failed when tested as a randomized adjuvant treatment for colon cancer. interest in sphincter preservation drives efforts to avoid APR for all stages of rectal cancer but especially early low distal tumors. When other patients with tumors 3 to 7 cm from the anal verge received 50. Local excision. not poorly differentiated. due to slow accrual. . Although total dose delivered by external beam usually is limited to between 50 and 55 Gy.e. higher boost fields tailored to the high-risk volume may be appropriate in certain situations if the small bowel can be displaced from the irradiated field. PRESERVATION OF SPHINCTER FUNCTION For patients with low-lying early stages of rectal cancers. with and without radiotherapy.1488 SECTION 29 / Neoplasms of the Alimentary Canal 40 Gy. although 28 of the 30 patients evaluated had T3 tumors. electrocoagulation. transanal. A brachytherapy boost may be given as a volume implant with permanent iodine-125 seeds placed intraoperatively or as a temporary implant using iridium-192. This minimizes the risk of excess radiation to deeper. allow- ing direct visualization of the tumor. The high-risk area is defined at surgery. APR has been the standard of care. In properly selected patients (i. Besides local excision. which allows for deeper portions of the tumor to be irradiated at successive treatments. the 14% local recurrence rate compared favorably to that of patients treated by APR. the local failure rate with endocavitary radiation is 5%. well to moderate histologic differentiation. depth of bowel wall invasion. Approximately 95% of tumors in the series by Sischy were locally controlled at 5 years. may determine if this will become the treatment of choice Patients with rectal cancers that have a low risk of regional lymph node involvement are candidates for treatment with conservative local approaches. a rectoscope attached to a low-energy (50 kV) contact x-ray machine is inserted transanally. mobile. The procedure can be performed on an outpatient basis and is particularly suitable for those who are medically inoperable. For distal rectal cancers. because a substantial number of these elderly patients with significant preexisting medical conditions died from co-morbid diseases. In the Papillon technique. and need for a permanent colostomy. there is substantial tumor regression. this approach can be delivered on an outpatient basis with minimal morbidity and excellent long-term control. The radiation is delivered as a single dose. IORT using an electron beam from a linear accelerator can also deliver a boost dose. approximately one-third of expertly selected patients may be cured with such an approach.500 to 3. Patients who are not surgical candidates and have mobile or partially fixed tumors too large for endorectal radiation may be treated with primary external-beam radiation. Tests of sphincter function by anal manometry found no significant difference in mean maximum squeeze or resting pressure after radiation therapy. To some degree. endocavitary radiation. Twenty to 30 Gy are delivered in three to four applications spaced 1 to 3 weeks apart. local excision. sphincter-sparing surgery).. Nevertheless. Papillon had similar results. In theory. In best but not consistently achieved results. Patients with T3. urologic dysfunction. others found a 20% local failure rate with 45 Gy. Sphincter function was rated as good to excellent in over 75% of the patients. there is controversy whether radical resection is required or if equivalent local control and survival rates may be obtained with nonsurgical approaches or conservative surgical techniques (e. Some of the theoretical stage for stage concerns with sphincter sparing has been reviewed. can be delivered with a brachytherapy implant or IORT. tumor size < 4 cm). or anterior resections. downstaging allows sphincter preservation. Endocavitary radiation therapy also may be combined with interstitial radiation to deliver a boost with brachytherapy or combined with external-beam radiation. Postoperative methods in the form of combined-modality therapy with LEV and FU 45 to 50. grade. local therapies have included fulguration. however. allowing normal tissues such as small bowel to be moved out of the way before irradiation. This NCCTG trial attempted to develop the promising Joint Center strategies for B3 or T3 N1-2 M0 colon cancer described above. In an iridium implant. histology. with 2 to 3 weeks between fractions and a dose per fraction of 2. usually between 10 and 20 Gy. To avoid the morbidity associated with APR. and lymphatic or blood vessel invasion. the empiric approach would be that patients with T1 or T2 tumors with poor characteristics found at pathology are treated with postoperative radiation therapy. As yet undefined success with surveillance and salvage. When the method of identifying toxicity is not described or is not of the highest standard. acceptable candidates for local excision either alone or with the addition of postoperative radiation therapy can be defined by tumor size. including impotence.. 5-FU sensitization may increase the efficacy of radiation therapy. the 4-year actuarial local failure rate was 23%. T1 and T2. Although it appears that higher radiation doses improve local control. alternative approaches to treatment have been evaluated. T4 tumors are candidates for preoperative radiotherapy because. Several techniques may be used to deliver an increased radiation dose to the area at highest risk for recurrence while respecting the tolerance limits of normal tissue.g. underlying normal tissues. Only 222 patients were tested. In the Papillon technique. Complications included anastomotic disruption and leak in 4 and 6% of patients. multiple studies have evaluated whether preoperative radiation therapy with sphincter-preserving surgery will result in outcome equivalent to that with APR while preserving anal-rectal function. those with tumors ≤ 4 cm in maximum diameter. In both situations. Brachytherapy provides another method of delivering a boost radiotherapy dose. also has been used as an alternative to radical surgery to preserve sphincter function. With postoperative radiation therapy there is also an important role for close observation and even selective reoperation and further intraoperative radiotherapy. very low-energy x-rays (50 kVp) exit through a large rectoscope that is inserted transanally and placed directly over the tumor. B2 or stage III. combined abdominal transsacral. if successful. Survival statistics are not as good. It is an option for a few expert practitioners and trialists. second resectors. In between the doses. no direct comparison has been made between the various techniques for delivering a boost dose. compared with 67% for patients not receiving IORT or additional postoperative radiation. the absence of unreported side effects cannot be assumed. Toxicity of radiation remains an important unresolved end point in comparing proposed treatments. This is an alternative for highly selected patients in the context of institutional review and individual informed consent. When patients with tumors in the distal 3 cm of the rectum received 45 to 60 Gy followed by transabdominal. Similarly. Patients are treated with approximately four fractions.000 cGy. This is not yet a standard of care. and endocavitary radiation. Boost doses. a similar large number in both test groups suffered recognizable relapse. Patients at the Massachusetts General Hospital receiving preoperative radiation and a complete surgical resection with IORT had a 5-year actuarial local control of 88%. exophytic. Because radical surgery results in significant functional impairment and morbidity.e. and without any evidence of deep ulceration or invasion).

