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.13 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 recurrence46 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 IIIII rectal cancer has proven results.69 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.1216 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.13,14,1922 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.2325 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 Crohns 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).2931 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. AJCCAmerican 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.3638 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.4852 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.58,6668 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.68,7173 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 possible7476 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., Addisons, Parkinsons, schizophrenia) and the higher cancer rates seen in aging and other conditions associated with low intracellular potassium (e.g., obesity, alcoholism, Crohns and Cushings 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%.97100 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,97,98,101103 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), Gardners syndrome, Peutz-Jeghers syndrome (all of which display autosomal dominant inheritance), Turcots 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 Gardners and Turcots 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 Gardners syndrome.100,105 Congenital hypertrophy of the retinal pigment also has been described in Gardners 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 Gardners 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 Gardners 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.97,98,100102 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

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.127 Close linkage to two microsatellite areas on chromosomes 2128 and 318 has been documented in colorectal cancer that is associated with HNPCC. Similar genetic changes have also been seen in 13% of sporadic cancers.20,21 The biologic behavior of these genetically similar sporadic tumors was consistent with the familial type.14,15 Data show germline alterations in short, repeated DNA sequences not associated with loss of heterozygosity of chromosome 2.13,128 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. 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, increased patient survival, and inversely with loss of heterozygosity.111,127 Microsatellite instability is found in areas involving genes for DNA repair and indicates defective repair of the genome.114,129 Such areas of replication error positivity were found in 77% of colorectal cancers in patients with HNPCC.11,20 The specific genes involved in these areas of microsatellite instability have been identified as hMSH1,130 hMSH2,131,132 hPMS1,133 and hPMS2.133 The combination of genomic instability with loss of normal reparative mechanisms is thought to result in development of the neoplastic state.134 Both types of germline defects, the APC genotype (seen in FAP) and the mismatch repair gene microsatellite instability genotype (seen in HNPCC), can result in the syndrome of multiple colon adenomas and brain tumor, as described in Turcots syndrome.106 Those cases of glioblastoma multiforme found to have the HNPCC genotype had exceptionally long survival, which is consistent with the long, stage-specific survival noted in the Lynch syndromes for colorectal cancer.106,111 Awareness of the two different causative genotypes in Turcots syndrome should direct screening efforts for additional cancers in the proband and the kindred.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. They are even inconclusive in patients with high-risk ulcerative colitis where the Tn, p53, and ras markers supplement the finding of severe dysplasia. The study of ras protein in fecal material or endoscopy effluent may prove to be useful should the methodology become commercially economical. Although none of these tests has more than a 50 to 60% sensitivity, they may, nevertheless, with development, increase the number of early detections where colonoscopy and traditional evaluation of pathologic morphology now fails. It is not known if the high-risk, high-proliferative tumors, which, by analogy to other cancers, may be the most responsive to acute chemotherapy, actually are the beneficiaries of adjuvant therapy. This is, however, an important working hypothesis. In conjunction with established morphologic criteria, the absence of poor prognostic markers makes adjuvant therapy not cost-effective. Attempts to define a target group should be approached with caution (because of the continued failure to demonstrate a strong association between morphology, even flow cytometry and outcome in rectal cancer). Furthermore, there is substantial complexity in using numerous enzymes some considered targets of chemotherapy to predict the outcome of adjuvant therapy with 5-FU, as described below. A mouse model exhibits an autosomally dominant inherited predisposition to multiple intestinal neoplasia (Min). The murine homolog of the APC gene (mAPC) has been found tightly linked to the Min locus and is mutated in the affected lineage. In the area of gene therapy, the potential exists to reverse some significant molecular and genomic events leading to development of the neoplastic state.. In cultured human colon carcinoma cells, the introduction of normal chromosome 5 or 18 (i.e., restitution of the suppressor gene loci) can revert the morphology of the cells, reduce their cloning efficiency, and completely suppress their ability to form tumors in athymic nude mice.121 In some colon carcinoma cell lines,

it has been possible to alter the transformation properties by introducing the tumor suppressor APC gene.135 CHEMOPREVENTION Minimizing exposure to recognized predisposing elements in the diet and environment is one ultimate aim in the prevention of cancer. A collateral approach would seek to block the action of carcinogens during the latent period before the appearance of cancer.136138 Essential to the evaluation of potential chemopreventive agents is (1) determination of suitable (safe and effective) doses of agents (e.g., difluoromethylornithine) that have known anticarcinogenic activity in animals,139 (2) determination of evaluable biomarkers of carcinogenesis, and (3) determination of suitable intermediate clinical end points, because full-blown neoplasia may take decades to occur.138,139 Once these three factors are determined, clinical trials can proceed in suitable populations with elevated susceptibility to the cancer under study. Antioxidants. 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.136 Vitamins C and E have been shown to inhibit nitrosamine formation,140 reduce fecapentaene production,136 and have a beneficial effect in several experimental colon cancer studies.136 Two large prospective, controlled clinical trials did not show a statistically significant advantage in susceptible populations, however.141,142 In contrast, another prevention study involved randomized daily dietary supplementation of either -tocopherol (50 mg/d) and/or -carotene (20 mg/d) versus placebo to male smokers aged 50 to 69 years over a period of 5 to 8 years (mean, 6.1 years). 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 -tocopherol (i.e., vitamin E) compared with those who did not.143 This alone is not sufficient to recommend systematic use. Other indications for vitamin E possibly allow a general recommendation; however, there was an adverse increase in lung cancer in smokers. Some multivitamin prevention studies suggest that folates may be operative in chemoprevention. Other vitamins may also be beneficial, but findings are neither consistant nor ideally tested.144,145 The use of a multivitamin does not substitute for a balanced diet, which may contain other prevention molecules as yet unrecognized, but at worst it would seem innocuous, and might be. Other antioxidants, such as N-acetyl-L-cysteine, a thiol, have been beneficial in reducing the formation of DNA-carcinogen adducts and the occurrence of experimental tumors of the lung, liver, and colon.138 Acceptance as a chemopreventive agent in humans, however, will require two successful controlled clinical trials in populations susceptible to colon cancer. Nonsteroidal Anti-inflammatory Drugs. Indomethacin was shown to reduce the number of experimental tumors induced in rats by a nitrosamine compound.146 Nonsteroidal anti-inflammatory drugs (NSAIDs), such as piroxicam, have been shown to inhibit experimental colon tumors,147 and sulindac has induced regression of large bowel polyps in patients with FAP.148,149 This effect may relate to reduction in endogenous prostaglandin generation.148 Spontaneous, albeit usually temporary, polyp regressions have also been described.150 Antiinflammatory drugs are clearly active preclinically and impact polyps (apoptosis). The first randomized trial failed the recognition of obvious balancing risks, and recognition that chemoprevention is ideally multifactorial has prevented clear recommendation for chemoprevention.151,152 Controlled population studies indicate that a benefit from aspirin and NSAIDs (but not acetaminophen) does exist.153,154 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 rectum154157; 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.153 The Nurses Health Study also showed risk reduction by regular use of aspirin, but doses and duration needed to be four to six tablets per week for at least 10 years.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. The mechanism of action is complex, and proof of clinical benefit for wide use is inconclusive. Although specific inhibitors demonstrate chemoprevention in the labo-

ratory, multiple biochemical targets may be involved, not just cyclooxygenase inhibition. The choice of an ideal chemopreventive narrowly targeted is problematic. Several lines of evidence find association between prolonged use of nonsteroidals, specifically aspirin, in low dosage (81 mg), as potentially reducing the RR of colon cancer.151160 Strong notes of caution remain operative. 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. NSAIDs do not provide complete protection, and in some hereditary syndromes, like other chemopreventives, they may provide little protection. It follows that the use of chemopreventives in no way changes the standard of practice regarding patient history, physical examination, colonoscopy, and the proper evaluation of symptoms that may be attributable to cancer. Judicious multifactorial diet management remains the best general practice with or without chemopreventives. TUMOR MARKERS CARCINOEMBRYONIC ANTIGEN In 1965, Gold and Freedman showed that human colon carcinomas displayed a specific antigen.161 The antigen also was detected in embryonic and fetal gut, pancreas, and liver, and the name carcinoembryonic antigen (CEA) was proposed.162 CEA is an acid glycoprotein (molecular weight, 200,000) in the periphery of the tumor cell membrane.163 It is most heavily concentrated on the luminal surface and is capable of being easily released into the surrounding body fluids.163 Sequence analysis of the CEA gene showed that its nucleotide sequence has homology with members of the immunoglobulin supergene family.164 The biologic significance of CEA to the cancer itself is unknown.165 It may function as an intercellular adhesion molecule166 and, in so doing, enhance the metastatic potential of otherwise weakly metastatic cells.165 Measurement of CEA levels in serum sometimes is important in diagnosis, prognosis, and management of human colorectal cancer. CEA is elevated in the plasma of some patients in the presence of tumors of the colon as well as breast, lung, pancreas, ovary, and other adenocarcinomas, even including occasional sarcomas.167169 Measurement of CEA levels in plasma has been used as indirect evidence of tumor presence. It is not recommended absent prior cancer or strong current suspicions of cancer because it does not provide conclusive evidence alone. CEA is not recommended for screening or for routine office visits for heretofore healthy patients.171173 CEA level may not correlate directly with tumor burden.167169 CEA elevation correlates with the degree of tumor differentiation, and patients with poorly differentiated tumors can sometimes have normal tests despite significant tumor volume.171 In general, however, CEA correlates with stage of disease and is elevated most strikingly .in the plasma of patients with hepatic metastases.167,169,170 Preoperative, and particularly postoperative, CEA elevations predict for an increased risk of recurrence167,168 and form another unproven basis for expanding the indications regarding need for adjuvant treatment for stage B tumors. 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.167,168,171 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. Such rewarding outcomes are infrequent. 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 $5,000 to $10,000.172 In contrast, physical examination is useless for early detection and colonoscopy is barely cost-effective .172 Official guidelines call for serial assays every 3 months.173,174 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.173,174 Otherwise unexplained, large confirmed rises in CEA levels warrant investigation in patients being monitored after prior resection.172 Levels of CEA also can be used to follow the response of metastatic tumor to treatment. Rising levels indicate tumor progres-

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1477

sion; falling levels indicate response. Caution is required, however, because this assay is not an accepted criterion of response. Approximately 20% of patients with documented disease progression nonetheless show a false decrease in CEA levels. False positives must also be considered, where rise in CEA is not evidence of progression. Hydronephrosis and biliary obstruction have been associated with marked elevation of CEA levels. Elevated levels in the presence of renal dysfunction must be interpreted with caution.175 False-positive values also have been noted during inflammatory liver and biliary disease, hepatic injury caused by chemotherapy or anesthesia, and cigarette smoking.167 Smoking cannot explain values above 10 ng/mL. Because of poor sensitivity and nonspecificity, serum CEA levels are not suitable as a screening test for colorectal or other cancer among healthy subjects. In patients with identified colorectal cancer evaluated preoperatively, CEA elevations of 5 ng/mL or more had a sensitivity of only 43%, even less in the early, ideally operable stages, and a specificity of only 90%.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.177 Staining was positive in tumors of epithelial origin: carcinomas of the GI bronchus, ovary, and cervix.177 However, some colon epithelium adjacent to benign or malignant disease also stained for CEA.177 In general, CEA positivity in a histologic specimen indicates the presence of malignancy, helps to identify epithelial origin (as in the case of unknown primaries), and helps to identify micrometastases in lymph nodes.177 Radioactive anti-CEA antibodies are one method of finding recurrent tumors and of staging for resection of recurrent disease. This method requires an expert user and cautious confirmation of findings, which would support or contraindicate potentially life-saving surgery. Radiation detectors used intraoperatively can help. 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. CEA testing assay findings must be coordinated with other objective tests. Findings must be confirmed. Its role in monitoring metastatic disease is controversial. 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. CEA testing is clearly useful for prompting pursuit of suspected recurrence or progressive disease. Early recognition of failure may now be more important than formerly because there are alternative drugs and other therapeutic approaches. The change in CEA should be large (>10 ng/mL), confirmed, and unrelated to change in renal or liver function. CEA tests are also useful in preoperative evaluation since very high values should prompt consideration of further staging. Failure to return to normal after surgery is a useful indication to undertake a search for residual or recurrent tumor. Persistent abnormal assays are not an indication for treatment. CA19-9 Antibody and Monoclonal Antibody. Hybridoma technology was used to raise a monoclonal antibody against colon carcinoma cells.179 This antibody was shown to react against a monosialoganglioside antigen180 The antibody did not react against a panel of other gangliosides, but it did react to elements in human meconium.180 The eliciting antigen was termed CA 19-9. In colon cancer, presurgical elevated values of higher than the upper limit of normal, 37 U/mL, 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.181,182 When a tumor does not produce CEA, 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. Cathepsin B. Cathepsin B is a lysosomal cysteine protease that can degrade matrix components, thus attenuating tissue basement membranes. This results in a higher metastatic potential and a worse prognosis.183,184 Immunoblot studies of formalin-fixed, paraffin-embedded tissues revealed that increased expression of cathepsin B correlated with stage of cancer and inversely with survival (p < .001). Within stage III/IV ,

1478 SECTION 29 / Neoplasms of the Alimentary Canal

low expression correlated with a longer survival compared to high expression (p < .02).183 Adenomas had low cathepsin activity similar to that of normal mucosa, and stage I/II had less elevated levels of cathepsin B than in stage III/IV . This suggests that cathepsin B, a matrix-degrading protease, is important to the progression from benign/low-grade neoplasm to an invasive/metastatic malignancy.183,184 Cathepsin B assays have no tested clinical applications as yet. SCREENING Screening procedures for colon cancer can be divided into two categories.185,186 First are the procedures for patients who fall into highrisk groups, and second are for those with no known risk factors other than age. New issues are arising with the availability of new genetic probes and markers to identify the individual at risk.187192 Physician responsibility extends to the emotional, psychosocial, and economic impacts of the testing process. Issues include the ethics of informed decision-making for genetic testing and the psychological consequences of a test result.188,189 Consequences may differ in adults and in children189,191,193,194 and impact (disadvantageously) on a patients insurability and employability. These issues also affect large epidemiologic studies.193 One must be prepared at both the institutional and individual levels to counsel patients after test results are known.192 Appropriate support, advocacy, and social work assistance can enhance community education, trial recruitment, and post-testing follow-up efforts.192 Socioeconomically disadvantaged populations are adverse to appropriate screening and treatment.195 As many as 70% did not believe that they were at higher risk for bowel cancer, 77% were too embarrassed to have a proctoscopic examination, 78% did not want to know if they had bowel cancer, 80% preferred to die rather than have their bowel removed for cancer, and 81% cited transportation problems as a barrier to seeking appropriate screening.195 One should not assume, however, that matters are ideal in the advantaged or educated population. The failures of physicians in dealing with their patients clear-cut symptoms, despite the objective efficacy of diagnostic studies and screening programs for both high-risk and sporadic cases, probably reflect the fact that adverse beliefs are universal and also affect physicians. Disordered bowel function on a temporary basis is a protean symptom, yet physicians are all too often accustomed to discounting it without considering polyps or cancer in their differential diagnosis. Consensus recommendations are updated regularly by several gastroenterolgy and oncology specialty groups. Screening is strongly recommended within defined guidelines. The earlier literature that cast doubt on the efficacy of screening on the basis of cost, poor compliance, 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. Current screening recommendations include guaiac testing, sigmoidoscopy, and (tentatively) colonoscopy. Ideal guaiac testing is not simply random testing but test on several stools accompanied by a 3day meat-free diet. Annual guaiac testing starting at 45 years and starting at 50 years endoscopy at 3- to 5-year intervals (or more often depending on findings). SCREENING HIGH-RISK INDIVIDUALS Patients with Prior Colon Cancer. Patients who have already had colon or rectal cancer carry a significantly increased risk of a metachronous lesion.196 Often, these lesions are not cancers but are premalignant adenomatous polyps. Removal can prevent cancer and often can be done endoscopically, obviating further abdominal surgery. Over a 5- to 10-year period of surveillance following primary tumor resection, about 50% of patients develop metachronous bowel polyps.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.199 Even a 5% risk would probably justify surveillance studies. First-Degree Relatives of Patients. A family history remains the primary starting point for identifying individuals who are at risk. Individuals with first-degree relatives who have colorectal cancer are at significantly greater risk (RR = 1.72) for developing colorectal can-

cer than the population at large.200,201 This RR is most pronounced in those with index cases under 45 years of age (RR = 5.37).200 Relatives of patients with colon cancer may have the familial polyp syndromes and HNPCC.105,111,201 In clinical situations, a broader view than the requirements of the Amsterdam criteria is appropriate.111,200 Patients who are identified by a high-risk family history may benefit from a screening study of the entire large bowel mucosa.17,200 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.111,186 Removal of polyps was found to reduce the incidence of subsequent cancer by 90, 88, and 76% (p < .001) when compared with two unpolypectomized cohorts and to a general population registry, respectively.23 A 3-year colonoscopy interval was just as effective as shorter intervals in detecting recurrence of polyps or a carcinoma.202 Familial Adenomatous Polyposis. Patients with familial polyposis coli (FPC) and their first-degree relatives should be screened, with attention to newly appreciated ethical and psychosocial guidelines.189 Colonscopic screening should occur at, or just after, adolescence, when the phenotype is first expressed. 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.203 If patients choose to ignore the risk of FPC, all will eventually develop colon or rectal cancer. The latency between diagnosis of polyposis and development of cancer is variable, averaging from 10 to 15 years. Once cancer has developed, it behaves, stage for stage, like sporadic colorectal carcinoma. 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. New molecular biologic techniques can define whether young relatives of patients with FPC have the genetic constitution responsible for FPC, the absence of, or mutation of, the FAP locus on chromosome 5.118,189 Entry into clinical trials of prevention or prophylactic colonectomy becomes a reasonable topic for expert consideration in individuals who bear the FAP mutation. As described earlier, the most stringent clinical criteria are required in order to initiate genetic testing for individual application(s). Crohns Disease. Patients with Crohns disease also fall into the high-risk category. The segment of bowel involved in the inflammatory process is not predictable. Removal of the involved bowel (large or small) does not prevent the recurrence of Crohns disease, nor does it reduce the potential for subsequent malignant transformation in other parts of the bowel. Thus, there is little or no available surgical opportunity for preempting intestinal epithelial transformation in these patients. Frequent colonoscopy is prudent. Despite the presence of inflammatory changes in the small intestine, cancer is uncommon in the small bowel. Ulcerative Colitis. Patients with ulcerative colitis have a defined increased probability of intestinal epithelial transformation. This predictability relates to population groups only and not to individual patients, but it subjectively underscores a role for systematic endoscopic screening. Histologic identification of conversion from mild to severe dysplasia indicates a need to remove the large bowel before cancer develops; severe dysplasia often does not accurately quantify the urgency of intervention or the absolute risk of developing cancer. If the endoscopist, no matter how conscientious, relies entirely on colonoscopy and biopsy, some patients will die of metastatic colon cancer. The decision to remove the entire large bowel and rectum often is made subjectively based on the gastroenterologists conservatism or aggressiveness and the patients choice between fear of a permanent ileostomy and fear of colorectal cancer. New molecular markers may define field changes that can quantify more accurately the progression from dysplasia to transformation in patients with ulcerative colitis.116,204,205 Such proposed markers require clinical trials. At present, however, 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. Individual advice usually is based on population statistics.