At present. tumors with perforation or associated fistula. In the NCCTG 794751 study. increased benefit and may have added to survival (4 vs. The surgeon can use techniques such as reperitonealization of the pelvic floor. Possibly.0 cm lateral to the pelvic side walls. the radiation oncologist should be familiar with the pathology report and operative note. In selected patients. 21 Gy (median) at 2. Most of the morbidity associated with pelvic radiation therapy relates to the volume of small bowel in the radiation field and the dose that it receives. Three-dimensional treatment planning and dose-volume histogram analysis may aid in maximizing the dose to the appropriate site while minimizing the treatment of normal tissues. Surgery is associated with adhesions that may cause a small bowel obstruction or. a significant proportion of these patients ultimately will fail either regionally or distally (see Table 103. whose posterior extent is approximately at the level of the sacral promontory. prior abdominal or pelvic surgery. In 71% of patients. T4 tumors. Lateral borders for the AP-PA fields usually are placed 1. Meta-analyses fail to support therapy for B2 patients even though several studies clearly show benefit. there are patient subgroups with resected colon cancer that are at significant risk for local failure. adjuvant intervention can be applied . For pelvic radiation in rectal cancer. especially if disease is extensive. and many had decrease in hepatomegaly. and the increased amount of small bowel irradiated adds to morbidity. Although older studies often put the cephalic border as high as the L1 or L2 vertebral bodies. then the boost dose of radiation can be given to the area at highest risk for recurrence while limiting the volume of normal tissue receiving the higher doses. most patients with colon cancer and a tumor that penetrates to or even through the serosa (i. If the tumor volume or surgical bed can be precisely located. using a three. efforts should be directed at maximally excluding it from the radiation fields. The caudal border is placed 3 to 5 cm below the primary tumor or anastomosis in patients who have had a low anterior resection and 1. unlike colon cancer. ultimately. Although randomized trials. at best. patients with clearly operable resectable tumors. radiation fields are set up with the cephalic border. use of an omental flap. Although many patients are diagnosed by colonoscopy. whole-liver radiotherapy clearly failed in a large prospective adjuvant trial performed by the GITSG. and 5-FU chemotherapy.5 cm below the perineal scar to include the perineum in patients who have undergone an APR. the recommended adjuvant treatment consists of a combination of 5-FU and LV for patients with resected T2-3 N1 M0 stage III colon carcinoma based on a decrease in the risk of recurrence and a onethird reduction in the death rate. Use of clips placed at surgery to outline the tumor volume or delineate a close or positive resection margin can be very helpful.4). The role of adjuvant radiation therapy plus chemotherapy in resected colon carcinoma is not as well defined as it is for rectal cancer. this result should be interpreted as finding adjuvant chemotherapy alone (equally effective) compared to combined-modality therapy for resectable high-risk colon cancer. The actual somewhat-modified-by-a-treatment-control phase III test failed in part due to poor accrual. they have only a slight effect on reducing local failures. B1. CT or MRI also can be helpful in describing the treatment volume. Planning of Radiation Therapy The normal tissue tolerance of small bowel to radiation limits the dose that it can safely receive. Although in earlier studies. Neither chemotherapy alone nor monoclonal antibodies reduce the risk of local failure of colon cancer in a clinically important fashion. These patients may possibly benefit from adjuvant local radiation therapy. Currently. The internal iliac and presacral lymph nodes are at risk and are included in the field. higher doses delivered by cone-down fields with external-beam radiotherapy or with a brachytherapy or IORT boost may be appropriate. The posterior border of the lateral fields should include the entire sacrum with margin. there is little justification for fields extending to this level.000 cGy increase the risk of late complications such as small bowel obstruction.040 cGy or to 5. typically placed at the L5-S1 junction to stay above the peritoneal reflection. The external iliac nodes also are included if the tumor extends down into the anal canal or invades organs that share the same lymphatic drainage The initial pelvic field typically is treated to 4. and patients with clearly fixed tumors or tumors so distal that sphincter sparing requires preoperative adjunctive therapy. patients were treated anteroposteriorposteroanterior (AP-PA) with two fields.0 to 3. Small bowel toxicity can be exacerbated by medical conditions such as hypertension or diabetes. in approximately one-third of patients with B3 and almost one half of patients with C3 tumors. postoperative treatments have found the most consistent strong support. Role of Radiation Therapy in Colon Carcinoma.500 to 5. by limiting small bowel motility. Boost radiation. trials continue to evaluate the sphincter-sparing strategy of local excision. When resection is technically possible. 14 months). In rectal cancer. Local failure occurred frequently in patients with local extension. Blocks then can be custom shaped to minimize the treatment of small bowel. nonrandomized trials of preoperative radiotherapy have found reasonably strong support for treatment when there is tumor fixation. For early tumors. An earlier adjuvant trial had been found promising. In contrast. radiotherapy may have a palliative role against symptom-producing liver metastases. such as gene probes for specific sequences necessary for invasion or metastases. Patient groups who appeared to benefit from local postoperative radiation included those with stage B3 and C3 lesions. The benefit of adjuvant chemotherapy was most pronounced in decreasing distant failure. has as its intent the identification of subgroups at increased risk for recurrence so that. The ongoing search for additional prognostic markers. a barium enema is useful for treatment planning. or placement of an absorbable mesh to hold small bowel up and out of the pelvis. Although controversial. Cooperative groups have found that there is a radiotherapy learning curve and minimizing errors requires a combination of experience and quality control procedures. as described below. Retrospective trials assessing the impact of postoperative radiation in patients with high-risk colon cancer have sometimes shown a benefit both in local control and disease-free survival compared with historical control groups treated by surgery alone.5 to 2.. Oral contrast should be given sufficiently earlier than simulation to allow for adequate transit time to visualize small bowel during treatment planning. Although the overall local failure rate is lower in colon than in rectal cancer. the anterior border typically is placed at the posterior aspect of the symphysis pubis or 2 to 3 cm anterior to the sacral promontory. Nevertheless.In considering preoperative versus postoperative radiotherapy. selective postoperative radiation therapy. Positioning the patient prone and bladder distention also can aid in excluding small bowel from the radiation field. CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1489 Because the volume of small bowel that is irradiated relates to toxicity. Doses higher than 4. it is important to make a distinction between candidates for standard stoma-free resection. and the subject of only a few reports describing small series of patients. and close follow-up.e.or four-field technique with lateral fields and either PA or AP-PA fields helps to reduce the dose to small bowel. similar to the high-risk pilot trials described above.500 cGy in 180-cGy fractions daily over 5 weeks. Other high-risk factors include gross extension beyond the bowel wall and blood vessel or lymphatic vessel invasion.0 Gy daily. To identify the high-risk area. increase the toxicity from radiation therapy. Adjuvant Chemotherapy and Immunotherapy. B2) do not have a statistical risk of recurrence that is sufficiently high to justify postsurgical adjuvant treatment to the entire group. pain relief was achieved. comparisons of preoperative to postoperative therapy. An initial pilot trial of adjuvant 5-FU and radiation therapy appeared encouraging. and subtotally resected tumors with gross or especially microscopic residual disease. severe diarrhea developed in 5% of patients treated with adjuvant radiation alone and in 20% of those receiving combined radiotherapy and chemotherapy. there is a clear consensus for adjuvant treatment of stage II tumors and an impression that some stage I tumors should be treated. have been difficult. Most local failures occur in the posterior one half to twothirds of the true pelvis so that tissues located anteriorly and especially small bowel can be excluded from the lateral fields. Treatment must be individualized. A boost dose to the tumor or surgical bed is given to 5.400 cGy if all small bowel can be excluded from the final cone-down field.

e.. it will still be necessary to perform prospective tests of adjuvant therapy. Subsequent trials tested LEV and 5-FU. radiation (rectal cancer). The LV/FU proved equal or slightly better than the LEV/FU in these trials. it found no benefits for patients with resected rectal cancer. has the ability to reduce the metastatic potential in nude mice of highly metastatic human melanoma and breast cancer cell lines.9). with a flat survival curve. 5-FU plus LEV reduced the recurrence rate by 40% (p < .e. compared with 20% of those without (p < . Investigators were more comfortable with LV than LEV because it has a known mechanism of action and demonstrable impact on response rates in advanced disease trials. thereby providing a possible means of identifying those at risk early in the clinical course of disease. respectively. allelic loss of chromosome 18q has independent and strong prognostic value on survival. Dukes’ C) patients when LEV and 5-FU adjuvant treatment was compared with surgery done (Fig. Once a high-risk group is clearly identified. Finding deletions of this locus (by DNA probing of the surgically resected specimen) has prognostic value in all stages of colon cancer. but the success of salvage resection for controls upon relapse and unexplained deaths from other noncancer causes in the LEV/FU group negated the promising advantage. Again. Flow cytometry has initially failed to provide prognostic guidance for patients with rectal cancers but remains an unconfirmed promising candidate prognostic test for patients with colon cancers. Levamisole and Fluorouracil. Adjuvantly treated patients had a significantly improved disease-free and overall survival compared with those treated by surgery alone (p < . for the 5 to 8 years of follow-up for the treated patients. COLON ADJUVANT THERAPY HISTORY The GITSG study 6175 was one of the first modern studies for patients with stage III colon cancers. Patients with Dukes’ C (i. with obstruction or perforation) patients also benefited. A significant overall survival benefit occurred in the stage III (i. and immunotherapy (colon cancer) have been tested and found to be effective in rigorously conducted studies. for colon cancer on Fu infusion added to radiotherapy for rectal cancer and on identification of high-risk B2 patients warrants updating the consensus recommendations.6 Overall. found LEV/FU as expected effective for patients with C tumors but found it a marginal failure for patients with B2 tumors. These are actually large improvements considering the inclusion of B2 patients in the trials. Presumptively. 5-FU. B. also concluded that there was no effective adjuvant therapy for patients with high-risk colon cancer. Patients with stage C colon cancer treated adjuvantly. stage III) colon cancer treated with curative-intent surgery were randomized to receive (starting within 1 to 5 weeks of surgery) 5-FU and LEV after surgery.1490 SECTION 29 / Neoplasms of the Alimentary Canal in a selective fashion. and some even find no overall benefits for patients with resected B2 or C tumors. currently. To increase both cure rate and survival. Therefore. particularly in stage II colorectal cancer.003) (Fig. In contrast. Figure 103.8 and 0.. Other trials of LEV/FU have produced some conflicting results. some find no benefit for B2 patients favoring LEV/FU. Meta-analyses. designed and performed at about the same time. LEV appeared to substantially improve disease-free survival.. The first widely accepted case for adjuvant treatment in colon cancer with 5-FU and LEV is based on two large trials. in contrast. or no adjuvant treatment. immunotherapy. Recurrence free interval. Some patients find benefit. High-risk B2 (i. The initial GITSG adjuvant colon study found no benefit from either chemotherapy.0007). unlike levamisole.64. survival. allelic loss present) whose survival is similar to that of stage III disease. LEV alone after surgery. the latter would benefit from timely and effective adjuvant therapy. The seemingly small percentages translate into large numbers of patients and are actually strong support for the widest possible use of adjuvant therapy for high-risk patients.. testing for such allelic loss.177 A. no allelic loss) whose survival is similar to that of stage I colon cancer and a poor prognosis group (i. or chemoimmunotherapy compared with surgery alone. LV/FV for 6 months has become the standard of therapy for stage I colon cancer. PATIENTS WITH HIGH-RISK COLORECTAL CARCINOMA The consensus conference convened by the NCI defined therapy recommendations based on the initial successful trials. 103.6 The calculated approximate cost of adjuvant colon cancer treatment for stage III is $2. by cDNA transfection studies. 6 months of LV/FU were effective and equal to either 12 months of LEV/FU or LV/FV . may assist in identifying a good prognosis group (i. without consistent evidence of benefit. Recently. Some of these trials did report a slight. LEV alone did not improve disease-free survival compared with that of control patients. A meta-analysis finds 5% improvement in colon adjuvant trials and 9% in rectal adjuvant trials with a majority odds ratio of 0. clinically unimportant advantage for bacille Calmette-Guérin (BCG) immunization and/or combination chemotherapy with semustine.0001) and the death rate by 33% (p < . but a combination of other causes of noncancer deaths and surgical resection of recurrent disease may have obscured the outcome benefit. Additionally. New information on monoclonal antibody treatment for colon and rectal cancers on LV and FU. vincristine.e. chemotherapy. The failure of the original NCCSG trial to benefit patients with B2 tumors is complex. Trials demonstrated that 6 months of LEV/FU were ineffective. Additional well-controlled trials.094 per year of life saved. The possibility that LEV/FU benefits any B2 patients must be viewed cautiously because there were no supporting findings from the meta-analysis. a highly publicized Dutch trial that was prematurely reported as a failure provided another phase IV successful test of LEV/FU and even found benefit for the B2 patients.e.. B2 patients did not benefit. The combination of LV and 5-FU was effective in several schedules: day 1–5 bolus 5-FU (Mayo Clinic) and weekly bolus FU schedules (RPMI). in contrast. This cost-effective advantage persists. and FU. 73% of patients with the deletion ultimately developed metastatic disease. the NSABP’s trials consistently found a large advantage for both LEV/FU and other adjuvant chemotherapy for patients with resected B2 cancers. Lev—levamisole.10). 103. .e.9. Adding LEV to LV/FV produced no additional benefit over either 6 or 12 months.03). Chromosome 17 at q21 position contains a late-acting tumor suppressor locus near to or identical with the nm23-H1 allele that. several multi-modality treatments combining surgery. and this needs to be tested in prospective studies.