The empiric rule is to consider proctocolectomy after 10 years of active ulcerative colitis; up to 50% of patients with a history of continuing ulcerative colitis for more than 10 years eventually develop bowel cancer. The prognosis is no different stage for stage than for sporadic colon cancer, but treatment of these patients may appear to be technically and practically more difficult. Patient familiarity with blood loss in the stool often prevents this alarming symptom from conveying appropriate warning. Endoscopic surveillance of the large bowel is significantly more difficult, and usually less sensitive, in patients with ulcerative colitis than in noncolitic subjects because of the extensively diseased colon. Patients with colitic mucosa therefore are more likely to be diagnosed with later-stage lesions. Eventually, identification of practical molecular markers of early malignancy may resolve much of the debate about time for surgery. Until then, clinically, 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. 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. Surgical procedures in which the entire colonic and rectal mucosa are removed, but the rectal sphincter is preserved, improve the psychologic and aesthetic cost benefit ratio in favor of early cancer prevention surgery.203 Such procedures are not applicable to all patients, however, because of co-morbidities, excessive frequency of bowel movements, and increased risk of subsequent surgery for complications. In such cases, 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. 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. Screening now has a clear and powerful beneficial impact for low-risk patients. Initially, population-screening studies produced conflicting results.206209 It is no surprise that testing stool samples for occult blood is not aesthetically acceptable to many people.195 However, 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.210 Studies in which a positive fecal occult blood was promptly followed by sigmoidoscopy, however, did show mortality reductions of one-third or greater.210,211 Random occult blood screening is not considered to be cost-effective because of false positives from meat. Nevertheless, the test is part of the office visit, and findings demand judicious follow-up steps. Testing after a 3-day meat-free diet is effective when positives are followed by endoscopy.112 Benefit may result from incidental colonoscopy even without mass screening. Because excisions of early adenomas preempt the eventual development of colon cancer, it produces considerable cost benefits, in addition to a decreased risk of death.212215 Additional societal and financial benefits accrue in terms of fewer workdays lost, spousal and family disruption, disruption of childrens scholastic performance, and the cost of social support services.212 These provide additional incentives for earlier diagnosis. The Strang Clinics experience supports rectal examination and testing stool for occult blood as an essential part of every complete physical examination.216,217 Only patients who have appropriate diagnostic work-ups, after finding occult blood on systematic stool sampling, are more apt to have early bowel cancers or precancers (i.e., polyps) than a control cohort. 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.210212 Despite the complexities in evaluating costeffectiveness, screening with annual fecal occult blood tests, sigmoidoscopy, or a once-ever colonoscopy does have a favorable cost per year of life saved.213215 Systematic testing for occult blood can be recommended for patients of appropriate age. The cost is trivial when the patient is already in the doctors office. In contrast, the medicolegal defense of failure to perform the test is difficult and very costly. Screening is now a highly specialized subject of investigations. Some conclusions are based on complex and sometimes controversial

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1479

analyses analyses, but the main conclusions apply to every clinician almost regardless of specialty. Physicians are the most effective in achieving compliance with screening even for educated high-risk patients. Colonoscopy is preferred to fecal testing, but patient preference is for fecal occult blood testing, which also works provided that the methodology and follow-up are optimum fecal occult blood testing lacks ideal sensitivity. Colonoscopy at the age of 50 should be repeated every 5 years and more often if polyps are found. Genetic methods have limited utility and require expert selection and consultation. Virtual colonoscopy will not be cost-effective unless the physicians are dealing with a population in which it improves participation by 20%. Otherwise, virtual colonoscopy requires a 50% decrease in cost to match colonoscopy. Colonoscopy and virtual colonoscopy have equal sensitivity, but only colonoscopy provides a tissue diagnosis and polypectomy. Colonoscopy and polypectomy are in part responsible for the decline in mortality, which could be even sharper with greater use of screening practices. It is important to begin earlier, 10 years before the earliest case in a high-risk family, screening fecal occult blood. For ulcerative colitis testing, screening sigmoidoscopy and colonoscopy surveillance have been proven effective but far from ideal.218 The story recommendation for colonoscopic surveillance of patients with genetic high-risk characteristics is logical and recommended, but not proven, practice.219 Patients over the age of 50 years should have regular sigmoidoscopy every 5 years and a fecal occult blood test every year. Screening has become an established standard of care. Unfortunately, there is difficulty in achieving patient and even physician cooperation. Screening includes rectal examinations, especially for those over 40, and guaiac tests yearly. Reducing the rate of tests to every 2 years has an adverse effect. If there are polyps, colonoscopy should be performed to inspect the entire colon; repeat examinations are made every 2 to 3 years when polyps are found. 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, or if an index family member was young or had a right-sided cancer. In practice, there are numerous but not identical guidelines, and they are changing and sometimes require expert application.218225 Future Prospects. Ideally, investigators will define in detail the genes and gene products involved in regulating intestinal epithelial transformation. This may entail genomic investigation of colonic epithelium with a gene chip, unless there is a common step as yet unrecognized. The risk of such transformation at any instant is limited to a relatively small population, which could be in part identified by family history. This defined population could then undergo diagnostic and therapeutic endoscopic examination. Methods to reverse the transformation are in development testing both preclinically and clinically. Clinical Presentation. Patients often present with the classic symptoms of right- or left-sided colon cancer or cancer of the rectum (Table 103.2) 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, sigmoidoscomy, or colonoscopy). Patients who present with anemia of unknown origin, and whose blood cell indices confirm that chronic blood loss is the likely etiology, regardless of whether their stool is positive for occult blood at the time of digital examination, should have both the upper and lower GI epithelium examined, preferably by endoscopy. Anemia is one of the few relatively early potential findings. The order of examination will depend on the rapidity of the bleeding, acuity of the patients symptoms, and whether recent studies have already been done in the upper or lower GI system. In general, colonoscopy has preference over roentgenography and full colonoscopy over sigmoidoscopy. The most efficient method to screen the large bowel mucosa is colonoscopic examination. Colonoscopy allows both necessary diagnostic biopsy and therapeutic intervention, particularly if bleeding is caused by a polyp on a stalk that is easily removed by the endoscopic snare. It is important to avoid some of the common errors such as deferring rectal examination and occult blood testing for the specialist, placing undue confidence in a sporadic single negative test for occult fecal blood, and, most importantly, of discounting cancer by assuming that the cause of rectal

1480 SECTION 29 / Neoplasms of the Alimentary Canal

Table 103.2. Comparison of the Five Most Frequent Symptoms in Right Colon, Left Colon, and Rectal Cancer
Right colon (984 patients) Left colon (99 patients) Rectum and rectosigmoid (258 patients)

Abdominal pain74% Weakness29% Melena-27% Nausea24% Abdominal mass23%

Abdominal pain72% Melena53% Constipation42% Nausea25% Vomiting23%

Variation in symptoms

Melena85% Constipation46% Tenesmus30% Diarrhea30% Abdominal pain26%

Symptom

Right colon

Left colon

Rectum

Pain Obstruction Bleeding Weakness

Ill-defined Infrequent Brick red Common

Colicky* Common Red, mixed with stool Infrequent

Steady, gnawing Infrequent Bright red, 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. obstruction occurs, tumor often located at ileocecal valve. Weakness secondary to anemia. Accounts for brick red color of stool and persistent, sometimes massive blood loss. Adapted from Baker (545).

bleeding is due to a benign co-morbid condition such as hemorrhoids. Iron-deficiency anemia warrants colonoscopy, unless there are very good alternative explanations such as menorrhagia, 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. Hemorrhoids and constipation are common and thus frequently are associated with occult cancers, and the presence of hemorrhoidal bleeding can obfuscate a more proximal source of bleeding. It is of great concern to screening advocates that patients and physicians alike do not give clearly recognizable bleeding proper attention. RIGHT COLON SYMPTOMS Anemia is the most common complication of cecal and right colon cancer and the only common complication leading to early diagnosis. Unfortunately, it is most often found late in the disease. Occasionally, 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). Less frequently, fever of unknown origin may eventuate in the diagnosis of perforated, right-sided colonic tumor. The fever is due to pericecal or right paracolic abscess. In young patients with virulent familial right-sided tumors, the first symptoms may be those caused by metastases. LEFT COLON SYMPTOMS The most usual symptom in patients with circumferential adenocarcinomas of the descending colon, sigmoid, or middle to upper rectum is an alteration in bowel habits. This may be described as unaccustomed or newly appearing constipation or diarrhea or as alternating periods of both. Abdominal cramps may be absent, mild, or severe and chronic. Often, the patient is inattentive to early change in bowel habits, incorrectly ascribing it to some minor variation in diet. Occasionally, patients present with the classic narrowed-caliber pencil or ribbon stool, or even paradoxic diarrhea from an almost totally constricting distal large bowel adenocarcinoma (see Table 103.2). Those who commonly present with such symptoms may be quite young.226,227 Vague bowel symptoms commonly lead to alternate diagnostic explanations because such symptoms are common and are associated with many benign conditions. Even physicians seem to find this a difficult diagnosis when they themselves are symptomatic. Even high-grade obstruction often has only vague symptoms.

Systematic diagnostic efforts coupled with a high index of suspicion are appropriate to these symptoms because colon cancer is common, often curable when treated at early stage, and usually fatal in advanced stages. Younger individuals with colorectal cancer have been reported to have a worse prognosis stage for stage.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. Nevertheless, 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. The same may be true for African-American patients who have disproportionately more right-sided tumors. RECTAL SYMPTOMS Patients who have distal rectal carcinomas may present with spotting of blood in their stool, particularly during the initial phases of polyp or malignant tumor development. Even when digital examination is carefully performed, the physician often may miss a frond-like, premalignant villous tumor. Such lesions can be totally resected before the epithelial transformation progresses to malignancy. Such lesions often can be removed with sphincter preservation, but, some investigational methods aside, only if the diagnosis is made before the tumor invades the rectal wall.228 Numerous benign, inflammatory, 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. Presence of a hemorrhoid does not exclude a co-existing, more ominous lesion proximally. Physical examination of the anus and rectum as a source of bleeding should, at minimum, include a digital examination and endoscopy of the anus rectum and sigmoid. More advanced symptoms of distal rectal adenocarcinoma, in addition to those described for left colon lesions, consist of tenesmus (i.e., the feeling of having to defecate without stool in the anal canal) or pain on defecation. Tenesmus and pain often reflect ulcerated tumor and may portend the involvement of superficial sphincter muscles in the process of cancer invasion. 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.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. Establishment of any specific risk factor for colorectal cancer in a given patient should increase the suspicion of the examiner. Digital and, after age 50, or sooner where family history requires it, endoscopic examination of the rectosigmoid should be part of every initial work-up. The absence of physical signs noted on the initial examination does not obviate further screening of the entire GI mucosa colonoscopy and, if needed, upper endoscopy, if the physician concludes that the presenting symptoms imply the possibility of GI cancer. 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.229235 Double-contrast roentgenography is usually cheaper than endoscopy. 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.236240 The major advantage of endoscopy is increased specificity and sensitivity, with the additional advantage of obtaining histologic proof by biopsy if a lesion is seen. Colonoscopy may also provide one-step definitive therapy. Colonoscopy and radiologic approaches have been compared in a number of reports.241246 Roentgenographic and endoscopic techniques, when applied together, are better than either alone. We prefer endoscopy first. Verification of a radiologic diagnosis by endoscopic examination and histologic proof of diagnosis by biopsy should be mandatory. Such verification also provides the opportunity for surveillance of the remainder of the large bowel mucosa. If postoperative radiation is contemplated as part of the primary therapeutic regimen, barium studies are a useful complement to define the location of the target bowel and, thus, to enable accurate delivery of the radiation dose.

In specialized centers, sonography of the fluid-filled colon, magnetic resonance imaging (MRI), and positron emission tomography technology can substitute for or supplement other tests. Together, colonoscopy and computed tomography (CT) with contrast usually provide the most information and the highest specificity. Virtual colonoscopy, pending cost reduction, is limited to research and to patients who cannot or will not have colonoscopy or double-contrast studies.247,248 In sensitivity and specificity, it is not yet superior to colonoscopy. PREOPERATIVE WORK-UP If a bowel tumor or premalignant lesion cannot be removed endoscopically, additional studies are necessary before surgery. 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. The resolution of the CT scanner, even the most modern with dynamic imaging, or MRI is suboptimal.249 Nevertheless, high-quality CT can be cost-effective. The exception may be patients with small primary tumors outside the pelvis. CT with contrast provides information about the liver, ureters, and colon, and sometimes nodes, and it serves as a baseline for follow-up studies. MRI and PET are reserved for times when clinical, laboratory, or special request highresolution double-phase CT produces suspicion, but no conclusion, concerning liver metastases, especially if the finding will change treatment or lead to attempted resection or hepatic arterial infusion. The surgeon, surgical team, and available operating room facilities must be prepared to proceed with resection of a solitary hepatic lesion if such is encountered. If the symptoms include tenesmus, or physical examination reveals evidence of carcinoma involving the perirectal space, a preoperative CT scan or MRI of the pelvic and perineal region may be required. Rectal ultrasound may otherwise largely replace CT or MRI, for rectal lesions. The role of rectal ultrasound is important for low rectal lesions where sphincter-sparing surgery is an option. Presenting symptoms of back pain, sciatica, presence of a flank mass, or fever of unknown origin require appropriate preoperative studies, which may include bone scans and MRI. Intraoperative exploration using visual and tactile staging, in addition to the application of intraoperative ultrasound to the liver, provides better staging than any preoperative radiologic or biochemical modality. Radiopharmaceutical guided surgery both as part of preoperative evaluation for recurrence and for intraoperative guidance has some role. Difficult methodology and need for experience limit these applications to expert users. Intraoperative radio-guided surgery may increase the sensitivity of exploration of the soft tissues and lymph nodes.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. Pathologic examination of the removed tumor specimen is the major source of prognostic parameters. It provides complete information on the depth of tumor invasion and the presence or absence of microscopic regional lymph node involvement. Biochemical and molecular marker studies may provide additional information. These are all investigational. Proper preparation of the tissue may facilitate some of these tests. Specific tests aimed at establishing the presence or absence of coexistent disease should be ordered as indicated. The results may define the cost-effectiveness of all subsequent diagnostic and therapeutic maneuvers. Tests that may facilitate a patients entry into national adjuvant studies include CT, CEA assay, and complete liver function tests. Diagnostic and therapeutic steps to improve cardiac and pulmonary function before surgery often are appropriate. Colorectal surgery, with the exception of complete obstruction, is not an emergency. Diagnostic tests that starve the patient and contribute to weight loss can and should be avoided, especially now that there are new, low-residue dietary supplements that make long, repeated periods without nutrition unnecessary. SURGICAL THERAPY OF PRIMARY COLON AND RECTAL CANCER PROPHYLACTIC SURGERY: OBJECTIVES Preventive and therapeutic surgeries are equally important in these diseases. The importance of prophylactic surgery cannot be overemphasized. Endoscopic polypectomy

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1481

during regular, 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.e., universal sporadic and/or familial polyposis and ulcerative colitis) reduces the risk of invasive cancer.251 Endoscopic removal of polyps, although often obviating formal laparotomy, must still adhere to the major principles of cancer surgery. Thus, the entire cancer (or precancer) should be removed. This requires complete pathologic review of the specimen, especially analysis of the depth of any carcinoma invasion into the muscularis mucosa, and pathologic definition of free margins. 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. T2 NX M0 polypoid cancers have a 10 to 30% chance of being T2 N1 M0 disease. The decision to proceed to colectomy in such a case depends on the age of the patient, presence or absence of co-morbidity that might militate against the risks of general anesthesia, and acquiescence of the patient to the possibility that microscopic disease will remain undiagnosed without celiotomy. 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 103.3). 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; subsequent surgery is not required.252 If the endoscopic specimen has been removed piecemeal or has fragmented, either surgery or interval endoscopic follow-up will be necessary. In addition, once one polyp has been found, the remainder of the bowel must be thoroughly examined colonoscopically and subject to systematic follow-up. THERAPEUTIC SURGERY: GOALS AND OBJECTIVES Once a colorectal cancer develops, it is essential to establish the extent of disease. Early stages are treated primarily by surgery. If at the time of diagnosis regional or distant metastases are discovered, a combination of surgical and other therapeutic modalities is indicated. Surgery for metastatic disease has its particular indications as well (e.g., for the management of liver metastases, isolated lung metastases, or diffuse small volume peritoneal carcinomatosis) and even isolated central nervous system metastases. Indeed, resection of isolated liver metastases is now widely confirmed associated with prolonged survival in 30% patients or more.253 Also, excision of lung or pelvic nodules sometimes leads to surgical cures. Five-year survival approaches 50 to 70% in ideal resection candidates. The indications for single and multiple resections have expanded, and the overall results appear to be improving. It is unproven, but suspected, that this is due to postresection systemic adjuvant therapy for these high-risk patients. Localized peritoneal carcinomatosis can often be controlled for years, especially when the metastatic tumor is well differentiated.254,255 Grade is not itself a critreion for other types of resection. Surgery often is necessary to palliate local phenomena caused by the primary tumor, such as bleeding and/or obstruction.

Table 103.3.

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; 450 mg/m2 q wk

304

103

34

From Moertel and colleagues9

1482 SECTION 29 / Neoplasms of the Alimentary Canal

PREOPERATIVE EVALUATION Overall evaluation of the patient with colorectal cancer is mandatory. Therapeutic plans should be established before surgery is commenced. A biologic understanding of the disease is fundamental to the therapeutic decision. Knowledge of the field at risk and routes of dissemination dictate the surgical approach. Considerations include the patients age, co-morbid conditions, and risk of a given surgical procedure. Some patients with small tumors may undergo a limited colectomy with curative intent. In others, a very extensive local tumor may be treated successfully, with an attempt at cure, by an exenterative procedure. A patient with a locally extensive tumor invading adjacent soft-tissue organs and/or bony structures may benefit from a complex, extended resection together with urinary and soft-tissue flap reconstruction.256,257 Some 20% survive 5 years, especially patients with biologically less aggressive, well-differentiated, but locally extensive cancers. Similarly, omentectomy and adjuvant therapy may extend survival, especially for patients with low-grade tumors. Some patients may effectively be cured.254,255 If the tumor arises spontaneously without an obvious genetic predisposition or field carcinogenesis, a standard resection encompassing the lymphatic drainage is sufficient. If the cancer arises in a pedunculated polyp but without invasion of the muscularis mucosae, an endoscopic excision with a snare through the polyp base is adequate. The extent of bowel to be resected depends on the vascular anatomy of the area involved. A right hemicolectomy achieves the desired purpose regardless of the tumor location in the cecum, ascending colon, or hepatic flexure. Transverse colon cancers may be resected with a segmental and/or an extended right or left hemicolectomy. A tumor in the splenic flexure or descending colon requires a left hemicolectomy. 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, allowing for sufficient margins and resection of regional lymph nodes in the specimen. A particular variation of surgical technique is used for cancers of the rectosigmoid junction and the rectum. In these, the concepts of wide margins and resection of lymph nodes mandate dissection to both lateral pelvic walls of the mesorectum, with division of the superior and middle hemorrhoidal vessels as distant from the bowel as possible. In the longitudinal axis, it is easy to achieve a long proximal margin, but this is not so with the distal margin if sphincter preservation is to be attempted. For very low-lying rectal cancers, important progress has been possible with use of the mechanical stapler that allows for sphincter preservation.258 This allows for anastomosis very close to the dentate line and often accomplishes a potentially curative procedure.258 As a consequence, the number of abdominoperineal resections has steadily decreased. 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. As is true for several procedures, more experienced surgeons achieve better outcomes. Recently, 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, favorable impact on outcome.259263 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; (2) removal of regional mesenteric draining lymphatics (there is a predictable lymphatic spread of the disease, and some patients have regional mesenteric involvement without concurrent distant involvement); (3) adequate visual, tactile, and now intraoperative ultrasound staging at the time of primary resection; and (4) minimization of psychological and functional consequences of surgery without sacrificing any of the first three precepts. Thus, the right hemicolectomy, transverse colectomy, or left hemicolectomy are founded on anatomic structures, specifically the ileocolic, middle colic, and left colic arteries, defining what is both a convenient anatomic boundary for standard colonic resection and

also providing for adequate regional lymph node clearance,263 because the major draining lymphatics follow these blood vessels in the mesentery. Standard resections are depicted in Figures 103.6 through 103.8. There also is reason to ensure adequate coordination with the pathologist. Failure to recognize the presence of involved serosa or nodes, even though the tumor is out, has dire implications in the context of failure to make an optimum choice for adjuvant therapy. Anything less than the standard surgical procedures summarized here is difficult to justify because none of these operations produces a significant, long-lasting psychologic or functional deficit. The basics of cancer surgery cannot be assumed or taken for granted. There are

Figure 103.6. The epicolic, paracolic, intermediate, and principal lymph node groups accompanying the vessels of the colon.

Figure 103.7. Segments of bowel and lymph node containing mesentery to be removed for carcinoma of the cecum (A-A'), hepatic flexure (A-B), splenic flexure (C-C'), and descending colon (C-D).

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1483

Figure 103.8. Segments of bowel and lymph node containing mesentery to be removed for carcinoma of the transverse colon, the apex of the sigmoid (A-B), and the lower sigmoid or rectosigmoid (A-A').

recurring observations that stage-adjusted results are better in expert hands. These issues have become more cogent as the management of mesorectal, mesenteric, regional, and hepatic extension assumes a greater importance. SIGMOID RESECTDION Defining adequacy of sigmoid resection is not easy. 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. However, ligation of this vessel, which defines the anatomic boundary between the peritoneal cavity and pelvis, does not cause increased morbidity, and it allows adequate proximal and distal margins and adequate length for an anastomosis without tension. Extra effort to achieve ideal margins is especially important in surgery for the low sigmoid colon and rectum. Short cuts or technical inadequacies by the surgeon performing a limited resection likely will lead to inadequate proximal, distal, or radial margins, thus needlessly increasing the probability of regional recurrence. RECTAL CANCER SURGERY The surgical convention for rectal cancer has been changing steadily. Older standards dictated that any distally located adenocarcinoma of the rectum that could be palpated digitally required abdominoperineal resection, as first standardized by Miles. Even without a formalized study, and in part because of patient demand, surgeons have been placing low anterior reanastomoses closer and closer to the anal verge. The most extreme extension of this is the colo-anal reconnection. One of the limiting factors in the surgical cure of patients with distal rectal carcinoma is the distal margin. A 2.0- to 2.5-cm wet margin distal to the tumor has been shown to help prevent submucosal lymphatic or isolated suture-line recurrence of rectal carcinomas. The most important limiting factor is the radial margins, particularly in males with low-lying tumors. Ideally, the choice between an anterior approach, colo-anal approach, or APR should not make a difference in the surgeons ability to achieve a satisfactory radial margin. Standard techniques for low anterior resection and APR have changed little over the years,264 with the exception of automatic stapling devices.258 Interest in new techniques for transsacral, transcoccygeal, or transanal removal of T1, T2, or early T3 distal carcinomas with no obvious perirectal extension has generated several national trials to combine the benefits of external-beam irradiation, 5-FU, and limited surgery. In patients with T2 or microscopically invasive T3 lesions, a 10 to 70% chance of microscopic nodal spread exists. To provide the same

basic precepts of cancer treatment as APR or low anterior resection, but without the need for permanent colostomy as in APR or of celiotomy as in the low anterior resection technique, chemoradiation to potentially involved perirectal nodes and mesorectum is added after pathologically defined complete resection of T2 or T3 cancers. All patients are closely followed after resection. Because of the interest in sphincter sparing for distal rectal cancer now conventionally contraindicated, 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.265 Primary surgical failure excluded 51 of 177 potential patients. Close surveillance and further surgery for local relapse is a critical requirement. The success in treating recurrence may determine the as yet unproven acceptability of such colostomy-sparing methods. Until trials have been completed and successful experienced practitioners of limited excision surgery identified, one cannot assume acceptable risk from any novel but unproven curative surgical approach. The patient must be made formally aware of his or her possibly increased risk, unless some well-documented co-morbidity is present that may establish a different cost-benefit evaluation. At this time, it is clear that combined-modality therapy reduces, but does not eliminate, the risks of local recurrence. Risk is only reduced by one-third to two-thirds, and the major benefit actually may be in the reduced frequency of distant metastases. Improved local control alone usually does not correspond to improved overall survival. Research programs aside, the availability of standard adjuvant therapy does not offer any rationale for short cuts or limited surgery, which may only add to the patients risk of local or distant recurrence. The availability of adjuvant therapy in theory strongly encourages more extensive surgery including that of metastatic disease. As the rate of local recurrence has decreased 25 to 30% with mesorectal resection, the practice of adjuvant use of radiochemotherapy has been, selectively, decreased without proof. The role of chemotherapy alone as a replacement for combined-modality therapy has rarely been tested, and its success, although assumed because of the colon adjuvant successes, or equivalence to well-tested radiochemotherapy, is not established. LOCAL TREATMENT OF RECTAL CANCER Alternatives to the classic surgical approaches, particularly for very distal adenocarcinomas, have been applied in numerous single-institution settings for many years.266269 Most local treatment modalities have been performed on highly selected patients with severe co-morbid diseases or in expertly selected patients with mobile, superficial, exophytic, distal adenocarcinomas with little or no chance of microscopic nodal involvement. Treatment plans have included multiple coagulation sessions,266 local excision with or without subsequent external-beam radiation, or chemotherapy267,268 and endocavitary irradiation developed by Papillon.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. Advanced laparoscopic techniques permit colorectal resections, with the possible advantage of easier postoperative recovery. Large randomized trials are in progress, seeking to assess safety and survival, quality of life, costs, and effectiveness as measured by disease-free survival in patients with open versus laparoscopic colectomy.270,271 A decisive analysis probably awaits the Dutch Scandinavian randomized COLOR trials outcome. Earlier comparison based on open selection trials found comparable outcome, staging, lymph node number, and survival. Nevertheless, these trials are inconclusive.271,272 In these trials, 15 to 20% of laparoscopies were converted to open operations. It remains possible, but unlikely, that early comparable experience with laparoscopy was due to favorable case selection. The laparoscopy has many of the biologic effects of open laparotomy, and assessment of the comparative risk of spread or local recurrence remains inconclusive. Port site recurrence is probably uncommon, unlike the experience with laparoscopic surgery for gallbladder cancer.273 PERITONEAL DISEASE Some patients present with a primary cancer and peritoneal carcinomatosis; they may benefit from cytoreductive

1484 SECTION 29 / Neoplasms of the Alimentary Canal

surgery by resecting most of the bulky disease, followed by intraperitoneal chemotherapy.254,255,274,275 Radical resection of all peritoneal disease followed by intraperitoneal hyperthermic chemotherapy is sometimes followed by prolonged disease-free survival.254,255,274,275 Large tumors with direct extension can be resected en bloc, yielding opportunities for adjuvant radiotherapy and chemotherapy. Complete resection is critical to subsequent adjuvant therapy. HEPATIC RESECTION The most frequent site of colorectal cancer metastasis is the liver. Approximately one-third of colon cancer metastases occur solely in the liver; of these, one half are amenable to resection when intraoperative ultrasound confirms the localization of metastases. A number of selection criteria define the likelihood of successful hepatic resection: primary tumor B versus C, size of metastasis, number of metastases, satellitosis, time to recurrence, CEA level, extent of margin, and extent of surgery.276 Many patients still prove ineligible on careful work-up because of extrahepatic disease (21%) and occult lymph node disease (19%); others have unresectable locations.276 Surgical excision of isolated or anatomically confined liver metastases is the primary standard against which other treatments for hepatic metastasis must be compared, such as cryotherapy, electrode diathermy, and alcohol injection.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. Second resections are feasible and sometimes successful, as are multi-step resections of liver and lung metastases.278 Five-year survival in selected series exceeds 20%.278 Survival approaches 50% in some good prognostic groups. When metastases in the liver are widespread or nonresectable because of size and/or anatomic location, different locoregional modalities of treatment have been investigated: intra-arterial hepatic chemotherapy by catheter or via implanted pump, alcohol intratumoral injections, and cryoablation.279 Each of these approaches remains investigational, however, and although encouraging results have been reported, prospective, randomized trials and further follow-up are necessary to determine their objective value. Increased rates of response and improved local control may not improve quality of life or survival for unselected patients. Eligibility for and long-term success of hepatic resection may have been expanded by adjuvant systemic and additional hepatic artery infusion,280 as well as by neoadjuvant systemic chemotherapy methods that produce substantial responses prior to attempting hepatic resection.281 These have been selectively combined with tumor embolization prior to hepatic resection.281 Preoperative embolization may also render metastasis more resectable and trigger the compensatory function of the remaining liver. Resection of metastases is increasing in frequency. Overall, 5-year survival remains about 30%, despite bigger, more frequent, and more difficult resections. None of the prognostic factors such as site of primary (rectum), size (greater than 5 cm), number of lesions (five, CEA (> 200), or short interval less than 12 months after initial surgery clearly exclude attempting resection. Synchronous discovery of a primary and resectable metastatic disease carries an even better relative prognosis than late recurrent disease. 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. The surgeon must remove the contiguous organ, or whatever else is necessary, to ensure pathologically free margins. Even if such patients who have T4 or B3 or C3 lesions usually cannot be cured, an attempt to prevent systemic and regional recurrence is often justified. Patients with perforating, obstructing, or regionally extensive carcinomas suffer a high rate of recurrence; nonetheless, with complete resection, some of these patients are, in fact, cured. The potential contribution of standard or intraperitoneal adjuvant therapy remains to be proven. 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.