To some degree. There are objective examinations of side effects. A different LV-5-FU regimen (FU. increasing 3-year event-free survival from 62 to 71% and overall survival from 78 to 83%. Survival of patients with stage C colon cancer treated adjuvantly. In order for adjuvant therapy to be fully used. probably incorrectly in view of the practical benefit achieved in large trials and the meta-analysis. SUMMARY There are criticisms of the initial studies and of adjuvant therapy for colon cancer: (1) academic criticism—that there was no 5-FU control. Adding interferon (INF) alfa-2a to LV/FU in trial CO-5 failed. The choice of controls does not change the fact that the combination works. In addition. The drug may produce vague symptoms of neurasthenia and mild changes in liver functions. Ideally. Controlled trials of FU and low-dose LV given for 6 months as postoperative adjuvant therapy for colon cancer find that the benefit of LV/5-FU can be achieved with only 6-month cycles of treatment. without LEV . 20 mg/m2/days 1–5 IV and 5-FU 425 mg/m2/days 1–5 every 4 to 5 weeks is now recognized to be the shortest. the North American consensus strongly supports trials with treatment controls. even inappropriate criticisms. Oral tegafur with LV is currently in trial. The TNM staging surplants earlier widely used systems. when comparing 1 year of treatment. the superior speed of LV . and the failure or questionable failure marginal role of LEV in combination with . less than 10 nodes may have similar implications. Experience and good support probably make a difference in tolerance.10. there are real practical overall problems posed by the acute and chronic side effects of threatment. two of three trials favor a role for LEV more than a role of dose intensity as the critical element in successful trials. Use of conventional 5FU alone. The efficacy of adjuvant FU and folinic acid in colon cancer has been demonstrated by the International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. may be more important than LEV is not supported by analyses. Rectal cancer should not be viewed as identical to colon cancer. size. In context. LV and 5-FU (LEV) for 6 months was superior to 5-FU LEV for 6 months by 10%. This translates into a 5% improvement in survival achieved with only 6 months of treatment. The theoretical consideration that the total dose of 5-FU. The trial does not favor treatment of B2 patients who as a research group have an 80 to 82% 5-year survival. in spite of the failures of chemotherapy alone. Adding LEV to 5-FU and LV added little or nothing. however. these are weak. Some European investigators are far less convinced by the American trial findings.029) and events by 35% (p < . the descriptions of operative and pathologic findings must include more than the current conventional information. They are viewed as a reason to use all expert supply resources before and during radiotherapy. Patients aged 70 to 75. In contrast. Low-dose LV. Both are equal. In the case of rectal cancer. and the combination of LV/FU also probably fails. the surgeon and pathologist will specify degree of serosal invasion in order to distinguish between serosal and regional peritoneal stage IV tumors. Adjuvant therapy is considered standard therapy for patients with stage III colon cancer. fatal extrapelvic recurrence and the rate of debilitating local failure. albeit slightly less. Some conclude there is actually a net quality of life benefit.9 The mechanism for interaction of FU and LEV remains unknown. 375–400 mg/m2. The combination of LEV/5-FU fails against rectal cancer. especially for the elderly.0001). vincristine. It is now important to describe the size and resectability of distant lesions Comparison of LEV and FU with a regimen of FU biomodulated with LV and with a combination of all three drugs has changed the standard of therapy. LEV does have side effects. must be considered suboptimal for patient welfare. They need to be discussed in considering the overall benefits of sphincter-sparing and postoperative adjuvant therepy. treatment is variously described as producing little serious risk or quality of life loss compared to the impact of recurrent disease. systemic research aside. but this needs to be confirmed. Less than six nodes examined is possibly equivalent to a C tumor. (surgery only) controls. Currently. LEV “alone” is consistently ineffective as adjuvant therapy. plus LV. and 5-FU (MOF) in patients with Dukes’ stage B and C colon cancer). a potential mechanism has been elucidated involving the enhancement of HLA class 1 protein expression by a specific interaction at the messenger RNA level. The practice of limiting adjuvant therapy to the young is probably incorrect. (2) humanistic criticism—that there is possibly no quality of life advantage. chemotherapy is necessary for rectal cancer. may live an additional 10 to 15 years. Even patients with co-morbid conditions usually live longer than the 2. It is informative to describe the extent of nodal involvement thoroughly. This combination was found to reduce mortality by 22% (p < . At the molecular level. The three trials included in the IMPACT analysis found a 22% and a 33% reduction in deaths at 3 years. the risk can be preselected or selectively minimized by choice among effective options. This was equal to LV and 5-FU LEV . and (3) economic criticism—that there are hidden costs. when compared to 6 months of treatment with LV/5-FU. and associated inflammation.to 3-year median time to progression of colorectal cancers. however. even if there are some literal truths. Six months of treatment with LEV/5-FU is inferior. of which the most serious. Source: Moertel and colleagues. is very rare. a not uncommon problem. They are less than the side effects of recurrent disease. including nodal level. The prospectively randomized NSABP trial C-03 compared LVmodulated 5-FU to a regimen containing semustine (MeCCNU). The fear is probably greater among inexperienced physicians than patients. after numerous failures and minimum overall survival impact found in meta-analyses. and least toxic treatment. There is no evidence that elderly patients fail to benefit. This appears to demonstrate that LEV is usually unnecessary considering the success of 6 months of treatment with LV/FU. A disease-free survival advantage (30% at 3 years) and an overall survival advantage (32% at 3 years) was demonstrated for patients treated with LV-modulated 5-FU compared to those treated with MOF. multifocal leukoencephalopathy. at 5 years. demonstrating the efficacy of LV and FU for 6 months versus control. These investigators had previously achieved the same results. 10 grams or more in the first 3 months. Fear of side effects is often cited as a reason to decline adjuvant therapy. distortion. if healthy. 70 versus 60%.) In the case of rectal cancer. Because of its fewer side effects. in other adjuvant trials. and trials of other oral agents are in various stages of development.CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1491 Figure 103. The efficacy of LEV is questioned. the clinician needs to know the numbers of nodes involved and the number examined. rather than avoiding adjuvant chemotherapy. 200 mg/m2 daily for 5 days every 28 days for six cycles) was evaluated in patients with resected Dukes’ B and C cancer against a control group. They do benefit. They doubt that LEV or even LV when added to 5-FU produces a worthwhile adjuvant therapy regimen and continue until recently to perform controlled trials with no adjuvant treatments. In combination with radiation therapy it demonstrably reduces both distant. least expensive. all of which are reversible. In the case of colon cancer.

There have been failed attempts at ASI. at an estimated cost of $1.1492 SECTION 29 / Neoplasms of the Alimentary Canal LV/FU. survival benefits (p < . followed by four monthly infusions of 100 mg each to a group treated with surgery only. now incorrectly considered low-risk patients. particularly rectal adjuvant therapy. . it is theoretically an ideal noncross-resistant partner for combination chemotherapy. Four anaphylactic reactions controllable by steroids also were reported. These positive findings have not been universally accepted. specific vaccine appeared to produce significant benefit regarding time to recurrence and overall survival in patients with colon cancer.026). Nevertheless. the hazard ratio for recurrence of the ASI-treated group compared with the surgeryalone group was 0. but proof of principle may be difficult because there are too many exclusions and biologically ineligible patients and because of poor immune responses. The benefit of chemotherapy was limited only to high-risk males. 500 mg. the immunotherapy arm BCG administration was shown to reduce the incidence of new primary tumors when added to the semustine/5-FU treatment.000 to 30. IMMUNOTHERAPY BCG Vaccination.400 per year of life saved. Trials testing it alone and in combination with chemotherapy are ongoing or in follow-up phase. approximately one-third fewer patients would die from colorectal cancer. Other attempts at regional adjuvant therapy include the radiotherapy efforts described above. This study remains unchanged. This cannot assume benefit for the same patients who benefit from LEV 5-FU or LV/5-FU. and 5-FU continuous infusions probably are probably superior to MOF and certainly less toxic. but still clinically important.051) and the risk of death by 26% (p < . Monoclonal Antibody Treatments. It is available commercially and for compassionate approval in several countries. The Southwest Oncology Group also evaluated BCG and found it a possible chemopreventive agent. representing a 75% reduction in the risk of recurrence (p < .05) occurred. Only those patients with high TS levels showed a survival benefit from 5-FU–based adjuvant chemotherapy.243 (Cox model estimate). as does the minimum risk of side effects due to chemotherapy. except where there is an allergic reaction to LV or a trial question. chemotherapy alone. This benefit was restricted to the patients with colon cancer. It follows that there may be a rapid systemic 5-FU (and or MMC) chemotherapy effect. This randomized trial of MAb for adjuvant therapy of resected Dukes’ C produced a 30% reduction in the risk of death at 5 years. perhaps even testing preoperative therapy. With the exception of the NSABP rectal cancer adjuvant trial R01. the benefits were limited to stage II patients. it remains reserved for research. With 8 years of follow-up. Survival is still the most important criterion for establishing the benefit of any therapy to be added to surgery.000 lives saved per year. Although this would normally indicate that the ASI was especially powerful because it could impact outcome in spite of the small numbers of patients. Analysis of rectal cancers indicated that expression of the thymidylate synthesis (TS) protein varied with stage and was an independent prognostic indicator. this effect was achieved with a shorter time of treatment than that with conventional bolus regimens. The positive findings are somewhat counterintuitive. Although. This translates into approximately 20. The MRC AXIS trial also found a 4 to 5% overall benefit for patients with resected colonic (not rectal) cancer. this randomized trial was too small. Nevertheless. Because of its independent mechanism of action and side effects. With a median follow-up of 68 months. Its degree of efficacy remains unknown. Detailed attempts to investigate these persistent doubts find little or no practical basis for depriving high-risk patients. It had no detectable effect on local recurrence. Subsequent trials make the R-01 regimen of MOF obsolete in that both LV. the methenol extracted residue of BCG tended to have an adverse effect on overall survival in the initial GITSG trial. a mortality reduction of 30% and recurrence reduction of 27% (p < . BCG cannot be considered a standard treatment. the candidates for such research are not ideally well defined. This neoadjuvant approach with either portal or systemic infusions of 5-FU is still totally investigational. Incorporation of BCG with tumor in order to develop an active.200 to $1. OTHER ADJUVANT REGIMENS Taylor and colleagues’ original data concerning portal vein infusion found benefit with brief postoperative treatment. now not offered therapy. Active specific immunotherapy has been tested again and found to produce overall survival benefit. however. which deprives many patients of potential benefits. Trials have shown that the combination of postoperative chemotherapy and external-beam radiation therapy significantly increase overall survival of patients with stage II and stage III rectal adenocarcinoma. The degree of benefit from portal vein infusion does not quite approach that achieved with LV and 5-FU. Poor patient and physician acceptance and poor coordination of disciplines especially failed surgical prospective preparations for adjuvant therapy. MAb 17-1A is viewed as most promising for low tumor burden and Go tumor applications. of very promising trials or systematic well-tolerated standard adjuvant treatments. They significantly diminish regional recurrence when compared to conventional radiation therapy alone. At a median follow-up of 5 years (p < .05). If high-risk patients were treated and were to accrue to present-day adjuvant trials. it demonstrates durable benefit. to receive either surgery alone or surgery plus active specific immunotherapy (ASI) with autologous tumor cell-BCG vaccine. but it would appear to represent a logical extension of Sugarbaker’s strategies. can be critical. At median follow-up of 8 years. but the brevity of portal vein infusion makes it attractive. Eighty patients were randomized. Meta-analyses of 10 such trials find only 4 to 8%. including an ECOG trial. in some trials. it approaches other systemic adjuvant treatments in efficacy. Laboratory-guided identification of additional high-risk patients. Other adjuvant biotherapy approaches tested Tagamet and PSK and produced some marginally promising findings. no other well-designed trial has shown the benefit of chemotherapy alone after surgery for patients with high-risk rectal cancers. Unfortunately. Panorex must remain an investigational drug because of the small size of the original trial and the need to complete analyses of new trials. Combined modality remains the adjuvant treatment of choice because of inconsistent or less success with either chemotherapy alone or with radiotherapy alone. the adjuvant intraportal treatment had reduced the risk of recurrence by 21% (p < . Intraperitoneal chemotherapy combined with systemic adjuvant therapy has also been proved feasible. after standard resections for Dukes’ B2 and C colon or rectal cancer. the ability to diminish regional recurrence and the subsequent symptoms of regional tumor growth is a worthy end in and of itself. A randomized trial of monoclonal antibody (MAb) 17-1A (Panorex) used postoperatively in Dukes’ C patients compared a short infusion. In contrast. The finding that only 7 to 10 days of treatment at the time of surgery is effective at all provides reason to evaluate the earliest possible start of systemic adjuvant therapy. practice studies and some literature describe great ambivalence toward adjuvant therapy. 5-FU. In the NSABP Colon Adjuvant Trial (Protocol CO1). Five of six trials found benefit to be systemic. or were treated with the earlier recommended conventional treatment plans. one dose) plus 5-FU (500 mg/m2 continuous infusion per 24 hours for 7 days) against no adjuvant treatment. Patients with rectal cancer all received definitive radiation to the tumor bed. however. A randomized trial evaluated intraportal mitomycin (10 mg/m2. is possible. analogous to successful preoperative trials in regional breast cancer. LEV is currently an almost obsolete historical option. This is the most rapid of the adjuvant treatments. No patients should be refused chemotherapy treatment based on a predictive test. Adjuvant 5-FU infusion via the portal vein decreased the rate of extrahepatic recurrence but did not decrease liver metastases. apparently independent of the portal route of administration. Adjuvant therapy has great public health significance. Preclinical evidence of cytolytic effects predicted the potential therapeutic success. with only mild constitutional and GI symptoms as the most frequent toxic effects. radiation given concomitantly to the rectal cancer group may have mitigated any advantage from immunostimulation by the vaccine. The concept of ASI remains attractive. with all sites of recurrence being reduced in the treatment group rather than hepatic recurrences only.016). or surgery only. The failure to see any hint of benefit in stage III patients is unexplained and cause for concern.01).