PELVIC RECURRENCE Patients with isolated perineal or pelvic recurrences after an unsuccessful (or inappropriate) low anterior resection of rectal cancer represent a special case. Curative-attempt exenterative approaches (including extended sacral resection) appear to produce an important minority, 20%, of long-term disease-free patients. In addition to the long-term survivors, other patients have enjoyed 2- to 3-year periods of disease-free survival and surprisingly good rehabilitation before re-recurrence in the region of initial bulk disease.282 Improved techniques, including the use of unilateral or bilateral posterior thigh myocutaneous pedicle flaps to fill the perineal space, presurgical radiation therapy, ureteral reconstruction, and staging of major operative procedures, particularly in patients with co-morbidity, have led to a shortened length of hospital stay and quicker rehabilitation. This helps to justify such large surgical procedures as legitimate palliative attempts when performed by experienced practitioners of these methods. Another approach is external radiotherapy with or without chemotherapy followed by resection with or without intraoperative radiotherapy.283 SURGICAL CONSIDERATIONS IN ADJUVANT THERAPY The primary surgical approach must be the cornerstone of any appropriate therapy combination. Removal of adjacent soft tissue or contiguous organ structures must be undertaken without compromise or complacency generated by plans for adjuvant treatment. 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. Indeed, 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. Surgical Prognosis. Marked progress has been made in perioperative management. Anesthetic and operative mortalities have been reduced, and extensive resections now may be performed with relative safety. Thus, a substantial increase in the cure rate can be achieved.284 The direction of practice is to do more than resect the primary tumor ehen one discovers regional or metastatic disease. The scope of regional resection and resection of metastases in liver, lung, pelvis, and even peritoneum has increased. This aggressive practice is supported by the availability of adjuvant therapy, and the surgery is increasingly the province of the specialty of surgical oncology. Surgical cure of colorectal cancer is determined by the size, extent, and stage of the tumor and its biologic behavior. Smaller, superficial tumors without vascular or lymphatic invasion can be easily resected with a high chance of cure. In contrast, patients with larger, deeper, ulcerated tumors invading into the pericolonic fat and/or vessels and lymphatics are less likely to be cured by surgery alone, even if the resection is apparently complete and has clear margins. Thus, stage I, T1 N0 (A) patients have a 97% 5-year disease-free survival, stage II T2 N0 (B2) patients have a 90 to 78% rate, and stage III T2-3 N1 M0 (C) patients have only a 50 to 20% rate if no other therapies are used. The same good outcome of the stage II patients has not been found in all cooperative groups, but best outcome is rapidly becoming the standard measure of ideal surgery and staging. The presence of other pathologic and molecular markers of virulence increases the risk, compared to that defined by conventional surgical staging alone. Poor differentiation of the tumor or vascular, neural, and lymphatic invasion are also ominous but prognostically complex findings, which do not necessarily represent independent markers of prognoses. A single metastatic node adjacent to the tumor is compatible with more than a 50% chance of cure, especially if the tumor is of a low microscopic grade and does not distort the lymphatic architecture of the involved lymph node. The acute morbidity and mortality from surgery for colorectal carcinoma should be low. Significant, co-existent disease increases both mortality and morbidity. Age by itself is not a short-term prognostic factor but the extremes of age, youngest (right side) and oldest, do worse over several months and several years, respectively. Several studies confirm a worse prognosis in males. Neither age nor sex normally justifies changes from best standard practice. Morbidity rates (mainly thromboembolic, infectious, and anastomotic problems) should be less than 10%. In the case of patients operated on for acutely obstructed carcinomas where adequate bowel preparation

cannot occur, the decision to perform intraoperative bowel preparation or, perhaps, a temporary colostomy may obviate the increased risk of a leak if primary anastomosis is performed. Rectal stents remain investigational but when selectively used avoid some colostomies and two-stage procedures. At present, the most appropriate bowel cleansing consists of a copious oral solution of polyethylene glycol with sodium sulfate, bicarbonat and potassium chloride, Go-Lytely (Braintree Laboratories, Inc.). Addition of either oral preparative antibiotics or parenteral antibiotics perioperatively decreases the wound infection rate.285,286 Although improving, operative staging is imperfect. Thus, staging in colorectal cancer is not complete until pathologic examination of the removed specimen has been performed (see Table 103.1).287 The prognosis has progressingly improved in recent decades (Table 103.4).288,289 This improvement is not exclusively a function of a change in disease biology, nor is it exclusively a function of improved surgery. More likely, it includes the effects of stage migration because of better pathologic staging. If one examines a greater denominator of lymph nodes, patients who normally would have been staged as TX N0 now are being staged as TX N1, which improves the outcome of both the N0 and N1 groups. Outcome is further improved by earlier diagnosis attributable to testing for occult blood, fiberoptic endoscopy, increased awareness, more and better trained surgeons, and possibly reduced use of blood transfusions during surgery. Currently, blood transfusion is thought to affect adversely the rates of infection and complications and actual survival, but not the actual rate of relapse.289 Surveys conflict as to the actual impact of these practice changes. There is some doubt that new, proven practices are being applied with adequate frequency to impact national health statistics. Opportunities to improve outcome for patients with rectal cancer are especially recognizable, but implementation remains inadequate. Failure to convince physicians is the dominant reason for the poor use of these new practice opportunities. These important changes in practice, screening, pathology, and therapy create the need for prospective controlled trials in order to test any further, new candidate therapy, especially its effects on survival. RADIATION THERAPY Radiation therapy is used in a variety of settings for the treatment of patients with rectal cancer. Preventing local failure in these patients, even if not always associated with improved overall survival, is an important goal. Local recurrences, once clinically well established, are not easily or effectively treated and often are associated with progressive severe morbidity and decreased quality of life. Local failure can be defined in various ways, so that for any discussion, it is important to fully define the term. Risk of local failure can refer to first site of failure, isolated local failures, or total local failure, including those associated with distant metastases. Local failure also can be defined clinically by symptomatic failure with far different sensitivity and clinical implications, by imaging studies, by surgical exploration, or at autopsy. In most national trials, local failure was determined clinically and defined as the first site of failure. This underestimates the true risk to the patient of developing a later local recurrence and suffering from its consequences. When patterns of failure of rectal cancer after curative surgery were analyzed in a University of Minnesota reoperation series, over 90% of patients who recurred were noted to have either local or regional nodal failure as a component of their recurrent disease.287a For practical clinical purposes, the risk of local recurrence of

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1485

Table 103.4.

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.289

rectal cancer has been estimated at 50%. It decreases with lower T stage, smaller size, decreasing numbers and architectural damage of node metastasis, and more proximal location of the primary tumors.294,295 It also decreases with the expertise of the surgeon, absent vascular invasion and with female patients. 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. 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. Depth of bowel-wall invasion and nodal status are the two most important factors in predicting risk of local failure. These additional prognostic factors are currently only of use for trial analysis investigational direction of treatment choice. 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. These patients (MAC stage A and B1; TNM stage T1-2 N0 M0) are appropriately treated by surgery alone. When tumor invades through the rectal wall or involves lymph nodes, the risk of local failure increases to approximately 25 to 50%. Risk of local failure can be even higher if the tumor is adherent to or invades adjacent organs and structures. It is these patients (MAC stage B2, B3, C2, and C3; TNM stage T3-4 N0 M0 and T1-4, N1-3 M0) who remain at significant risk of local failure despite having an APR or low anterior resection. Biology probably plays some role in the high local failure and poor survival rates after a potentially curative resection because, stage for stage, rectal cancer has a worse prognosis than colon cancer. However, 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. These tumors often are located deep in the pelvis, where the margins posteriorly on the sacrum, laterally on the pelvic sidewall, or anteriorly on the prostate often limit the surgeons ability to obtain wide radial margins around the primary rectal tumor mass. In studies analyzing radial margins after radical surgery, the median distance is unsatisfactory between 0.5 and 0.8 cm.290 Females have better biology and better anatomy for resection, which is reflected in a modestly improved stage-adjusted survival well demonstrated in NSABP adjuvant trials. 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, multi-institution prospective randomized trials were conducted to assess the role of adjuvant therapy. These trials evaluated the role of pelvic radiation, chemotherapy, or combination radiotherapy/chemotherapy in patients with Dukes stage B2 and C rectal cancers who had undergone APR or low anterior resections. Unlike colon cancer, the B2 rectal cancer patient is clearly at high risk of recurrence and is a candidate for adjuvant therapy. The B2 rectal cancer patients, as a group, benefit from adjuvant therapy. There are several established forms of adjuvant therapy for colon cancer using:chemotherapy with biochemical modulation and supplementary regional therapy, monoclonal antibodies, and levamisole (LEV). Others are problematic and probably too toxicfor example, mitomycin C and nitrosoureas. Not all are applicable or tested for rectal cancers. 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. The Gastrointestinal Tumor Study Group (GITSG) published the first modern trials.7,8 The GITSG 7175 study was a four-arm study comparing surgery without adjuvant therapy to surgery followed by chemotherapy alone, radiotherapy alone, or combination treatment with chemotherapy and radiotherapy. Chemotherapy consisted of semustine and 5-FU. The dose of 5-FU was 375 mg/m2 when given alone. Chemotherapy treatment continued for 18 months. Radiation therapy consisted of parallel opposed fields, with dose prescribed to mid-plane at the central axis. When radiotherapy was given with chemotherapy, the dose was 4,000 to 4,400 CGy over 4.5 to 5.5 weeks. This trial had several limitations. The study was terminated before completion of the targeted accrual goal. Only 202 patients were eligible

1486 SECTION 29 / Neoplasms of the Alimentary Canal

for analysis. This limited the trials statistical power to detect significant differences between the study arms. 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. In addition, 39% of patients did not receive their radiation per protocol specifications, and only 65% completed the prescribed chemotherapy in the combined-modality arm. Despite these limitations, patients on the combined chemoirradiation arm had the best outcome: the chemoirradiation arm showed a benefit in disease-free survival, and also showed improvement in overall survival compared with the surgery-only arm.7,8 Local or regional failure was assessed only if it was the site of initial recurrence. In the observation arm, 24% of patients, fewer than expected, initially recurred with locoregional disease, either alone or in combination with distant metastases. This compares to 27% in the chemotherapy arm, 20% in the radiotherapy arm, and 11% in the chemoirradiation arm. Because chemotherapy alone had no influence on loco-regional failure, the improved control rate with chemoirradiation over radiation alone suggests a synergistic effect between the two modalities. The benefit of combined-modality therapy was confirmed by the Mayo/North Central Cancer Treatment Group (NCCTG).291 This was a two-arm study comparing postoperative radiation with radiation plus chemotherapy. As in the GITSG study, chemotherapy consisted of 5FU given as an intravenous bolus injection and semustine. Initial local recurrence was reduced to 13.5%, significantly, in the radiation and chemotherapy arm, compared to 25% with radiation alone. The twofold improvement in local control with chemoirradiation over radiation alone is consistent with the GITSG trial results. Overall survival in the combined-modality therapy adjuvant arm was improved by 29%, also confirming the GITSC outcome. In stage II and stage III rectal cancer, results with single-agent 5FU in appropriately high doses (450500 mg/m2) were as good as those with semustine combined with lower doses of 5-FU (300400 mg/m2). 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. 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, substantially reduce local recurrence, and prolong patient survival. Such a regimen (now without semustine) may be recommended as therapy for individuals with resected TNM stage II (Dukes B2, B3) and III (Dukes C) rectal cancer.288 The contribution of adjuvant chemotherapy by itself was the subject of the NSABP R-01 study.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. There was a modest survival advantage in the adjuvant chemotherapy arm (53% vs. 43%) at 5 years. This contrasts with the GITSG study, where no significant survival benefit was seen with adjuvant chemotherapy alone, perhaps due to the weak statistical power of the GITSG trial. No survival advantage was noted in the NSABP radiotherapy arm. First site of treatment failure was locoregional in 24.5% of the surgery-only arm, compared with 21.4% of the adjuvant chemotherapy and 16.3% of the adjuvant radiotherapy arms. Additional trials followed with and without semustine given its nephrotoxicity and leukemogenicity. GITSG 7180 showed that semustine (MeCCNU) was not required in the adjuvant treatment of rectal cancer.293 These results were confirmed in an NCCTG study.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. The Mayo trials examined starting with chemotherapy, allowing more time for recovery from surgery before starting radiotherapy, and found no harm in the moderate delay of the radiotherapy element.291 Standard postoperative adjuvant therapy initially consisted of rapid intravenous injection of 5-FU, 500 mg/m2/d for 5 consecutive days during weeks 1 and 5, followed on week 9 by

radiation therapy of 50 to 54 Gy with concurrent 5-FU, 500 mg/m2/d for 3 consecutive days during weeks 1 and 5 of radiation, followed by two more cycles of 5-FU, 450 mg/m2/d for ideally 5 days.299 The bolus given with radiotherapy was replaced by 5-FU infusion, which is clearly superior to 5-FU bolus.11 Attempts to improve on the chemotherapy component, 5-FU alone, have been unsuccessful as yet. Intergroup (INT) trial 0114 was a four-arm trial for patients with TNM stage II and III rectal cancer evaluating 5-FU, 5-FU and LV , 5-FU and LEV , and 5-FU with both LV and LEV. All four trial arms received pelvic radiation therapy. The results show no survival advantage of any treatment regime over 5-FU alone in combination with radiation therapy. Current trials examine the complete replacement of 5-FU bolus courses with 5-FU infusions. 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. All three arms receive identical radiation therapy to a total dose of 50.4 to 54.0 Gy. PREOPERATIVE VERSUS POSTOPERATIVE ADJUVANT RADIATION THERAPY Although recently successful randomized adjuvant rectal cancer trials in the United States evaluated only postoperative radiation therapy, there are potential advantages to delivering radiation therapy before surgery. These include decreased toxicity, increased biologic effectiveness, improved surgical resectability, and increased chance of sphincter preservation. Recent American attempts to test this in randomized trials have failed because of poor accrual. Radiation therapy given preoperatively may be more effective than an equivalent dose given postoperatively. Oxygen is a strong radiation sensitizer. DNA damage is more readily repaired under hypoxic conditions. It is probable that fibrosis and altered vascularity from surgery limit the oxygen supply to the tumor bed. Another potential advantage of preoperative radiation therapy is sterilization of tumor cells in the perirectal tissues, thereby decreasing tumor cell seeding from surgical manipulation. By causing tumor shrinkage, radiation given preoperatively can convert unresectable disease into a situation that is amenable to surgical excision. Preoperative radiation may also permit a patient who otherwise would need an APR and colostomy to undergo a sphincter-sparing operation. There are now numerous demonstrations of such downstaging for unresectable cancers; however, the systematic application to resectable cancer compared to primary resection and postoperative adjuvant therapy remains unproven. In fact, attempts have often failed and only rarely and inconsistently succeeded. The most common and severe morbidity related to pelvic radiation is that associated with small bowel toxicity. This also argues for preoperative treatment but alone is not persuasive. Usually, this toxicity manifests by loose bowel movements or diarrhea that is self-limited or managed by antidiarrheal medication. Occasionally, small bowel toxicity is more severe, such as an obstruction requiring surgical intervention, hemorrhage, or fistula formation. Toxicity from radiation may be greater after surgical intervention because fibrotic adhesions from surgery tend to limit bowel motility. Surgery or secondary adhesions that inadvertently fixed a portion of bowel in the radiation fields can prohibitively increase radiation treatment related enteritis. The disadvantages of preoperative radiation include delayed definitive excision of the tumor, potential for increased surgical complications and delayed wound healing, and lack of pathologic staging. If preoperative radiation is given in the adjuvant setting, patients with early-stage disease and a small risk of local failure might be treated unnecessarily. However, by use of transrectal ultrasound to evaluate the extent of transmural penetration by the tumor, this risk of overtreatment can be reduced. Transrectal ultrasound is approximately 90% accurate in determining the extent of tumor invasion of the bowel wall. Retrospective studies have shown a benefit with preoperative radiation therapy both in local control. Despite the improvement in local control, however, only two trials also showed a benefit in overall survival. Given the potential advantages of preoperative radiation therapy and the results from retrospective studies, multiple randomized studies with preoperative radiation therapy have been conducted. Proof of principal remains elusive, although the trial findings encourage continued investigation of preoperative therapy. These trials can be

divided into those that used low doses of radiation (5002,000 cGy) and those that used intermediate doses (2,5004,000 cGy). Some trials tested accelerated schedules of radiotherapy. In three of four trials using 2,000 cGy preoperative radiation therapy or less, not surprisingly, no benefit was seen either in local control or overall survival. One trial using three 500-cGy fractions over 5 days showed a benefit in local control only. In the five trials using higher doses, local control was significantly improved over that with surgery alone. These results compare favorably with those of adjuvant postoperative radiation, without simultaneous chemotherapy, which are consistent failures, when evaluated for impact on overall survival. The preoperative trials are not, however, directly comparable to the postoperative adjuvant trials. Both the patient populations treated and the technical delivery of radiation therapy differed. The preoperative trials contained a heterogeneous patient population staged without benefit of imaging modalities such as CT, MRI, or transrectal ultrasound and often included patients with stage I disease and also patients with clinically unrecognized unresectable tumors or distant metastases. Including early-stage patients with a good prognosis, which can be successfully treated by surgery alone, and advanced-stage patients with distant metastases may obscure any potential benefit of local control on survival. The preoperative randomized trials used lower doses of radiation than those delivered in the postoperative trials. 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. Despite this poorer technique, patients treated with preoperative radiation had a higher compliance rate and less toxicity than those in the postoperative radiation trials. Few trials have directly compared preoperative with postoperative radiation therapy. The first Swedish multicenter trial randomized patients in the preoperative arm to 2,550 cGy and in the postoperative arm to 6,000 cGy. Despite the higher postoperative dose, the rate of local failure was lower in the preoperative arm (12 vs. 21%; p < 02). The rate of small bowel complications also was lower among the patients receiving preoperative radiation therapy. The incidence of perineal wound sepsis was higher in the preoperative arm, but this may relate to the large (510 cGy) fraction size used. Standard preoperative therapy alone continues to fail, although it comes close in analysis of several disease-free survival end points. The overall benefit is possibly real but modest and difficult to demonstrate with current eligibility and staging criteria. In one important exception after 10 failures of what seemed similar trials, a rapid course of preoperative radiation therapy improved both local control and survival. In a Swedish trial conducted between March 1987 and February 1990, 1,168 patients were randomized. All had initially resectable rectal cancer. For those given 25 Gy over 5 days, the local relapse rate was 11% (63 of 553) versus 27% (150 of 557; p .001) and improved 5-year survival from 48 to 58% (p .004). Overall survival at 9 years was 74 versus 65% for ideally resected patients. 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. It is uncertain if these best results are comparable to best repeatedly confirmed results achieved with postoperative combined-modality therapy. 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, improving local control. There is a wide institutional variation in risk of local failure. The risk of local failure was unacceptably higher than anticipated in controls. In spite of its favorable impact, reducing local recurrence (RR = 0.54), postoperative radiotherapy did not produce the expected low rate of local recurrence in the treatment group. Postoperative radiotherapy, especially for high-risk patients, has too little practical benefit. Although it works, 79 of 235 controls and 48 of 234 in the treatment group suffered local failure. Adjuvant preoperative radiotherapy also produced adverse effects documented during long-term follow-up of two randomized trials. Preoperative radiotherapy has significant side effects: thromboembolism, radionecrosis of bone with fractures, and late intestinal obstruction. In theory, postoperative radiotherapy may have fewer