adding LV doubles the rate of response compared to 5-FU alone. This evidence of benefit has been Figure 103. On the other hand. Source: Steele and colleagues. Disseminated colorectal cancer recurrence is much more common. With the present endoscopic techniques and higher incidence (in some series up to 50% within 5 years). Follow-up should be applied most frequently in the first 2 years and less frequently thereafter.11. there is a much lower than expected incidence of carcinomas in the distal sigmoid and rectum in patients who underwent repeated rigid sigmoidoscopic surveillance with removal of known polyps. Over 1 to 2 years. There is evidence for the clinically significant frequency of metachronous lesions (mainly polyps as opposed to cancers). Source: Steele and colleagues. two.11 and 103. There is a general consensus to use chemotherapy as an adjuvant after resection. The actual supporting evidence is not mature enough to fully support this practice. at present. and downstaging and resection of metastatic diseases are increasingly feasible. 103. Second. the standard systemic therapy for advanced systemic colorectal cancer is a combination of 5-FU and LV . unless it can be debulked. there has been a decrease in mortality and morbidity among patients who undergo major liver resection.12). A firm recommendation about routine follow-up for asymptomatic recurrence after 5 years is to continue surveillance for the development of metachronous bowel neoplasms.e. liver and liver plus lung are the most frequent sites involved. SYSTEMIC RECURRENCE Patients with peritoneal or diffuse multiorgan recurrence have a systemic advanced disease. Clearly. then a 3to 5-year interval colonoscopic examination probably is appropriate. Any more frequent interval examination probably would diagnose tumors that by definition are so aggressive subsequent therapy might be ineffective. It remains to be proven that aggressive debulking and intraperitoneal therapy can change this bleak assessment of prospects for patients with anastomotic recurrence.. At present. similarly represents a systemic disease.424 . isolated pulmonary. not the diagnosis of rare and almost always incurable anastomotic recurrences. randomized trials show benefit. Several controlled. at surgery or within 3 to 6 months after surgery. Colonoscopy is preferable to sigmoidoscopy as a method of follow-up. but. colonoscopic and/or double-contrast roentgenologic examination should be undertaken at once. ideally before primary tumor resection but. Eighty percent of patients who recur do so within 2 years of their primary tumor treatment. or isolated pelvic metastases provided that preoperative staging of the solitary liver or lung metastasis is confirmed by surgical staging and if pathologic confirmation of free margins is obtained after resection. The major requirement for a successful adjuvant therapy that improves overall survival appears to be the ability to control distant metastases. or three lesions. or blood in the stool. disease-free survival with hepatic artery infusions appears CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1493 Figure 103.Follow-up After Primary Therapy for Colorectal Cancer.12. Recent recommendations for surveillance guidelines have been published by a leading clinical group. Response rates have increased into development steps. Retrospective reviews of many patients who have undergone liver resection for isolated metastases and a multi-institution prospective registry in which patterns of recurrence were analyzed after liver resection have pointed out several important facts. and rates of hepatic relapse are less than anticipated. cure) at 5 years can be attained in approximately 25 to 30% of patients with isolated liver. there are no curative treatments. The group of patients with resectable pulmonary or liver recurrence probably represents 6. If no lesions are found at the first annual endoscopy. in the case of patients with distal obstructing lesions. As yet. Probablity of survival and disease-free survival of patients with rectal cancer and hepatic metastases resected with curative intent. but advances in cost-effective and tolerable treatments have occurred. Durable disease-free survival (i. only rarely have patients recurred after 5 years. Peritoneal disease. unexplained anemia. Most patients need systemic therapy. these polyps can and should be removed before they become cancers. but phase II and early phase III findings encourage trial efforts. An acceptable empiric approach is to obtain complete surveillance of the large bowel mucosa. Endoscopic evaluation of patients during follow-up is aimed at the diagnosis and treatment of premalignant neoplasms. the American Society of Clinical Oncology. Some regimens may yield 5-year survivors (see hepatic artery infusion chapter). ISOLATED RECURRENCE There are opportunities for curing a patient once recurrence is diagnosed. no known systemic therapy of choice has proven curative potential. Autopsy series showed a 7% incidence of synchronous or metachronous bowel cancers in patients with colon or rectal cancer. patients who cannot have all of their disease removed do not benefit in terms of survival compared with those who have no resection at all (Figs.000 to 7. Disease-free time has increased. then a yearly follow-up endoscopic examination is enough. First.000 patients per year in the United States. If no synchronous lesions are noted. Probability of survival in patients with potentially resectable hepatic metastases from rectal cancer. if synchronous polypoid lesions are found at the original screening examination or the first yearly follow-up. then a 1year colonoscopic re-examination is justifiable until no further recurrent or residual polyps are noted. Cryotherapy and use of chemotherapy after resection may improve these results.424 improved. In the presence of symptoms such as change in bowel habits. The success rate is highest when relapse occurs more than 1 year after surgery and when there are only one. Findings with selective attempts remain promising.

the clinical choice is based on experience. its biomodulation by LV . The other major regimen is the GITSG/RPMI weekly regimen. Historically.to 18-minute half-life of the drug. or active colitis. Laboratory findings make it clear that bolus and infusion 5-FU regimens should not be cross-resistant.5 to 3. It is increasingly important to be alert for circumstances in which (recurrent) regional or metastatic disease is now appropriately approached by new combined-modality treatments: resection hepatic artery infusion. challenge the standard 5-day loading schedule. ribonucleotide reductase.600/mg/M2. produce diarrhea as the limiting toxicity. Details of 5-FU schedule may prove to be extremely important. exceptional tumor regression. (With prolonged infusion of 300 mg/m2/d for 4 to 6 weeks. which are associated with survival impact. between tumors in the same patient. hand-foot syndrome is limiting and hematologic toxicity is trivial. or methotrexate (MTX) 5-FU–based combinations.e. Response rates with intravenous 5-FU were superior to those with intensive oral treatment (26 vs. The current status of 5-FU. Patients with liver metastases alone also benefit. 20 to 80% of resected patients relapse with advanced disease.4 g/m2 given weekly. which contribute to poor absorption of 5-FU. palmar-plantar erythrodysthesia) however. achieved through schedule modifications. and 8 hours and 24 hours. which has a different pattern of side effects. The meta-analysis found no evidence of impact on overall survival. but with one exception survival remained unchanged. Performance status and choice of treatment are the major variables. Bolus short 5-FU exposure schedules may depend on RNA inhibition absent LV .e. this work is neither uniformly reproducible nor certain enough as yet to justify withholding therapy.1494 SECTION 29 / Neoplasms of the Alimentary Canal called into question by meta-analyses. thymidine kinase. At diagnosis of colon cancer. Some randomized trials show increased response rates both for 5-day infusions and for prolonged multi-week infusions compared to conventional bolus regimens. Prolonged intravenous infusion produces hand-foot syndrome (i. a relatively new combination of LV with 24 to 48 5-FU infusions bolus and therapy also appears to improve survival and even to be superior to the Mayo regimen. respectively. TS generates the thymidylate that is needed for DNA repair and synthesis. 25 and 2. These doses are excessive when used in conjunction with modulators. Extended exposure to 5-FU can almost completely inhibit colony formation. It is probable that response rates have doubled and that several new and old drugs are effective in combination with LV/FU and noncross-resistant with LV/FV . A meta-analysis confirms that infusional 5-FU is distinctly different from bolus 5-FU. New oral prodrugs of FU are designed to circumvent enzymetic mucosal barriers. Differences in rate of infusion. Findings are both complex and promising. For safety. In the USA. newer agents such as the camptothecin analogues. With weekly 48-hour infusions of FU (median total dose 25 and 3. 38% of patients have regional spread of disease and 19% distant spread. produce large differences in the optimum dose of 5-FU and in rates of response. Methodology and overall findings and results vary between laboratories. which binds to thymidylate synthase (TS). even asymptomatic patients and especially patients with good performance status. The latter. Studies culminating in the above regimens demonstrated that dose intensity achieved through skillfull scheduling probably is essential to achieving high rates of response with 5-FU. irinotecan clearly improves disease-free and overall survival in two substantial trials. 5-FU has retained a continuing central role in the chemotherapy of advanced colorectal carcinoma. the consensus shifted to favor 12 mg/kg/d (or 500 mg/m2/d) for 5 days every 4 to 5 weeks when 5-FU is given alone. Recently. 5-FLUOROURACIL Since the synthesis of 5-FU by Heidelberger and colleagues. Response rates increased with increasing dose intensity. 30 minutes. although it had been observed in the lead Mayo Clinic phase III study. intraoperative radiotherapy. in plasma. uridine kinase. there is a cogent rationale for regimens using prolonged. 5-FU can inhibit tumor RNA synthesis by entering the uridine metabolism pathway and can inhibit DNA synthesis after conversion to fluorodeoxyuridylate. a continuing need exists for developing effective treatments for advanced disease. thymidine phosphorylase. Efforts to predict resistance to 5-FU by measuring several enzymes or mRNA are in progress. These provide rational targets for development of numerous prodrugs. 10 to 20 minutes. response) when infusions are used after failure of bolus regimens.000 mg/m2). In view of the short 12.or 48-hour high-dose infusions of 2. uracil dehydrogenase. Treatment of Advanced Colorectal Cancer. This may no longer be the ideal standard. Currently. Downstaging. Irinotecanis newly demonstrated to be a superior second treatment. with limiting mucosities and diarrhea. Most new efforts have proceeded in the direction of investigating biomodulators of 5-FU in combination with new drugs in order to achieve both superior rates of responses with fewer side effects and enhanced quality of life. The Mayo Clinic low-dose LV schedule is the most widely accepted standard primary treatment. therefore. with comparable hematologic side effects and less GI toxicity. specifically 24. There is also a new treatment available after failure of LV/FU. physiologic old age. necessitating dose reductions for 23% of patients. Hematologic and mucosal toxicity inhibited development of dose-intensive strategies.. especially in conjunction with modulators of 5-FU or combinations with new drugs. 5-Fluorouracil enters the malignant cell by an active carrier transport and then is converted along two enzymatic pathways to its biologically active metabolites. Also. A meta-analysis that omitted the Mayo trial found that LV improved the rate of response to 23 versus 11% for FU alone. but LV/FU produces quality of life benefit and. in some cases. These doses are unsafe when patients have poor performance status. Infusions of 5-FU probably dominantly produce DNA inhibition. and biochemical modulators. Since efficacy is similar. and oxaliplatin and the possible role of biologic agents in the medical management of metastatic colorectal cancer are presented here. BIOMODULATION OF 5-FLUOROURACIL BY LEUCOVORIN LV enhances the clinical toxicity of 5-FU. Variant TS enzymes (with low affinity for the 5-FU deoxyuridylate product [5FdUMP]) are resistant to fluoropyrimidine cytotoxicity. 19%). 7% for the bolus arm) were obtained with significantly lower rates of serious hematologic and GI toxicity. Although specific enzyme activities in individual tumors appears to predict resistance to 5-FU both in gastric and colorectal cancer. treatment should not be withheld on the basis of an assay. 5e-day loading courses were the standard against which all other schedules and combinations were measured. the response rate was 39% and grade 3 to 4 toxicity 21%. Both prolonged 5-FU infusion and new schedules of 5-FU administration. Systemic chemotherapy for advanced colorectal cancer clearly benefits patients. and can produce second responses in combination with 5FU after 5-FU alone had failed. Clinical anecdotes describe 10 to 20% rates of benefit (i. over 2 to 4 minutes. lowdose infusion. Any past colitis or other co-morbidity that could be exacerbated by low white blood cell count or enteritis calls for initial dose reduction of any 5-FU–containing regimen. even in what are considered to be drug-resistant colon cancer cells. convenience. and TS. and possibly between primary sites of disease: colon versus rectum and right versus left colon. improves primary rates of response. had limiting neurotoxicity and is not recommended for development. These schedules are attractive for development of combination chemotherapy. THYMIDYLATE SYNTHASE AS THE TARGET FOR FLUOROURACIL Enzymes involved in 5-FU metabolism include phosphoribosyltransferase. and . uracil phosphorylase.. or intraperitoneal therapy. Some safer and probably superior regimens for selected patients are already tested and successful in phase III trials and await critical confirmatory trials. survival benefit. in phase III studies. Weekly 24-hour infusions of LV/FU. 2 hours. easier to use and safer substitutes for 5-FU are now clinically available. treatment called for 15 mg/kg/d for 5 days plus halfdoses every other day until toxicity. These rates of response (30% for the infusion arm vs. In addition. The optimal single-agent 5-FU schedule has yet to be determined. liver dysfunction. Combining bolus and infusion regimens in phase II-III clinical trials produced favorable results when used with LV . inhibitors of catabolism. may create some of these opportunities.

In combination. because of unacceptably severe myelosuppression enteritis and hemorrhagic cystitis. A randomized. In a phase III trial. As a potential neoadjuvant treatment. successful combinations with irinotecan (see below). the RPMI regimen is limited by diarrhea. CPT11 produced convincing 30 and 22% response rates in new and previously treated patients with metastatic advanced colorectal cancer. particularly when compared with other available chemotherapeutic options.. Bimonthly treatment produces higher response rates than monthly treatment. DNA topoisomerase I-targeted chemotherapy had seemed to be particularly promising because of results in otherwise highly resistant colon cancer xenografts. Allergic reactions to LV are rare and can usually be managed with premedication and slow administration of LV provided that the reaction was mild. Cost benefit analysis of the various regimens also indicates that the quality of life of the low-dose LV and 5-FU combination is achieved at a more favorable cost. MTX/5-FU continues to be the subject of new positive reports and is the subject of ongoing adjuvant trial. Tomudex also failed in a phase III test against these bolus. COMBINATION OF OXALIPLATIN AND 5-FLUOROURACIL Attempts have been made to increase response rates by the addition of cisplatin to 5-FU. At the very least. Caution is required. limiting diarrheal side effects and. Its use with LV/FU led to a 51% response rate with low mucosal and peripheral neuropathy. Regimens with low-dose LV produced prospectively tested well documented quality of life advantages and better maintenance of weight. and successful use in downstaging metastatic tumors.000fold more active than the prodrug. it proved superior in direct comparison to the Mayo Clinic schedule. Until there are successful phase III trials recognizing that response rates are notoriously variable and difficult to link to survival and quality of life in patients with advanced colorectal cancer. which is 100. Loperamide ameliorated diarrhea sufficiently to permit dose escalation beyond 350 mg/m2. weight gain. both of which further improve response rates when added to LV/FU. MTX also may be useful as a component of a sequential MTX/5FU/LV program. such as single-agent 5-FU and 5-day LV/5-FU regimens. It is noteworthy that these MTX/FU regimens produce responses and probably survival impact when used as second. Both as primary and salvage therapy. these new drugs may already be the treatments of choice for selected patients in urgent need of objective response for quality of life or for downstaging curative and potential resection of a metastatic tumor. where MTX precedes the beginning of the 5-FU infusion by 7 to 24 hours and LV is used starting concomitantly with 5-FU so that the same LV both rescues from MTX toxicity and potentiates the 5-FU effect on TS. MTX/5-FU may improve the durability of responses and. improved performance status. The enzyme inhibitors of topoisomerase I and II act by preventing the religation of the cleaved strands. Nevertheless.or 90-minute intravenous infusions. thereby increasing fluorouridylate biosynthesis with its augmented incorporation into RNA. MTX (modulation) doubled the response rate to 5-FU alone.e. These produce acceptable hematologic but the somewhat unique GI dose-limiting toxicity of chronic diarrhea. Prolonged exposure to LV allows time for its polyglutamylation. The CPT analogues irinotecan (CPT-11) and topotecan have been synthesized. Every-3-week and every-1-week schedules have been well tested. in the absence of direct comparisons. Limiting gastroenteritis is sometimes fatal in the elderly if weekly treatment continues too long. half recover in 12 weeks.the concerns about limiting toxicity. a tree that is native to China.4%.9 months and 3-year survival 22%. Camptothecin (CPT) is an alkaloid derived from the Camptotheca acuminata. but the 2-day every-2-week schedule is notable for the 50% response rate achieved with moderate dosage intensity and without substantial hematologic toxicity. Early clinical trials were abandoned.067). LOHP is otherwise well tolerated and does not require the premedication or precautions required when using DDP and does not produce the limiting bone marrow toxicity of CBCDA. For LOHP. Irinotecan is a prodrug that undergoes deesterification by carboxy lesterase to SN-38. 32 versus 14. An optimum LV/5-FU regimen has not yet been identified. These analogues are much safer than camptothecin for the urinary track. The value of response and probable impact on survival are still debated. Slow infusion also prevents inefficient and wasteful premature renal excretion of LV. with a favorable overall survival (p < . survival. It appears between 13 to 23 weeks in half of the patients. the three-drug combination was equivalent (but not superior) in quality of life when compared to an optimum short (2-day) LV/5-FU schedule. while avoiding some of the concerns outlined earlier. 19 versus 10%. LV/5-FU allows patients to live as long as with 5-FU alone and allows them to live better. It produces 10 to 27% overall response rate as salvage and primary single-agent therapy. In a substantial meta-analysis. It was less toxic and had clear quality of life advantages. Caution is required. major interest is fueled by high response rates. thereby inhibiting mitotic replication. however. and modestly improved overall survival. Oxaliplatin in combination with 5-FU produces acceptable. CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1495 Trimetrexate Neutrexin® is a MTX analogue that does not interfere with polyglutamylation.to 24-hour interval in the timing of 5-FU following MTX appears to be critical to the success of the regimen. some MTX/FU schedules may not be the equal of LV/FU. preparatory to hepatic resection. in some comparisons. Doses are from 300 to 350 mg/m2 every 3 weeks. the clinical conditions case unknown. The neurotoxicity of LOHP should not be dismissed. appears to match other new combinations in antitumor efficacy. LV is a racemic mixture. MTX exerts its potentiation of 5-FU cytotoxicity by increasing the intracellular content of phosphoribosylpyrophosphate because of a decrease in purine ribonucleotide and thymidylate biosynthesis. Its site of action for antitumor activity was identified as the inhibition of topoisomerase I. where increased well-being is a therapeutic goal. Trials of oral analogues are also in progress. The median survival was 15. and there is cold sensitivity and laringeal symptomology. Cisplatin has been largely superseded by the biochemically and clinically superior oxaliplatin (LOHP). Irinotecan (CPT-11) produces dose-limiting neutropenia and diarrhea. A 7. have as yet improved overall survival compared to LV/FU in ongoing trials. It is an active but not exceptional single agent. In a head-to-head study. CAMPTOTHECIN ANALOGUES (TOPOISOMERASE I INHIBITORS) Topoisomerases are enzymes that create (and later reseal) breaks in DNA to facilitate the uncoiling of supercoiled DNA before mitotic replication. and when successful they failed to improve overall survival. in 30. but for repetitive clinical administration. There is preclinical evidence that LV can block the activity of MTX as a modulator of 5-FU under some conditions. It differs from that of cisplatin. LOHP alone and in combination with LV/FU appears to be positioned behind CPTII alone and in combination as a salvage regimen. Cells in S phase are substantially more sensitive to these effects. however. These attempts have usually failed. Distal GI toxicity was substantial in trials of high-dose weekly LV . The L-isomer is used in half of the dosage of the racemic mixture. The Mayo regimen is limited by white blood cell count and mucositis in one-third of patients.to 1. clinicians select lower doses of 240 mg/m2 to . neither oxaliplatin nor irinotecan. it increased the rate of hepatic resection by 16 to 18%.and third-line regimens. Topoisomerase I acts on single strands and topoisomerase II on double strands of DNA. The major benefits reported include improved quality of life (i. COMBINATION OF METHOTREXATE AND 5-FLUOROURACIL MTX enhances the effect of 5-FU when used in a sequential manner 18 to 24 hours earlier than 5-FU. Quality of life is of importance in the setting of advanced metastatic disease. infusion days 1 and 2 of a 2-week regimen. prospective trial found both response and survival benefits for the 24-hour sequence compared with the 1-hour sequence. Direct comparisons to LV find no advantage. As primary therapy. Management of the diarrhea requires intensive loperamide. MTX plus 5-FU is well tolerated and feasible as an outpatient regimen. it is under investigation as a method of combining an antifolate with LV/5-FU. response rates range from 38 to 50%. Its neurotoxicity may prove of concern. Prolonged infusion tests are in progress and in theory may be the ideal schedule for these drugs. relief of symptoms).