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1487

complications, but the comparative quality of life impact of pre- and postoperative radiotherapy remains to be defined as much as does the therapeutic benefit. Of interest and some surprise, Q-Twist methods support combined-modality therapy versus radiation therapy alone for adjuvant therapy of rectal cancer. In the postoperative adjuvant trials, local control and overall survival were best among those patients treated with both 5-FUbased chemotherapy and radiotherapy. The experience using combined chemoirradiation preoperatively has been more limited, but it may have practical advantages over postoperative treatment. Advantages of preoperative radiation therapy may in theory be further potentiated by addition of a radiation sensitizer like 5-FU. Early initiation of systemic therapy compared with waiting and delay until surgical healing, postoperatively, allows for earlier treatment of potential micrometastatic disease, when the tumor burden is presumably smaller. Attempts to test preoperative chemoirradiation have proven difficult although the dosage of 5-FU for such trials has been defined. The relative merit of preoperative versus postoperative combined modality will not be defined in American trials. In addition to INT-0147, the NSABP R03 trial was also closed prematurely because of poor patient accrual. Too many physicians will not randomize; they either believe or do not believe in preoperative radiotherapy. A German trial comparing pre- and postoperative neoadjuvant radiotherapy is in progress with satisfactory ongoing accruals of patients with resectable rectal cancer. Some evidence-based recommendations may yet be anticipated. LOCALLY ADVANCED RECTAL CANCER Although often analyzed as a group, patients with locally advanced rectal cancer constitute a diverse and heterogeneous population. 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, cervix, uterus, bladder, or prostate. Tumors may be fixed to the pelvic sidewall or sacrum. Advanced fixation can lead to a completely frozen pelvis. Pelvic bone destruction can occur from direct invasion. There is no standardization of what is considered to be resectable disease. Resectability depends on the skill or aggressiveness of the surgeon and whether the assessment is made clinically or intraoperatively. Complete tumor resection may require extending a standard APR to include a posterior vaginectomy or it may require total pelvic exenteration. Patients with locally advanced disease can benefit from aggressive local treatment. The goal is to resect the tumor completely while attempting to minimize functional impairment. Because a surgical approach alone will often leave behind gross or microscopic residual disease or produce functional deficits, adjunctive treatment is recommended. In patients with advanced but resectable disease, preoperative radiation may allow for a less radical surgical procedure or a sphincter-saving approach. In patients with unresectable disease at presentation, preoperative radiation may cause sufficient tumor shrinkage to allow resectability in half. In one series, 134 patients with either tethered or completely fixed tumors received 45-cGy pelvic radiation therapy followed by a 4.8- to 9.6-Gy boost. Although 86% of patients had tumors located in the low rectum (6 cm from the anal-rectal junction), over 75% were able to undergo sphincter-sparing surgery. Pelvic control and survival were 86 and 68% in the partially fixed group and 80 and 60% in the completely fixed group, respectively. If an incomplete resection is performed, then intraoperative radiotherapy (IORT) or a brachytherapy implant can potentially sterilize the remaining tumor cells. If incomplete surgery can be anticipated, external radiation therapy precedes surgery and IORT or brachytherapy. 5-FUbased chemotherapy can be used to enhance tumoricidal activity, acting both as a radiation sensitizer and on subclinical disease outside the radiation field. Five-year survival in locally advanced rectal cancer has ranged from 18 to 69%. Despite complete resections, the risk of pelvic recurrences, remains high (2550%). Pelvic Radiation. There appears to be a dose-response relationship, especially with doses above or below 40 to 45 Gy. Local control was 91% in patients receiving 50 Gy but only 67% in those receiving

1488 SECTION 29 / Neoplasms of the Alimentary Canal

40 Gy. Similarly, others found a 20% local failure rate with 45 Gy, compared to a local failure rate of 8% with 55 Gy given preoperatively. 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. Although total dose delivered by external beam usually is limited to between 50 and 55 Gy, 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. Boost doses, higher doses than can be given safely with external-beam therapy, can be delivered with a brachytherapy implant or IORT. 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. In an iridium implant, plastic catheters placed against the high-risk area are afterloaded to allow optimal dose distribution based on computer-derived dosimetry. IORT using an electron beam from a linear accelerator can also deliver a boost dose; IORT can also be delivered with a high-doserate remote afterloader. The high-risk area is defined at surgery, allowing normal tissues such as small bowel to be moved out of the way before irradiation. The radiation is delivered as a single dose, usually between 10 and 20 Gy, with the aid of a special applicator placed directly over the target area and then lined up in the treatment machine. 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%, compared with 67% for patients not receiving IORT or additional postoperative radiation. Although it appears that higher radiation doses improve local control, no direct comparison has been made between the various techniques for delivering a boost dose. Brachytherapy provides another method of delivering a boost radiotherapy dose. Postoperative methods in the form of combined-modality therapy with LEV and FU 45 to 50.4 cGy failed when tested as a randomized adjuvant treatment for colon cancer. This NCCTG trial attempted to develop the promising Joint Center strategies for B3 or T3 N1-2 M0 colon cancer described above. Only 222 patients were tested, due to slow accrual; a similar large number in both test groups suffered recognizable relapse. PRESERVATION OF SPHINCTER FUNCTION For patients with low-lying early stages of rectal cancers, APR has been the standard of care. Because radical surgery results in significant functional impairment and morbidity, including impotence, urologic dysfunction, and need for a permanent colostomy, alternative approaches to treatment have been evaluated. Particularly for patients with early rectal cancers, 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.g., local excision, sphincter-sparing surgery). 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, stage II, B2 or stage III, C nodes. In both situations, 5-FU sensitization may increase the efficacy of radiation therapy. This is not yet a standard of care. It is an option for a few expert practitioners and trialists. As yet undefined success with surveillance and salvage, second resectors, 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. Early-stage tumors with high-grade architecture or vascular invasion, and perhaps all low distal tumors in men are considered high risk in spite of their small size. Nevertheless, interest in sphincter preservation drives efforts to avoid APR for all stages of rectal cancer but especially early low distal tumors. Besides local excision, local therapies have included fulguration, electrocoagulation, and endocavitary radiation. In the Papillon technique, endocavitary radiation, a rectoscope attached to a low-energy (50 kV) contact x-ray machine is inserted transanally, allow-

ing direct visualization of the tumor. Twenty to 30 Gy are delivered in three to four applications spaced 1 to 3 weeks apart. The procedure can be performed on an outpatient basis and is particularly suitable for those who are medically inoperable. In appropriately selected patients (i.e., T1 and T2, well to moderate histologic differentiation, exophytic, mobile, tumor size < 4 cm), the local failure rate with endocavitary radiation is 5%. Endocavitary radiation therapy also may be combined with interstitial radiation to deliver a boost with brachytherapy or combined with external-beam radiation. In the Papillon technique, very low-energy x-rays (50 kVp) exit through a large rectoscope that is inserted transanally and placed directly over the tumor. Patients are treated with approximately four fractions, with 2 to 3 weeks between fractions and a dose per fraction of 2,500 to 3,000 cGy. In between the doses, there is substantial tumor regression, which allows for deeper portions of the tumor to be irradiated at successive treatments. This minimizes the risk of excess radiation to deeper, underlying normal tissues. In properly selected patients (i.e., those with tumors 4 cm in maximum diameter, not poorly differentiated, and without any evidence of deep ulceration or invasion), this approach can be delivered on an outpatient basis with minimal morbidity and excellent long-term control. Approximately 95% of tumors in the series by Sischy were locally controlled at 5 years. Papillon had similar results. Survival statistics are not as good, however, because a substantial number of these elderly patients with significant preexisting medical conditions died from co-morbid diseases. This is an alternative for highly selected patients in the context of institutional review and individual informed consent. 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. In best but not consistently achieved results, approximately one-third of expertly selected patients may be cured with such an approach. For distal rectal cancers, APR has become the standard treatment because high local failure rates have been observed with more conservative surgery. To avoid the morbidity associated with APR, 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. When patients with tumors in the distal 3 cm of the rectum received 45 to 60 Gy followed by transabdominal, transanal, combined abdominal transsacral, or anterior resections, the 14% local recurrence rate compared favorably to that of patients treated by APR. Complications included anastomotic disruption and leak in 4 and 6% of patients, with and without radiotherapy. When other patients with tumors 3 to 7 cm from the anal verge received 50.4 Gy followed by either low anterior resection or coloanal anastomosis, the 4-year actuarial local failure rate was 23%, although 28 of the 30 patients evaluated had T3 tumors. Sphincter function was rated as good to excellent in over 75% of the patients. Tests of sphincter function by anal manometry found no significant difference in mean maximum squeeze or resting pressure after radiation therapy. Toxicity of radiation remains an important unresolved end point in comparing proposed treatments. When the method of identifying toxicity is not described or is not of the highest standard, the absence of unreported side effects cannot be assumed. Local excision, either alone or with the addition of postoperative radiation therapy, also has been used as an alternative to radical surgery to preserve sphincter function. To some degree, acceptable candidates for local excision either alone or with the addition of postoperative radiation therapy can be defined by tumor size, depth of bowel wall invasion, histology, grade, and lymphatic or blood vessel invasion. Some of the theoretical stage for stage concerns with sphincter sparing has been reviewed. 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. In theory, the empiric approach would be that patients with T1 or T2 tumors with poor characteristics found at pathology are treated with postoperative radiation therapy. Patients with T3, T4 tumors are candidates for preoperative radiotherapy because, if successful, downstaging allows sphincter preservation. With postoperative radiation therapy there is also an important role for close observation and even selective reoperation and further intraoperative radiotherapy.

In considering preoperative versus postoperative radiotherapy, it is important to make a distinction between candidates for standard stoma-free resection, patients with clearly operable resectable tumors, and patients with clearly fixed tumors or tumors so distal that sphincter sparing requires preoperative adjunctive therapy. In rectal cancer, unlike colon cancer, there is a clear consensus for adjuvant treatment of stage II tumors and an impression that some stage I tumors should be treated. Although randomized trials, comparisons of preoperative to postoperative therapy, have been difficult, nonrandomized trials of preoperative radiotherapy have found reasonably strong support for treatment when there is tumor fixation. When resection is technically possible, postoperative treatments have found the most consistent strong support. For early tumors, trials continue to evaluate the sphincter-sparing strategy of local excision, selective postoperative radiation therapy, and close follow-up. Role of Radiation Therapy in Colon Carcinoma. The role of adjuvant radiation therapy plus chemotherapy in resected colon carcinoma is not as well defined as it is for rectal cancer. Although the overall local failure rate is lower in colon than in rectal cancer, there are patient subgroups with resected colon cancer that are at significant risk for local failure. These patients may possibly benefit from adjuvant local radiation therapy. Local failure occurred frequently in patients with local extension, T4 tumors, in approximately one-third of patients with B3 and almost one half of patients with C3 tumors. Other high-risk factors include gross extension beyond the bowel wall and blood vessel or lymphatic vessel invasion. 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. Patient groups who appeared to benefit from local postoperative radiation included those with stage B3 and C3 lesions, tumors with perforation or associated fistula, and subtotally resected tumors with gross or especially microscopic residual disease. An initial pilot trial of adjuvant 5-FU and radiation therapy appeared encouraging, similar to the high-risk pilot trials described above. The actual somewhat-modified-by-a-treatment-control phase III test failed in part due to poor accrual. Possibly, this result should be interpreted as finding adjuvant chemotherapy alone (equally effective) compared to combined-modality therapy for resectable high-risk colon cancer. An earlier adjuvant trial had been found promising. Currently, 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, as described below. The benefit of adjuvant chemotherapy was most pronounced in decreasing distant failure. Neither chemotherapy alone nor monoclonal antibodies reduce the risk of local failure of colon cancer in a clinically important fashion; at best, they have only a slight effect on reducing local failures. Although controversial, and the subject of only a few reports describing small series of patients, radiotherapy may have a palliative role against symptom-producing liver metastases. In 71% of patients, pain relief was achieved, and many had decrease in hepatomegaly. Boost radiation, 21 Gy (median) at 2.0 to 3.0 Gy daily, increased benefit and may have added to survival (4 vs. 14 months). In contrast, whole-liver radiotherapy clearly failed in a large prospective adjuvant trial performed by the GITSG. Planning of Radiation Therapy The normal tissue tolerance of small bowel to radiation limits the dose that it can safely receive. Doses higher than 4,500 to 5,000 cGy increase the risk of late complications such as small bowel obstruction. 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. Small bowel toxicity can be exacerbated by medical conditions such as hypertension or diabetes, prior abdominal or pelvic surgery, and 5-FU chemotherapy. Surgery is associated with adhesions that may cause a small bowel obstruction or, by limiting small bowel motility, increase the toxicity from radiation therapy. In the NCCTG 794751 study, severe diarrhea developed in 5% of patients treated with adjuvant radiation alone and in 20% of those receiving combined radiotherapy and chemotherapy.

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1489

Because the volume of small bowel that is irradiated relates to toxicity, efforts should be directed at maximally excluding it from the radiation fields. The surgeon can use techniques such as reperitonealization of the pelvic floor, use of an omental flap, or placement of an absorbable mesh to hold small bowel up and out of the pelvis. Positioning the patient prone and bladder distention also can aid in excluding small bowel from the radiation field. Oral contrast should be given sufficiently earlier than simulation to allow for adequate transit time to visualize small bowel during treatment planning. Blocks then can be custom shaped to minimize the treatment of small bowel. If the tumor volume or surgical bed can be precisely located, 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. To identify the high-risk area, the radiation oncologist should be familiar with the pathology report and operative note. Use of clips placed at surgery to outline the tumor volume or delineate a close or positive resection margin can be very helpful. Although many patients are diagnosed by colonoscopy, a barium enema is useful for treatment planning. CT or MRI also can be helpful in describing the treatment volume, especially if disease is extensive. 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. Although in earlier studies, patients were treated anteroposteriorposteroanterior (AP-PA) with two fields, using a three- or four-field technique with lateral fields and either PA or AP-PA fields helps to reduce the dose to small bowel. For pelvic radiation in rectal cancer, radiation fields are set up with the cephalic border, typically placed at the L5-S1 junction to stay above the peritoneal reflection, whose posterior extent is approximately at the level of the sacral promontory. Although older studies often put the cephalic border as high as the L1 or L2 vertebral bodies, there is little justification for fields extending to this level, and the increased amount of small bowel irradiated adds to morbidity. 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 1.5 cm below the perineal scar to include the perineum in patients who have undergone an APR. Lateral borders for the AP-PA fields usually are placed 1.5 to 2.0 cm lateral to the pelvic side walls. The posterior border of the lateral fields should include the entire sacrum with margin; the anterior border typically is placed at the posterior aspect of the symphysis pubis or 2 to 3 cm anterior to the sacral promontory. 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. The internal iliac and presacral lymph nodes are at risk and are included in the field. 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 4,500 cGy in 180-cGy fractions daily over 5 weeks. A boost dose to the tumor or surgical bed is given to 5,040 cGy or to 5,400 cGy if all small bowel can be excluded from the final cone-down field. In selected patients, higher doses delivered by cone-down fields with external-beam radiotherapy or with a brachytherapy or IORT boost may be appropriate. Treatment must be individualized. Cooperative groups have found that there is a radiotherapy learning curve and minimizing errors requires a combination of experience and quality control procedures. Adjuvant Chemotherapy and Immunotherapy. At present, most patients with colon cancer and a tumor that penetrates to or even through the serosa (i.e., B1, B2) do not have a statistical risk of recurrence that is sufficiently high to justify postsurgical adjuvant treatment to the entire group. Nevertheless, a significant proportion of these patients ultimately will fail either regionally or distally (see Table 103.4). Meta-analyses fail to support therapy for B2 patients even though several studies clearly show benefit. The ongoing search for additional prognostic markers, such as gene probes for specific sequences necessary for invasion or metastases, has as its intent the identification of subgroups at increased risk for recurrence so that, ultimately, adjuvant intervention can be applied