In another phase III trial. with a long (9–14 hour) terminal elimination phase. is active in oral form and may have an improved therapeutic index compared with that of 5FU. but one cannot expect this in new trials. High rates of response have been seen for patients failing standard systemic treatment—12 of 15 partial responses in one report. Response rates are 18 to 19%. and pain-free survival all improved. capectabine had comparable response rate. Irinotecan (CPT-11) has been approved by the FDA for patients with stage IV colorectal cancer who have failed 5-FU based chemotherapy. and uracil to saturate degradatative enzymes. Tomudex with MMC as a salvage regimen produced a severe flu-like syndrome and elevated cytokines and required hospitalization. both topotecan and 9-amino CPT completely failed to produce tumor regression in colorectal cancer trials when used in their conventional schedules. Tomudex is also in trials with radiation therapy for rectal cancer. This needs to be confirmed because it raises prospects of a level of activity equal to the more toxic oxaliplatin and irinotecan. is currently reserved for trials or patients with urgent need for response. toxicity. Initial clinical experience found first-line therapy with tomudex plus LOHP to be active. Irinotecan in combination with 5-FU/LV produces 40% to 50% rates of response. Tomudex may be another method of overcoming a tumor’s resistance when resistance is based on TP and DPD enzymatic activity. It has different toxicity limits compared to 5-FU as both bolus and infusion regimens. and diaphoresis are reversible with diphenhydramine and largely preventable by atropine and possibly the addition of ondansetron and diphenhydramine (the latter two are unproven). in theory. a combination of tegafur. Although all of the clinically available analogues are absorbed. 29%) and disease-free survival median (5 vs. Tomudex in combination with 5-FU in various schedules is well grounded preclinically and is already in early phase III trials. Although raltitrexed was superficially equivalent to the Mayo regimen. both the deGramont 2-day and Lokich protracted infusion regimens were superior to raltitrexed in quality of life. Gilbert’s syndrome and any liver dysfunction require major dose reduction or avoidance. then 2 mg every 2 hours or 4-mg every 4 hours until 12 hours have passed without diarrhea. . Doxifluridine. Irinotecan plus oxaliplatin in combination has achieved 42 and 44% response rates as primary and secondary therapy. Severe diarrhea occurred in only 11%. in addition. a second-generation inhibitor of TS. Several 5-FU schedules are suitable: simple 500 mg/m2 bolus weekly. but not resistance due to high levels of TS. raltitrexed. CPT11 after 5-FU failed was superior to alternative 5-FU regimens. is an antifolate analogue that becomes polyglutamylated. 27 vs. Randomized trials demonstrate limited superiority of the CPT II/LV/FU combination compared to either LV/f-FU or CPT II alone.8 vs. in another randomized trial. It has been proposed as being particularly suitable for elderly patients. CPT-11 must precede 5-FU. CPT11 as a 70 to 75 mg/m2 24-hour infusion each week produced a provocative 28% objective response in heavily pretreated patients. Combining the best 24-hour infusion (LV 500mg/m2 and 5-FU 2. primary use of CPTII in combination may be no more effective than crossover use of CPTII for salvage. irinotecan has been developed as a weekly dose of 125 mg/m2 for 3 or 4 weeks in a row The rate of response and of grade 4 diarrhea were both 23%. with a possibly significant enterohepatic recycling phase and additional excretion into saliva. 5-day loading and high-dose 1. Tomudex followed by bolus 5-FU at 24 hours offers another possible salvage regimen. ~16% (7/43) achieved response and 46% had stable disease after 5-FU had failed. response rates with FUDR infusions approach 78% and median survival approaches 2 years with some disease-free 5-year survivors versus 52% response in earlier trials. a Russian FU prodrug. Loperamide is given in a high-intensity schedule of 4 mg after the first diarrheal movement. oral CPT analogues are in development. Its possible lask of cross-resistance with 5-FU under special conditions has been suggested again. as expected. Use of combinations. Findings included improved response rates (49 vs. and overall survival for toxicity comparisons. and diarrhea that are associated with flushing. but may be unnecessary. Dose intensification of irinotecan to 175 mg/m2 every 2 weeks with bolus 5-FU (450–950 mg/m2) produced 10 of 17 responses. and performance status. this might also create additional sources of bias in efficacy comparisons. Capectabine (XELODA®) is a complex prodrug that liberates fluorocytidine after its absorption. weight loss. These combinations are leading candidates for the next generation of adjuvant trials. which is an analogue of FU. Unexpectedly. New schedules appear to be promising. Favorable comparisons include its ease of administration once every 2 to 3 weeks and safety. It may be almost as active as 5-FU and is already considered competitive with the 5-day LV/FU Mayo Clinic regimen. but in two phase III studies. High levels of DPD and TP increase resistance to 5-FU but not to tomudex. proven difficult to demonstrate. OTHER DRUGS Tomudex (ZD 1694). Pharmacokinetics show that both CPT-11 and SN-38 have a biphasic elimination. FDA approval for advanced colorectal cancer seems likely because of the potential convenience of the oral drug. The Mayo schedule is inherently biased regarding LVFU since 42 to 50% of patients experience intolerable or unacceptable consequences. is not necessar- ily causal. An acute cholinergic syndrome may follow the administration of CPT-11. It is more suitable for intraperitonal therapy and hepatic artery therapy because of it s formulation and high degree of first-pass catabolism in the liver. Use of 90-minute infusions remains the most popular dosing schedule. such as the 300mg/m2 prolonged infusions.3 mg/kg days 1 to 14 with LV 15 m/d and dexamethasone 1. 25 vs. and. where objective response in theory can possibly translate into improved eradication of disease.to 2-day schedules. CPT is best given before 5-FU. Tomudex may have crossover activity. the further improvement on adding irinotecan. The evidence suggests that these schedules produce similar side effects and efficacy. To date. UFT. which gains therapeutic advantage because of high levels of cytidinediaminase in tumors. This represents a candidate regimen for development. Oxaliplatin is clearly not crossresistant with irinotecan. On adding dexamethasone to LV . 3 months). In the USA. 8 of 20 were seemingly similar to FU/LV+LOHP in activity. given in the too toxic Mayo Clinic schedule. cramps.1496 SECTION 29 / Neoplasms of the Alimentary Canal 350 mg/m2 as 30. New (oral) substitutes for 5-FU might better be compared to the less toxic and possibly more effective European FU/LV or FU 48-hour biweekly schedules. A randomized comparison of UFT plus leucovorin (orzel®) versus 5FU/LV . Thus. disease-free survival. is orally active. as yet. A new analogue without need for polyglutamylgation (1843U89) is in development. 24%).to 90-minute infusions every 3 weeks. improved tolerance to orzel.6g/m2) with irinotecan 80 mg/m2 may increase response to 64% (45–83%). and progression free survival (PFS) end points. some of whom have serious toxicities with LV/5-FU. 1-year survival (36 vs. although a reasonable expectation. found an equal 11% response rate and. warmth. sweat. Overall survival remained unchanged. Theoretically. 14%). FUDR was once thought to be a 5-FU equivalent analogue. and pleural fluid. the tail of the survival curve for tomudex was slightly inferior to LV/FU. Further escalation of irinotecan to 200 to 210 mg/m2 produced 5 of 11 responses. Excretion primarily is in the urine and bile. A randomized trial demonstrated that CPT11 alone (after 5-FU had failed) was superior to supportive care. third-line success with CPTII has. The opposite. There is heightened interest because uptake of the active drug and conversion to 5-FU is greater in tumors than in normal tissue. In a comparison to the Mayo Clinic LV/FU schedule. 30-minute infusions are equally well tolerated. Other side effects include alopecia in approximately 50% of patients and a low incidence of asthenia and hepatic enzyme elevation. A pilot study found a high 42% rate of response. 40% were stable with minor response and stable disease. due to symptoms or with tumors threatening imminent complications. Disease-free survival at 6 months almost doubles (42 vs. In theory. 3. This was not seen by other investigators.4 mg/d. Hepatic artery infusion with 5-fluorouracil deoxyribonucleoside (FUDR) can be combined with systemic irinotecan 60 to 100 mg/m2. severe vomiting. The acute. The infusion consists of FUDR 0. perhaps 40% achieved subjective benefits. there is limited clinical testing of this concept. One-year survival was higher at 45% compared to 32%.