1490 SECTION 29 / Neoplasms of the Alimentary Canal

in a selective fashion. 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. Once a high-risk group is clearly identified, it will still be necessary to perform prospective tests of adjuvant therapy. Chromosome 17 at q21 position contains a late-acting tumor suppressor locus near to or identical with the nm23-H1 allele that, by cDNA transfection studies, has the ability to reduce the metastatic potential in nude mice of highly metastatic human melanoma and breast cancer cell lines. Finding deletions of this locus (by DNA probing of the surgically resected specimen) has prognostic value in all stages of colon cancer; 73% of patients with the deletion ultimately developed metastatic disease, compared with 20% of those without (p < .03), thereby providing a possible means of identifying those at risk early in the clinical course of disease. Additionally, allelic loss of chromosome 18q has independent and strong prognostic value 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 of stage I colon cancer and a poor prognosis group (i.e., allelic loss present) whose survival is similar to that of stage III disease. Presumptively, the latter would benefit from timely and effective adjuvant therapy, and this needs to be tested in prospective studies. To increase both cure rate and survival, several multi-modality treatments combining surgery, radiation (rectal cancer), chemotherapy, and immunotherapy (colon cancer) have been tested and found to be effective in rigorously conducted studies. PATIENTS WITH HIGH-RISK COLORECTAL CARCINOMA The consensus conference convened by the NCI defined therapy recommendations based on the initial successful trials. New information on monoclonal antibody treatment for colon and rectal cancers on LV and FU, 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. A meta-analysis finds 5% improvement in colon adjuvant trials and 9% in rectal adjuvant trials with a majority odds ratio of 0.8 and 0.64, respectively. These are actually large improvements considering the inclusion of B2 patients in the trials, without consistent evidence of benefit. 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. COLON ADJUVANT THERAPY HISTORY The GITSG study 6175 was one of the first modern studies for patients with stage III colon cancers. The initial GITSG adjuvant colon study found no benefit from either chemotherapy, 5-FU, immunotherapy, or chemoimmunotherapy compared with surgery alone. Additional well-controlled trials, designed and performed at about the same time, also concluded that there was no effective adjuvant therapy for patients with high-risk colon cancer. Some of these trials did report a slight, clinically unimportant advantage for bacille Calmette-Gurin (BCG) immunization and/or combination chemotherapy with semustine, vincristine, and

FU. The first widely accepted case for adjuvant treatment in colon cancer with 5-FU and LEV is based on two large trials. Patients with Dukes C (i.e., 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, LEV alone after surgery, or no adjuvant treatment. Adjuvantly treated patients had a significantly improved disease-free and overall survival compared with those treated by surgery alone (p < .003) (Fig. 103.9). LEV alone did not improve disease-free survival compared with that of control patients. A significant overall survival benefit occurred in the stage III (i.e., Dukes C) patients when LEV and 5-FU adjuvant treatment was compared with surgery done (Fig. 103.10). High-risk B2 (i.e., with obstruction or perforation) patients also benefited.6 Overall, B2 patients did not benefit, but a combination of other causes of noncancer deaths and surgical resection of recurrent disease may have obscured the outcome benefit. This cost-effective advantage persists, with a flat survival curve, for the 5 to 8 years of follow-up for the treated patients. 5-FU plus LEV reduced the recurrence rate by 40% (p < .0001) and the death rate by 33% (p < .0007).6 The calculated approximate cost of adjuvant colon cancer treatment for stage III is $2,094 per year of life saved. Subsequent trials tested LEV and 5-FU. 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, unlike levamisole. The combination of LV and 5-FU was effective in several schedules: day 15 bolus 5-FU (Mayo Clinic) and weekly bolus FU schedules (RPMI). The LV/FU proved equal or slightly better than the LEV/FU in these trials. Trials demonstrated that 6 months of LEV/FU were ineffective; in contrast, 6 months of LV/FU were effective and equal to either 12 months of LEV/FU or LV/FV . Adding LEV to LV/FV produced no additional benefit over either 6 or 12 months. Therefore, currently, LV/FV for 6 months has become the standard of therapy for stage I colon cancer. Levamisole and Fluorouracil. Recently, 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. Again, it found no benefits for patients with resected rectal cancer. Other trials of LEV/FU have produced some conflicting results. Some patients find benefit; some find no benefit for B2 patients favoring LEV/FU, and some even find no overall benefits for patients with resected B2 or C tumors. The failure of the original NCCSG trial to benefit patients with B2 tumors is complex. LEV appeared to substantially improve disease-free survival, 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. In contrast, the NSABPs trials consistently found a large advantage for both LEV/FU and other adjuvant chemotherapy for patients with resected B2 cancers. Meta-analyses, in contrast, found LEV/FU as expected effective for patients with C tumors but found it a marginal failure for patients with B2 tumors. The possibility that LEV/FU benefits any B2 patients must be viewed cautiously because there were no supporting findings from the meta-analysis.

Figure 103.9.

Patients with stage C colon cancer treated adjuvantly.177 A. Recurrence free interval. B. survival. Levlevamisole.

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1491

Figure 103.10. Survival of patients with stage C colon cancer treated adjuvantly. Source: Moertel and colleagues.9

The mechanism for interaction of FU and LEV remains unknown. At the molecular level, a potential mechanism has been elucidated involving the enhancement of HLA class 1 protein expression by a specific interaction at the messenger RNA level. LEV does have side effects, however, of which the most serious, multifocal leukoencephalopathy, is very rare. The drug may produce vague symptoms of neurasthenia and mild changes in liver functions, all of which are reversible. LEV alone is consistently ineffective as adjuvant therapy. Some European investigators are far less convinced by the American trial findings. 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, (surgery only) controls. In contrast, the North American consensus strongly supports trials with treatment controls. Adjuvant therapy is considered standard therapy for patients with stage III colon cancer. Rectal cancer should not be viewed as identical to colon cancer. The combination of LEV/5-FU fails against rectal cancer, and the combination of LV/FU also probably fails. Currently, in spite of the failures of chemotherapy alone, systemic research aside, chemotherapy is necessary for rectal cancer. In combination with radiation therapy it demonstrably reduces both distant, fatal extrapelvic recurrence and the rate of debilitating local failure. The practice of limiting adjuvant therapy to the young is probably incorrect. Patients aged 70 to 75, if healthy, may live an additional 10 to 15 years. Even patients with co-morbid conditions usually live longer than the 2- to 3-year median time to progression of colorectal cancers. In order for adjuvant therapy to be fully used, the descriptions of operative and pathologic findings must include more than the current conventional information. The TNM staging surplants earlier widely used systems. Ideally, the surgeon and pathologist will specify degree of serosal invasion in order to distinguish between serosal and regional peritoneal stage IV tumors, a not uncommon problem. It is informative to describe the extent of nodal involvement thoroughly, including nodal level, size, distortion, and associated inflammation. In addition, the clinician needs to know the numbers of nodes involved and the number examined. Less than six nodes examined is possibly equivalent to a C tumor. In the case of rectal cancer, less than 10 nodes may have similar implications, but this needs to be confirmed. 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. 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. Low-dose LV, 20 mg/m2/days 15 IV and 5-FU 425 mg/m2/days 15 every 4 to 5 weeks is now recognized to be the shortest, least expensive, and least toxic treatment.

Six months of treatment with LEV/5-FU is inferior, when compared to 6 months of treatment with LV/5-FU. LV and 5-FU (LEV) for 6 months was superior to 5-FU LEV for 6 months by 10%, 70 versus 60%, at 5 years. Both are equal, however, when comparing 1 year of treatment. Adding LEV to 5-FU and LV added little or nothing. These investigators had previously achieved the same results, demonstrating the efficacy of LV and FU for 6 months versus control. This was equal to LV and 5-FU LEV . This appears to demonstrate that LEV is usually unnecessary considering the success of 6 months of treatment with LV/FU, without LEV , in other adjuvant trials. The prospectively randomized NSABP trial C-03 compared LVmodulated 5-FU to a regimen containing semustine (MeCCNU), vincristine, and 5-FU (MOF) in patients with Dukes stage B and C colon cancer). 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. A different LV-5-FU regimen (FU, 375400 mg/m2, plus LV, 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. This combination was found to reduce mortality by 22% (p < .029) and events by 35% (p < .0001), increasing 3-year event-free survival from 62 to 71% and overall survival from 78 to 83%. 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. The three trials included in the IMPACT analysis found a 22% and a 33% reduction in deaths at 3 years. This translates into a 5% improvement in survival achieved with only 6 months of treatment. The trial does not favor treatment of B2 patients who as a research group have an 80 to 82% 5-year survival. Adding interferon (INF) alfa-2a to LV/FU in trial CO-5 failed. Oral tegafur with LV is currently in trial, and trials of other oral agents are in various stages of development. Fear of side effects is often cited as a reason to decline adjuvant therapy. The fear is probably greater among inexperienced physicians than patients. There are objective examinations of side effects. To some degree, the risk can be preselected or selectively minimized by choice among effective options. In the case of colon cancer, treatment is variously described as producing little serious risk or quality of life loss compared to the impact of recurrent disease. Experience and good support probably make a difference in tolerance. Some conclude there is actually a net quality of life benefit.) In the case of rectal cancer, there are real practical overall problems posed by the acute and chronic side effects of threatment. They are less than the side effects of recurrent disease. They need to be discussed in considering the overall benefits of sphincter-sparing and postoperative adjuvant therepy. They are viewed as a reason to use all expert supply resources before and during radiotherapy, rather than avoiding adjuvant chemotherapy. SUMMARY There are criticisms of the initial studies and of adjuvant therapy for colon cancer: (1) academic criticismthat there was no 5-FU control; (2) humanistic criticismthat there is possibly no quality of life advantage, especially for the elderly; and (3) economic criticismthat there are hidden costs. In context, these are weak, even inappropriate criticisms, even if there are some literal truths. The choice of controls does not change the fact that the combination works. Use of conventional 5FU alone, after numerous failures and minimum overall survival impact found in meta-analyses, must be considered suboptimal for patient welfare. The theoretical consideration that the total dose of 5-FU, 10 grams or more in the first 3 months, may be more important than LEV is not supported by analyses; two of three trials favor a role for LEV more than a role of dose intensity as the critical element in successful trials. There is no evidence that elderly patients fail to benefit. They do benefit, albeit slightly less. The efficacy of LEV is questioned, probably incorrectly in view of the practical benefit achieved in large trials and the meta-analysis. Because of its fewer side effects, the superior speed of LV , and the failure or questionable failure marginal role of LEV in combination with

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LV/FU, LEV is currently an almost obsolete historical option, except where there is an allergic reaction to LV or a trial question. OTHER ADJUVANT REGIMENS Taylor and colleagues original data concerning portal vein infusion found benefit with brief postoperative treatment. Meta-analyses of 10 such trials find only 4 to 8%, but still clinically important, survival benefits (p < .01). Adjuvant 5-FU infusion via the portal vein decreased the rate of extrahepatic recurrence but did not decrease liver metastases. Five of six trials found benefit to be systemic, apparently independent of the portal route of administration. This is the most rapid of the adjuvant treatments. Although, in some trials, it approaches other systemic adjuvant treatments in efficacy, it remains reserved for research. A randomized trial evaluated intraportal mitomycin (10 mg/m2, one dose) plus 5-FU (500 mg/m2 continuous infusion per 24 hours for 7 days) against no adjuvant treatment. At median follow-up of 8 years, the adjuvant intraportal treatment had reduced the risk of recurrence by 21% (p < .051) and the risk of death by 26% (p < .026), with all sites of recurrence being reduced in the treatment group rather than hepatic recurrences only. It follows that there may be a rapid systemic 5-FU (and or MMC) chemotherapy effect; this effect was achieved with a shorter time of treatment than that with conventional bolus regimens. The MRC AXIS trial also found a 4 to 5% overall benefit for patients with resected colonic (not rectal) cancer. The degree of benefit from portal vein infusion does not quite approach that achieved with LV and 5-FU, but the brevity of portal vein infusion makes it attractive, as does the minimum risk of side effects due to chemotherapy. This cannot assume benefit for the same patients who benefit from LEV 5-FU or LV/5-FU. 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, perhaps even testing preoperative therapy, analogous to successful preoperative trials in regional breast cancer. This neoadjuvant approach with either portal or systemic infusions of 5-FU is still totally investigational. Other attempts at regional adjuvant therapy include the radiotherapy efforts described above. Intraperitoneal chemotherapy combined with systemic adjuvant therapy has also been proved feasible. Its degree of efficacy remains unknown, but it would appear to represent a logical extension of Sugarbakers strategies; the candidates for such research are not ideally well defined. IMMUNOTHERAPY BCG Vaccination. In the NSABP Colon Adjuvant Trial (Protocol CO1), the immunotherapy arm BCG administration was shown to reduce the incidence of new primary tumors when added to the semustine/5-FU treatment. Nevertheless, BCG cannot be considered a standard treatment. The Southwest Oncology Group also evaluated BCG and found it a possible chemopreventive agent. In contrast, the methenol extracted residue of BCG tended to have an adverse effect on overall survival in the initial GITSG trial. Incorporation of BCG with tumor in order to develop an active, specific vaccine appeared to produce significant benefit regarding time to recurrence and overall survival in patients with colon cancer. Eighty patients were randomized, after standard resections for Dukes B2 and C colon or rectal cancer, to receive either surgery alone or surgery plus active specific immunotherapy (ASI) with autologous tumor cell-BCG vaccine. Patients with rectal cancer all received definitive radiation to the tumor bed. With a median follow-up of 68 months, the hazard ratio for recurrence of the ASI-treated group compared with the surgeryalone group was 0.243 (Cox model estimate), representing a 75% reduction in the risk of recurrence (p < .016). This benefit was restricted to the patients with colon cancer; radiation given concomitantly to the rectal cancer group may have mitigated any advantage from immunostimulation by the vaccine. The concept of ASI remains attractive, but proof of principle may be difficult because there are too many exclusions and biologically ineligible patients and because of poor immune responses. These positive findings have not been universally accepted. There have been failed attempts at ASI, including an ECOG trial. Active specific immunotherapy has been tested again and found to produce overall survival benefit. Unfortunately, this randomized trial was too small. Although this would normally indicate that the ASI was

especially powerful because it could impact outcome in spite of the small numbers of patients, the benefits were limited to stage II patients. The failure to see any hint of benefit in stage III patients is unexplained and cause for concern. The positive findings are somewhat counterintuitive. Monoclonal Antibody Treatments. A randomized trial of monoclonal antibody (MAb) 17-1A (Panorex) used postoperatively in Dukes C patients compared a short infusion, 500 mg, followed by four monthly infusions of 100 mg each to a group treated with surgery only. At a median follow-up of 5 years (p < .05), a mortality reduction of 30% and recurrence reduction of 27% (p < .05) occurred, with only mild constitutional and GI symptoms as the most frequent toxic effects. Four anaphylactic reactions controllable by steroids also were reported. This randomized trial of MAb for adjuvant therapy of resected Dukes C produced a 30% reduction in the risk of death at 5 years. It had no detectable effect on local recurrence. This study remains unchanged. With 8 years of follow-up, it demonstrates durable benefit. Panorex must remain an investigational drug because of the small size of the original trial and the need to complete analyses of new trials. It is available commercially and for compassionate approval in several countries. Trials testing it alone and in combination with chemotherapy are ongoing or in follow-up phase. Preclinical evidence of cytolytic effects predicted the potential therapeutic success. MAb 17-1A is viewed as most promising for low tumor burden and Go tumor applications. Because of its independent mechanism of action and side effects, it is theoretically an ideal noncross-resistant partner for combination chemotherapy. Other adjuvant biotherapy approaches tested Tagamet and PSK and produced some marginally promising findings. Survival is still the most important criterion for establishing the benefit of any therapy to be added to surgery; however, the ability to diminish regional recurrence and the subsequent symptoms of regional tumor growth is a worthy end in and of itself. 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. They significantly diminish regional recurrence when compared to conventional radiation therapy alone, chemotherapy alone, or surgery only. Analysis of rectal cancers indicated that expression of the thymidylate synthesis (TS) protein varied with stage and was an independent prognostic indicator. Only those patients with high TS levels showed a survival benefit from 5-FUbased adjuvant chemotherapy. No patients should be refused chemotherapy treatment based on a predictive test, however. With the exception of the NSABP rectal cancer adjuvant trial R01, no other well-designed trial has shown the benefit of chemotherapy alone after surgery for patients with high-risk rectal cancers. The benefit of chemotherapy was limited only to high-risk males. Subsequent trials make the R-01 regimen of MOF obsolete in that both LV, 5-FU, and 5-FU continuous infusions probably are probably superior to MOF and certainly less toxic. Combined modality remains the adjuvant treatment of choice because of inconsistent or less success with either chemotherapy alone or with radiotherapy alone. Adjuvant therapy has great public health significance. If high-risk patients were treated and were to accrue to present-day adjuvant trials, or were treated with the earlier recommended conventional treatment plans, approximately one-third fewer patients would die from colorectal cancer. This translates into approximately 20,000 to 30,000 lives saved per year, at an estimated cost of $1,200 to $1,400 per year of life saved. Poor patient and physician acceptance and poor coordination of disciplines especially failed surgical prospective preparations for adjuvant therapy, can be critical. Laboratory-guided identification of additional high-risk patients, now incorrectly considered low-risk patients, is possible. Nevertheless, practice studies and some literature describe great ambivalence toward adjuvant therapy, particularly rectal adjuvant therapy, which deprives many patients of potential benefits. Detailed attempts to investigate these persistent doubts find little or no practical basis for depriving high-risk patients, now not offered therapy, of very promising trials or systematic well-tolerated standard adjuvant treatments.

Follow-up After Primary Therapy for Colorectal Cancer. Eighty percent of patients who recur do so within 2 years of their primary tumor treatment. Follow-up should be applied most frequently in the first 2 years and less frequently thereafter; only rarely have patients recurred after 5 years. A firm recommendation about routine follow-up for asymptomatic recurrence after 5 years is to continue surveillance for the development of metachronous bowel neoplasms. There is evidence for the clinically significant frequency of metachronous lesions (mainly polyps as opposed to cancers). Autopsy series showed a 7% incidence of synchronous or metachronous bowel cancers in patients with colon or rectal cancer. With the present endoscopic techniques and higher incidence (in some series up to 50% within 5 years), these polyps can and should be removed before they become cancers. Clearly, 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. Colonoscopy is preferable to sigmoidoscopy as a method of follow-up. Endoscopic evaluation of patients during follow-up is aimed at the diagnosis and treatment of premalignant neoplasms, not the diagnosis of rare and almost always incurable anastomotic recurrences. It remains to be proven that aggressive debulking and intraperitoneal therapy can change this bleak assessment of prospects for patients with anastomotic recurrence. Findings with selective attempts remain promising. An acceptable empiric approach is to obtain complete surveillance of the large bowel mucosa, ideally before primary tumor resection but, in the case of patients with distal obstructing lesions, at surgery or within 3 to 6 months after surgery. If no synchronous lesions are noted, then a yearly follow-up endoscopic examination is enough. If no lesions are found at the first annual endoscopy, then a 3to 5-year interval colonoscopic examination probably is appropriate. On the other hand, 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. Any more frequent interval examination probably would diagnose tumors that by definition are so aggressive subsequent therapy might be ineffective. In the presence of symptoms such as change in bowel habits, unexplained anemia, or blood in the stool, colonoscopic and/or double-contrast roentgenologic examination should be undertaken at once. Recent recommendations for surveillance guidelines have been published by a leading clinical group, the American Society of Clinical Oncology. ISOLATED RECURRENCE There are opportunities for curing a patient once recurrence is diagnosed. Durable disease-free survival (i.e., cure) at 5 years can be attained in approximately 25 to 30% of patients with isolated liver, isolated pulmonary, 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 group of patients with resectable pulmonary or liver recurrence probably represents 6,000 to 7,000 patients per year in the United States. Disseminated colorectal cancer recurrence is much more common; liver and liver plus lung are the most frequent sites involved. Most patients need systemic therapy, but, at present, no known systemic therapy of choice has proven curative potential. Some regimens may yield 5-year survivors (see hepatic artery infusion chapter). 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. First, there has been a decrease in mortality and morbidity among patients who undergo major liver resection. Second, 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. 103.11 and 103.12). The success rate is highest when relapse occurs more than 1 year after surgery and when there are only one, two, or three lesions. Cryotherapy and use of chemotherapy after resection may improve these results. 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, but phase II and early phase III findings encourage trial efforts. Over 1 to 2 years, disease-free survival with hepatic artery infusions appears

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1493

Figure 103.11. Probability of survival in patients with potentially resectable hepatic metastases from rectal cancer. Source: Steele and colleagues.424

improved, and rates of hepatic relapse are less than anticipated. The major requirement for a successful adjuvant therapy that improves overall survival appears to be the ability to control distant metastases. SYSTEMIC RECURRENCE Patients with peritoneal or diffuse multiorgan recurrence have a systemic advanced disease. Peritoneal disease, unless it can be debulked, similarly represents a systemic disease. As yet, there are no curative treatments, but advances in cost-effective and tolerable treatments have occurred. Response rates have increased into development steps. Disease-free time has increased, and downstaging and resection of metastatic diseases are increasingly feasible. At present, the standard systemic therapy for advanced systemic colorectal cancer is a combination of 5-FU and LV . Several controlled, randomized trials show benefit, adding LV doubles the rate of response compared to 5-FU alone. This evidence of benefit has been

Figure 103.12. Probablity of survival and disease-free survival of patients with rectal cancer and hepatic metastases resected with curative intent. Source: Steele and colleagues.424

1494 SECTION 29 / Neoplasms of the Alimentary Canal

called into question by meta-analyses, but LV/FU produces quality of life benefit and, in some cases, survival benefit. Some safer and probably superior regimens for selected patients are already tested and successful in phase III trials and await critical confirmatory trials. There is also a new treatment available after failure of LV/FU; irinotecan clearly improves disease-free and overall survival in two substantial trials. 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 . Also, easier to use and safer substitutes for 5-FU are now clinically available. Treatment of Advanced Colorectal Cancer. At diagnosis of colon cancer, 38% of patients have regional spread of disease and 19% distant spread. In addition, 20 to 80% of resected patients relapse with advanced disease; therefore, a continuing need exists for developing effective treatments for advanced disease. The current status of 5-FU, its biomodulation by LV , or methotrexate (MTX) 5-FUbased combinations, newer agents such as the camptothecin analogues, and oxaliplatin and the possible role of biologic agents in the medical management of metastatic colorectal cancer are presented here. 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; intraoperative radiotherapy; or intraperitoneal therapy. Downstaging, exceptional tumor regression, may create some of these opportunities. Systemic chemotherapy for advanced colorectal cancer clearly benefits patients, even asymptomatic patients and especially patients with good performance status. Patients with liver metastases alone also benefit. Performance status and choice of treatment are the major variables, which are associated with survival impact. 5-FLUOROURACIL Since the synthesis of 5-FU by Heidelberger and colleagues, 5-FU has retained a continuing central role in the chemotherapy of advanced colorectal carcinoma. 5-FU can inhibit tumor RNA synthesis by entering the uridine metabolism pathway and can inhibit DNA synthesis after conversion to fluorodeoxyuridylate, which binds to thymidylate synthase (TS). Bolus short 5-FU exposure schedules may depend on RNA inhibition absent LV . Infusions of 5-FU probably dominantly produce DNA inhibition. In the USA, 5e-day loading courses were the standard against which all other schedules and combinations were measured. This may no longer be the ideal standard. Response rates increased with increasing dose intensity, but with one exception survival remained unchanged. Hematologic and mucosal toxicity inhibited development of dose-intensive strategies. Historically, treatment called for 15 mg/kg/d for 5 days plus halfdoses every other day until toxicity. For safety, 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. These doses are excessive when used in conjunction with modulators. These doses are unsafe when patients have poor performance status, physiologic old age, liver dysfunction, or active colitis. 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-FUcontaining regimen. Response rates with intravenous 5-FU were superior to those with intensive oral treatment (26 vs. 19%), with comparable hematologic side effects and less GI toxicity. New oral prodrugs of FU are designed to circumvent enzymetic mucosal barriers, which contribute to poor absorption of 5-FU. In view of the short 12- to 18-minute half-life of the drug, in plasma, there is a cogent rationale for regimens using prolonged, lowdose infusion. Extended exposure to 5-FU can almost completely inhibit colony formation, even in what are considered to be drug-resistant colon cancer cells. Some randomized trials show increased response rates both for 5-day infusions and for prolonged multi-week infusions compared to conventional bolus regimens. These rates of response (30% for the infusion arm vs. 7% for the bolus arm) were obtained with significantly lower rates of serious hematologic and GI

toxicity. Prolonged intravenous infusion produces hand-foot syndrome (i.e., palmar-plantar erythrodysthesia) however, necessitating dose reductions for 23% of patients. A meta-analysis confirms that infusional 5-FU is distinctly different from bolus 5-FU. Details of 5-FU schedule may prove to be extremely important, especially in conjunction with modulators of 5-FU or combinations with new drugs. Both prolonged 5-FU infusion and new schedules of 5-FU administration, specifically 24- or 48-hour high-dose infusions of 2.5 to 3.4 g/m2 given weekly, challenge the standard 5-day loading schedule. Differences in rate of infusion, over 2 to 4 minutes, 10 to 20 minutes, 30 minutes, 2 hours, and 8 hours and 24 hours, produce large differences in the optimum dose of 5-FU and in rates of response. (With prolonged infusion of 300 mg/m2/d for 4 to 6 weeks, hand-foot syndrome is limiting and hematologic toxicity is trivial. Weekly 24-hour infusions of LV/FU, 25 and 2,600/mg/M2, respectively, produce diarrhea as the limiting toxicity. With weekly 48-hour infusions of FU (median total dose 25 and 3,000 mg/m2), the response rate was 39% and grade 3 to 4 toxicity 21%, with limiting mucosities and diarrhea. These schedules are attractive for development of combination chemotherapy. Laboratory findings make it clear that bolus and infusion 5-FU regimens should not be cross-resistant. Clinical anecdotes describe 10 to 20% rates of benefit (i.e., response) when infusions are used after failure of bolus regimens. Combining bolus and infusion regimens in phase II-III clinical trials produced favorable results when used with LV . The optimal single-agent 5-FU schedule has yet to be determined. 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. The latter, achieved through schedule modifications, had limiting neurotoxicity and is not recommended for development. 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. THYMIDYLATE SYNTHASE AS THE TARGET FOR FLUOROURACIL Enzymes involved in 5-FU metabolism include phosphoribosyltransferase, uracil dehydrogenase, uracil phosphorylase, uridine kinase, thymidine phosphorylase, ribonucleotide reductase, thymidine kinase, and TS. These provide rational targets for development of numerous prodrugs, inhibitors of catabolism, and biochemical modulators. Although specific enzyme activities in individual tumors appears to predict resistance to 5-FU both in gastric and colorectal cancer, this work is neither uniformly reproducible nor certain enough as yet to justify withholding therapy. 5-Fluorouracil enters the malignant cell by an active carrier transport and then is converted along two enzymatic pathways to its biologically active metabolites. TS generates the thymidylate that is needed for DNA repair and synthesis. Variant TS enzymes (with low affinity for the 5-FU deoxyuridylate product [5FdUMP]) are resistant to fluoropyrimidine cytotoxicity. Efforts to predict resistance to 5-FU by measuring several enzymes or mRNA are in progress. Methodology and overall findings and results vary between laboratories, between tumors in the same patient, and possibly between primary sites of disease: colon versus rectum and right versus left colon. Findings are both complex and promising. Currently, treatment should not be withheld on the basis of an assay. BIOMODULATION OF 5-FLUOROURACIL BY LEUCOVORIN LV enhances the clinical toxicity of 5-FU, improves primary rates of response, and can produce second responses in combination with 5FU after 5-FU alone had failed. Irinotecanis newly demonstrated to be a superior second treatment. The Mayo Clinic low-dose LV schedule is the most widely accepted standard primary treatment. A meta-analysis that omitted the Mayo trial found that LV improved the rate of response to 23 versus 11% for FU alone. The meta-analysis found no evidence of impact on overall survival, although it had been observed in the lead Mayo Clinic phase III study. Recently, in phase III studies, 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. The other major regimen is the GITSG/RPMI weekly regimen, which has a different pattern of side effects. Since efficacy is similar, the clinical choice is based on experience, convenience, and

the concerns about limiting toxicity. The Mayo regimen is limited by white blood cell count and mucositis in one-third of patients; the RPMI regimen is limited by diarrhea. Limiting gastroenteritis is sometimes fatal in the elderly if weekly treatment continues too long. As primary therapy, neither oxaliplatin nor irinotecan, both of which further improve response rates when added to LV/FU, have as yet improved overall survival compared to LV/FU in ongoing trials. Nevertheless, 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. Prolonged exposure to LV allows time for its polyglutamylation. Slow infusion also prevents inefficient and wasteful premature renal excretion of LV. LV is a racemic mixture. The L-isomer is used in half of the dosage of the racemic mixture. Direct comparisons to LV find no advantage. Allergic reactions to LV are rare and can usually be managed with premedication and slow administration of LV provided that the reaction was mild. An optimum LV/5-FU regimen has not yet been identified, 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. In a phase III trial, it proved superior in direct comparison to the Mayo Clinic schedule. It was less toxic and had clear quality of life advantages. Bimonthly treatment produces higher response rates than monthly treatment, 32 versus 14.4%, with a favorable overall survival (p < .067). Tomudex also failed in a phase III test against these bolus, infusion days 1 and 2 of a 2-week regimen. Distal GI toxicity was substantial in trials of high-dose weekly LV . Regimens with low-dose LV produced prospectively tested well documented quality of life advantages and better maintenance of weight. At the very least, LV/5-FU allows patients to live as long as with 5-FU alone and allows them to live better. The value of response and probable impact on survival are still debated. 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. 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. 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, thereby increasing fluorouridylate biosynthesis with its augmented incorporation into RNA. MTX plus 5-FU is well tolerated and feasible as an outpatient regimen. A randomized, prospective trial found both response and survival benefits for the 24-hour sequence compared with the 1-hour sequence. A 7- to 24-hour interval in the timing of 5-FU following MTX appears to be critical to the success of the regimen. MTX/5-FU may improve the durability of responses and, in some comparisons, survival. In a substantial meta-analysis, MTX (modulation) doubled the response rate to 5-FU alone, 19 versus 10%, and modestly improved overall survival. The major benefits reported include improved quality of life (i.e., improved performance status, weight gain, relief of symptoms), particularly when compared with other available chemotherapeutic options, such as single-agent 5-FU and 5-day LV/5-FU regimens. Quality of life is of importance in the setting of advanced metastatic disease, where increased well-being is a therapeutic goal. Caution is required; some MTX/FU schedules may not be the equal of LV/FU. It is noteworthy that these MTX/FU regimens produce responses and probably survival impact when used as second- and third-line regimens. MTX/5-FU continues to be the subject of new positive reports and is the subject of ongoing adjuvant trial. MTX also may be useful as a component of a sequential MTX/5FU/LV program, 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. In a head-to-head study, 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. Caution is required. There is preclinical evidence that LV can block the activity of MTX as a modulator of 5-FU under some conditions, however, the clinical conditions case unknown.

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1495

Trimetrexate Neutrexin is a MTX analogue that does not interfere with polyglutamylation. It is an active but not exceptional single agent. Both as primary and salvage therapy, it is under investigation as a method of combining an antifolate with LV/5-FU, while avoiding some of the concerns outlined earlier. In combination, response rates range from 38 to 50%. COMBINATION OF OXALIPLATIN AND 5-FLUOROURACIL Attempts have been made to increase response rates by the addition of cisplatin to 5-FU. These attempts have usually failed, and when successful they failed to improve overall survival. Cisplatin has been largely superseded by the biochemically and clinically superior oxaliplatin (LOHP). It produces 10 to 27% overall response rate as salvage and primary single-agent therapy. Its use with LV/FU led to a 51% response rate with low mucosal and peripheral neuropathy. The median survival was 15.9 months and 3-year survival 22%. Oxaliplatin in combination with 5-FU produces acceptable, limiting diarrheal side effects and, in the absence of direct comparisons, appears to match other new combinations in antitumor efficacy. Its neurotoxicity may prove of concern. 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. The neurotoxicity of LOHP should not be dismissed. It appears between 13 to 23 weeks in half of the patients; half recover in 12 weeks. It differs from that of cisplatin, and there is cold sensitivity and laringeal symptomology. For LOHP, major interest is fueled by high response rates, successful combinations with irinotecan (see below), and successful use in downstaging metastatic tumors, preparatory to hepatic resection. As a potential neoadjuvant treatment, it increased the rate of hepatic resection by 16 to 18%. 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, LOHP alone and in combination with LV/FU appears to be positioned behind CPTII alone and in combination as a salvage regimen. 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. Topoisomerase I acts on single strands and topoisomerase II on double strands of DNA. The enzyme inhibitors of topoisomerase I and II act by preventing the religation of the cleaved strands, thereby inhibiting mitotic replication. Cells in S phase are substantially more sensitive to these effects. Camptothecin (CPT) is an alkaloid derived from the Camptotheca acuminata, a tree that is native to China. Its site of action for antitumor activity was identified as the inhibition of topoisomerase I. DNA topoisomerase I-targeted chemotherapy had seemed to be particularly promising because of results in otherwise highly resistant colon cancer xenografts. Early clinical trials were abandoned, however, because of unacceptably severe myelosuppression enteritis and hemorrhagic cystitis. The CPT analogues irinotecan (CPT-11) and topotecan have been synthesized. These analogues are much safer than camptothecin for the urinary track. Trials of oral analogues are also in progress. Irinotecan (CPT-11) produces dose-limiting neutropenia and diarrhea. Management of the diarrhea requires intensive loperamide. CPT11 produced convincing 30 and 22% response rates in new and previously treated patients with metastatic advanced colorectal cancer. Every-3-week and every-1-week schedules have been well tested. Prolonged infusion tests are in progress and in theory may be the ideal schedule for these drugs. Irinotecan is a prodrug that undergoes deesterification by carboxy lesterase to SN-38, which is 100- to 1,000fold more active than the prodrug. Doses are from 300 to 350 mg/m2 every 3 weeks, in 30- or 90-minute intravenous infusions. These produce acceptable hematologic but the somewhat unique GI dose-limiting toxicity of chronic diarrhea. Loperamide ameliorated diarrhea sufficiently to permit dose escalation beyond 350 mg/m2, but for repetitive clinical administration, clinicians select lower doses of 240 mg/m2 to