SUMMARY There are improving prospects and investigational options for advanced colorectal cancer. The use of IL-2 plus LAK cells has not been developed further due to toxicity.e. and MRI scans.e. Numerous trials of IL-2 plus LAK find a 10 to 12% rate of response. MONOCLONAL ANTIBODIES In an adjuvant setting. MAbs appear equal but await confirmation. Combinations of MAb with biologics eventually may be useful to augment immune-mediated antitumor effects. Efforts to transfer this approach to human investigation are in progress. Low TS would be required for response to chemotherapy. Until the cost can be cut by half. IFN. MAbs are among the most active lines of investigation surgery from therapy such as with EGF strategies to diagnostics. and other pathologic and molecular measures of virulence may improve prognostication and identity objective criteria for high risk patients. Some drugs in combination with 5-FU produce complete responses (i. In rectal cancer. Although gene therapy is eventually promising. 5-FU by chronotherapy produced a 40% objective response rate and a median survival of 16 months. complete responses. ROLE OF INTERFERONS AND INTERLEUKINS Interferons.or multiple-site metastases to the lung. The 17-1A MAb is under investigation in a phase III adjuvant trial for stage II colon cancer in the United States (CALGB 9581). Toxicity was substantial. Preclinical findings support the combination of IFN-_ and MAbs. it is obvious from these studies. Almost 75% of patients required dose reduction of 5-FU. Careful pathologic evaluation of the radial margins of resection is essential. Both taxanes have now failed to show activity in initial phase II trials. No response was seen in two patients with colon carcinoma. 4 months for nonimmunized control patients). the oncologist can help many patients and. diet. and its side effects are unacceptable. Transfection of the genes for IL-2 or GM-CSF by a retroviral vector into tumor cells has evoked immunologic response against the inoculated cytokine-secreting cells as well as recently injected native tumor cells. that to some degree local approaches work with a properly selected group of patients Use of low cytometry. A fusion gene was formed consisting of the CEA and cytosine deaminase gene. In head-to-head comparison. The physician’s responsibility and opportunity to help now extends to the many patients’ relatives who are now recognizably and predictably at risk. oxaliplatin and tomudex represent promising avenues for the future. The adjuvant setting immunization with an anti-idiotypic human MAb may prolong the survival of patients with advanced colorectal cancer (12 months vs. polypectomy. Since IFN may increase cell expression of targets for MAbs GENE THERAPY Future novel approaches include the use of gene therapy or gene engineered cells in order to convert a prodrug. Technology that recently became available for research. CT. and irinotecan). Continuous-infusion 5-FU at 300 mg/m2 for a prolonged period plus Mitomycin C (MMC). LV. Colon cancer has become a model for molecular biologists. and chemoprevention have become real issues. AZT increases response rates when used in combination with LU/FV. this is only cost-effective when patients refuse colonoscopy. cure a large number. Both pelvic and peritoneal and recurrent diseases are sometimes cured. The difficulty with many phase II neoadjuvant series is a lack of a pathologic specimen from which to analyze the cancer stage before treatment and whether therapy did in fact destroy or remove all of the cancer in nodes and mesorectum. Irinotecan. oxaliplatin. into a compound that is specifically toxic to the targeted cells. and their shorter than expected survival is unexplained.. This has now been confirmed. The role of TS expression in prognosis and outcome of adjuvant chemotherapy and in patients with rectal cancer illustrates the role of CT in these rectal adjuvant trials and may not fit some expectations derived from experience with advanced colorectal disease. No responses were seen in 21 advanced colorectal cancer patients without LAK cells. as well as leukopenia.e. the methods are complex and include multiple unsolved problems in clinical delivery of genes. marching cubes) of various imaging methods: plain films. This most likely will be a problem in any area where the colon is partially a retroperitoneal structure or where there is limited mobility and the ability of the surgeon to obtain wide margins therefore is compromised. high TS predicts for poor survival and benefit of adjuvant therapy contrary to theory. In this randomized trial. An IgG2a MAb has been reported to be effective with human effector cells in vitro for mediating cytolysis of tumor cells of colon and lung origin. Biomodulation of 5-FU by LV and MTX sometimes provides better tolerated regimens that have the potential for better quality of responses (i. including one fatal and one life-threatening secretory diarrhea. fluorescence in situ hybridization (FISH). greater durability). Interleukin-2. IFN/5-FU has failed to improve responses over LV/5-FU alone. Use of IFNs is based on in vitro data showing synergism with 5-FU in a doseand schedule-dependent manner Median survival of the previously untreated group of patients with metastatic advanced colorectal cancer treated with FU plus I-FN_ extended beyond 16 months. LV/FU is proven to be effective by a 20 to 33% decrease in CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1497 deaths during the first 5 years. produced a 40% objective response rate and 17. liver. There also was substantial central nervous system toxicity. which is not enough to encourage development. which is otherwise harmless to cells. Colon cancer cell lines and xenografts have been notorious for producing false-positive preclinical leads. PERSPECTIVE The most important aspect of treatment for colorectal cancer is the adequacy of initial surgery and the appropriateness of multi-modality treatment for patients who are identified as having a high risk of recurrence. this made the tumor cells express cytosine deaminase and thus become susceptible to FU derived from 5-fluorocytosine. The chemotherapy of advanced colorectal cancer is still based on the central use of dose-intensive 5-FU. Early diagnosis and cancer prevention by screening. local failure can occur. and allow new questions for tests of adjuvant therapy. but not as yet for routine patient management..6-month median survival. The role of NSAIDs and inhibitors of cyclooxygenase 2 enzyme are under investigation. . Ideal surgery still provides the best chance for curing a patient with colon or rectum cancer. 7 mg/m2 every 6 weeks. A prospective phase I/II Intergroup study of CALGB 8984 has evaluated local excision alone for T1 tumors and local excision with postoperative radiation therapy and concurrent 5-FU for T2 and T3 tumors. as reported in preclinical studies using MAb 17-1A. mortality and recurrence were both reduced by one-third by the administration of four monthly infusions of the 17-1A antibody. and the vigor of a followup plan and even salvage surgery and multi-modality therapy cannot make up for inadequate primary treatment. Initial efforts have failed. Regional therapy remains an active area of investigation. Adjuvant therapy is probably applicable before and after salvage resection. Systemic and adjuvant therapy is cost-effective and improves quality of life and disease survival. done over many years. Salvage resection cures some patients with isolated single. and this mandates cooperation between the surgeon and pathologist. or both. monoclonal antibody (MAb) examination of lymph nodes. A three-dimensional model has been created that simulates a virtual reality colonoscopy. Analyzing this study will help to determine whether local excision with or without radiation in appropriately selected patients can possibly result in survival and local control comparable to those obtained with historical APR series. or pelvis. The modest rate of response (26%) in the context of the frequent neurotoxicity (34%) and the perceived need for dose reduction indicate that IFN is not suitable for adoption into clinical practice.. after transfection.Taxotere has been highly active in preclinical experiments. This is as true for the colon as for the rectum. Nevertheless. In situations where the surgical margins are minimal. Surgery creates opportunities for adjuvant therapy. enables computational manipulation by a defined algorithm (i. harmless to normal tissues. because this is a common disease. Currently. The nonimmunized patients were separately registered to an oral chemotherapy trial. including seizures and expressive aphasia. Recombinant interleukin-2 (IL-2) has been used in phase I settings with and without IL-2-activated cells (LAK).

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