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350 mg/m2 as 30- to 90-minute infusions every 3 weeks. Loperamide is given in a high-intensity schedule of 4 mg after the first diarrheal movement, then 2 mg every 2 hours or 4-mg every 4 hours until 12 hours have passed without diarrhea. Irinotecan (CPT-11) has been approved by the FDA for patients with stage IV colorectal cancer who have failed 5-FU based chemotherapy. Use of 90-minute infusions remains the most popular dosing schedule, but may be unnecessary, 30-minute infusions are equally well tolerated. An acute cholinergic syndrome may follow the administration of CPT-11. The acute, severe vomiting, cramps, and diarrhea that are associated with flushing, warmth, and diaphoresis are reversible with diphenhydramine and largely preventable by atropine and possibly the addition of ondansetron and diphenhydramine (the latter two are unproven). Other side effects include alopecia in approximately 50% of patients and a low incidence of asthenia and hepatic enzyme elevation. Pharmacokinetics show that both CPT-11 and SN-38 have a biphasic elimination, with a long (914 hour) terminal elimination phase. Excretion primarily is in the urine and bile, with a possibly significant enterohepatic recycling phase and additional excretion into saliva, sweat, and pleural fluid. Gilberts syndrome and any liver dysfunction require major dose reduction or avoidance. In the USA, 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%. Response rates are 18 to 19%, and, in addition, 40% were stable with minor response and stable disease. Severe diarrhea occurred in only 11%; perhaps 40% achieved subjective benefits. The evidence suggests that these schedules produce similar side effects and efficacy. A randomized trial demonstrated that CPT11 alone (after 5-FU had failed) was superior to supportive care; 1-year survival (36 vs. 14%), and performance status, weight loss, and pain-free survival all improved. In another phase III trial, CPT11 after 5-FU failed was superior to alternative 5-FU regimens, such as the 300mg/m2 prolonged infusions. One-year survival was higher at 45% compared to 32%. New schedules appear to be promising. CPT11 as a 70 to 75 mg/m2 24-hour infusion each week produced a provocative 28% objective response in heavily pretreated patients. Irinotecan in combination with 5-FU/LV produces 40% to 50% rates of response. CPT-11 must precede 5-FU. Several 5-FU schedules are suitable: simple 500 mg/m2 bolus weekly, 5-day loading and high-dose 1- to 2-day schedules. Randomized trials demonstrate limited superiority of the CPT II/LV/FU combination compared to either LV/f-FU or CPT II alone. Findings included improved response rates (49 vs. 27 vs. 29%) and disease-free survival median (5 vs. 3.8 vs. 3 months). Disease-free survival at 6 months almost doubles (42 vs. 25 vs. 24%). Overall survival remained unchanged. Theoretically, primary use of CPTII in combination may be no more effective than crossover use of CPTII for salvage. Use of combinations, in theory, is currently reserved for trials or patients with urgent need for response, due to symptoms or with tumors threatening imminent complications. These combinations are leading candidates for the next generation of adjuvant trials, where objective response in theory can possibly translate into improved eradication of disease. Combining the best 24-hour infusion (LV 500mg/m2 and 5-FU 2.6g/m2) with irinotecan 80 mg/m2 may increase response to 64% (4583%). Dose intensification of irinotecan to 175 mg/m2 every 2 weeks with bolus 5-FU (450950 mg/m2) produced 10 of 17 responses. Further escalation of irinotecan to 200 to 210 mg/m2 produced 5 of 11 responses. Hepatic artery infusion with 5-fluorouracil deoxyribonucleoside (FUDR) can be combined with systemic irinotecan 60 to 100 mg/m2. High rates of response have been seen for patients failing standard systemic treatment12 of 15 partial responses in one report. The infusion consists of FUDR 0.3 mg/kg days 1 to 14 with LV 15 m/d and dexamethasone 1.4 mg/d. On adding dexamethasone to LV , 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. Thus, the further improvement on adding irinotecan, although a reasonable expectation, is not necessar-

ily causal. CPT is best given before 5-FU. To date, there is limited clinical testing of this concept. Unexpectedly, both topotecan and 9-amino CPT completely failed to produce tumor regression in colorectal cancer trials when used in their conventional schedules. Although all of the clinically available analogues are absorbed, oral CPT analogues are in development. Irinotecan plus oxaliplatin in combination has achieved 42 and 44% response rates as primary and secondary therapy. This represents a candidate regimen for development. Oxaliplatin is clearly not crossresistant with irinotecan. The opposite, third-line success with CPTII has, as yet, proven difficult to demonstrate. OTHER DRUGS Tomudex (ZD 1694), raltitrexed, a second-generation inhibitor of TS, is an antifolate analogue that becomes polyglutamylated. It may be almost as active as 5-FU and is already considered competitive with the 5-day LV/FU Mayo Clinic regimen. Favorable comparisons include its ease of administration once every 2 to 3 weeks and safety, but in two phase III studies, the tail of the survival curve for tomudex was slightly inferior to LV/FU. Although raltitrexed was superficially equivalent to the Mayo regimen, in another randomized trial, both the deGramont 2-day and Lokich protracted infusion regimens were superior to raltitrexed in quality of life, toxicity, and progression free survival (PFS) end points. Tomudex may have crossover activity; ~16% (7/43) achieved response and 46% had stable disease after 5-FU had failed. This needs to be confirmed because it raises prospects of a level of activity equal to the more toxic oxaliplatin and irinotecan. A new analogue without need for polyglutamylgation (1843U89) is in development. High levels of DPD and TP increase resistance to 5-FU but not to tomudex. Tomudex may be another method of overcoming a tumors resistance when resistance is based on TP and DPD enzymatic activity, but not resistance due to high levels of TS. Tomudex in combination with 5-FU in various schedules is well grounded preclinically and is already in early phase III trials. Tomudex followed by bolus 5-FU at 24 hours offers another possible salvage regimen. Tomudex with MMC as a salvage regimen produced a severe flu-like syndrome and elevated cytokines and required hospitalization. This was not seen by other investigators. Initial clinical experience found first-line therapy with tomudex plus LOHP to be active; 8 of 20 were seemingly similar to FU/LV+LOHP in activity. Tomudex is also in trials with radiation therapy for rectal cancer. Doxifluridine, which is an analogue of FU, is active in oral form and may have an improved therapeutic index compared with that of 5FU. It has been proposed as being particularly suitable for elderly patients, some of whom have serious toxicities with LV/5-FU. There is heightened interest because uptake of the active drug and conversion to 5-FU is greater in tumors than in normal tissue. FUDR was once thought to be a 5-FU equivalent analogue. Its possible lask of cross-resistance with 5-FU under special conditions has been suggested again. It has different toxicity limits compared to 5-FU as both bolus and infusion regimens. 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. UFT, a combination of tegafur, a Russian FU prodrug, and uracil to saturate degradatative enzymes, is orally active. A pilot study found a high 42% rate of response, but one cannot expect this in new trials. A randomized comparison of UFT plus leucovorin (orzel) versus 5FU/LV , given in the too toxic Mayo Clinic schedule, found an equal 11% response rate and, as expected, improved tolerance to orzel. FDA approval for advanced colorectal cancer seems likely because of the potential convenience of the oral drug. Capectabine (XELODA) is a complex prodrug that liberates fluorocytidine after its absorption, which gains therapeutic advantage because of high levels of cytidinediaminase in tumors. In a comparison to the Mayo Clinic LV/FU schedule, capectabine had comparable response rate, disease-free survival, and overall survival for toxicity comparisons. The Mayo schedule is inherently biased regarding LVFU since 42 to 50% of patients experience intolerable or unacceptable consequences. In theory, this might also create additional sources of bias in efficacy comparisons. 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.

Taxotere has been highly active in preclinical experiments. Colon cancer cell lines and xenografts have been notorious for producing false-positive preclinical leads. Both taxanes have now failed to show activity in initial phase II trials. Continuous-infusion 5-FU at 300 mg/m2 for a prolonged period plus Mitomycin C (MMC), 7 mg/m2 every 6 weeks, produced a 40% objective response rate and 17.6-month median survival. In this randomized trial, 5-FU by chronotherapy produced a 40% objective response rate and a median survival of 16 months. AZT increases response rates when used in combination with LU/FV. This has now been confirmed. ROLE OF INTERFERONS AND INTERLEUKINS Interferons. 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. Toxicity was substantial, including one fatal and one life-threatening secretory diarrhea, as well as leukopenia. Almost 75% of patients required dose reduction of 5-FU, IFN, or both. There also was substantial central nervous system toxicity, including seizures and expressive aphasia. In head-to-head comparison, IFN/5-FU has failed to improve responses over LV/5-FU alone, and its side effects are unacceptable. 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. Interleukin-2. Recombinant interleukin-2 (IL-2) has been used in phase I settings with and without IL-2-activated cells (LAK). No responses were seen in 21 advanced colorectal cancer patients without LAK cells. The use of IL-2 plus LAK cells has not been developed further due to toxicity. Numerous trials of IL-2 plus LAK find a 10 to 12% rate of response, which is not enough to encourage development. MONOCLONAL ANTIBODIES In an adjuvant setting, mortality and recurrence were both reduced by one-third by the administration of four monthly infusions of the 17-1A antibody. The 17-1A MAb is under investigation in a phase III adjuvant trial for stage II colon cancer in the United States (CALGB 9581). The adjuvant setting immunization with an anti-idiotypic human MAb may prolong the survival of patients with advanced colorectal cancer (12 months vs. 4 months for nonimmunized control patients). The nonimmunized patients were separately registered to an oral chemotherapy trial, and their shorter than expected survival is unexplained. Combinations of MAb with biologics eventually may be useful to augment immune-mediated antitumor effects, as reported in preclinical studies using MAb 17-1A. 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. No response was seen in two patients with colon carcinoma. Preclinical findings support the combination of IFN-_ and MAbs. MAbs are among the most active lines of investigation surgery from therapy such as with EGF strategies to diagnostics. 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, harmless to normal tissues, into a compound that is specifically toxic to the targeted cells. A fusion gene was formed consisting of the CEA and cytosine deaminase gene; after transfection, this made the tumor cells express cytosine deaminase and thus become susceptible to FU derived from 5-fluorocytosine, which is otherwise harmless to cells. 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. Efforts to transfer this approach to human investigation are in progress. Initial efforts have failed. Although gene therapy is eventually promising, the methods are complex and include multiple unsolved problems in clinical delivery of genes. SUMMARY There are improving prospects and investigational options for advanced colorectal cancer. Surgery creates opportunities for adjuvant therapy. 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. MAbs appear equal but await confirmation. Salvage resection cures some patients with isolated single- or multiple-site metastases to the lung, liver, or pelvis. Adjuvant therapy is probably applicable before and after salvage resection. Some drugs in combination with 5-FU produce complete responses (i.e., LV, oxaliplatin, and irinotecan). The chemotherapy of advanced colorectal cancer is still based on the central use of dose-intensive 5-FU. Biomodulation of 5-FU by LV and MTX sometimes provides better tolerated regimens that have the potential for better quality of responses (i.e., complete responses, greater durability). Irinotecan, oxaliplatin and tomudex represent promising avenues for the future. Regional therapy remains an active area of investigation. Both pelvic and peritoneal and recurrent diseases are sometimes cured. Systemic and adjuvant therapy is cost-effective and improves quality of life and disease survival. Colon cancer has become a model for molecular biologists. Early diagnosis and cancer prevention by screening, polypectomy, diet, and chemoprevention have become real issues. Currently, the oncologist can help many patients and, because this is a common disease, cure a large number. The physicians responsibility and opportunity to help now extends to the many patients relatives who are now recognizably and predictably at risk. 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. Ideal surgery still provides the best chance for curing a patient with colon or rectum cancer, and the vigor of a followup plan and even salvage surgery and multi-modality therapy cannot make up for inadequate primary treatment. The role of NSAIDs and inhibitors of cyclooxygenase 2 enzyme are under investigation. 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. Nevertheless, it is obvious from these studies, done over many years, that to some degree local approaches work with a properly selected group of patients Use of low cytometry, fluorescence in situ hybridization (FISH), monoclonal antibody (MAb) examination of lymph nodes, and other pathologic and molecular measures of virulence may improve prognostication and identity objective criteria for high risk patients, and allow new questions for tests of adjuvant therapy. Technology that recently became available for research, but not as yet for routine patient management, enables computational manipulation by a defined algorithm (i.e., marching cubes) of various imaging methods: plain films, CT, and MRI scans. A three-dimensional model has been created that simulates a virtual reality colonoscopy. Until the cost can be cut by half, this is only cost-effective when patients refuse colonoscopy. 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. 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. 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. In rectal cancer, high TS predicts for poor survival and benefit of adjuvant therapy contrary to theory. Low TS would be required for response to chemotherapy. Careful pathologic evaluation of the radial margins of resection is essential, and this mandates cooperation between the surgeon and pathologist. This is as true for the colon as for the rectum. In situations where the surgical margins are minimal, local failure can occur. 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.

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J Clin Oncol 1988;6:947. Brown ML, Nayfield SG, Shibley LM. Adjuvant therapy for stage III colon cancer: economics returns to research and cost-effectiveness of treatment. J Natl Cancer Inst 1994;86:424430. Zoetmulder FAN, Taal BG, Van Tinteren H, on behalf of the NACCP. Adjuvant 5FU plus levamisole improves survival in stage II and III colonic cancer, but not in rectal cancer. Interim analysis of The Netherlands Adjuvant Colorectal Cancer Project (NACCP). Proc Am Soc Clin Oncol 1999;1021. Cascinu S, Catalano V, Latini L, et al. A randomized trial of adjuvant therapy of stage III colon cancer: levamisole and 5-fluorouracil versus 5-fluorouracil alone. Proc Am Soc Clin Oncol, 923. Takimoto CH. Enigma of fluorouracil and levamisole. J Natl Cancer Inst 1995;87:471472. Wolmark N, Rockette H, Wickerham DL, et al. 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portal vein infusion as surgical adjuvant therapy for colorectal cancer. 42nd Annual Cancer Symposium of the Society of Surgical Oncology and 35th Annual Meeting of the Society of Head and Neck Surgeons, San Francisco, May 1989, pp 2124 (abstract 204). Gray BN, deZwart J, Fisher R, et al. The Australia and New Zealand trial of adjuvant chemotherapy in colon cancer. In Adjuvant Therapy of Cancer, vol 5. Edited by S Salmon. Philadelphia: Grune & Stratton, 1987;537546. Metzger U, Laffer U, Casteglione M, Senn HJ, Poon MA, OConnell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK, Wiesenfeld M. Biochemical modulation of treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol 1990;8:491. Labianca R, Pancera G, Beretta G, et al. A randomized study of intravenous fluorouracil 6 folinic acid in advanced metastatic co-lorectal carcinoma. Proc Am Soc Clin Oncol 1989;8:118. OConnell MJ. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer. A Mayo Clinic/North Central Cancer Treatment Group study. Cancer 1989;63:1026. Herrmann R. Biochemical modulation of 5-fluorouracil. Cancer Treat Rev 1990;17(suppl A):51. Martin DS, Stolfi RL, Colofiore JR. Failure of high dose leucovorin to improve therapy with the maximally tolerated dose of 5-fluorouracil: a murine study with clinical relevance? J Natl Cancer Inst 1988;80:496. Buroker TR, OConnell MJ, Wieand HS, Krook JE, Gerstner JB, Mailliard JA, Schaefer PL, Levitt R, Kardinal CG, Gesme DH Jr. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 1994;12:1420. Price T, Cunningham D, Hickish T, et al. Phase III study of chronomodulated vs protracted venous infusional 5-fluorouracil both combined with mitomycin in first line therapy for advanced colorectal carcinoma. Royal Marsden Hospital, London and Surrey, UK; Royal Bournemouth and Poole Hospitals, UK. PROC AM SOC CLIN ONCOL 1999 1008. Marsh JC, Bertino JR, Rome LS, et al. Sequential methotrexate, 5-fluorouracil and leucovorin in metastatic colorectal cancer: a controlled comparison of two intervals between drug administration. Proc Am Soc Clin Oncol 1989;8:103. Ajani JA, Kanojia MD, Bedikian AV. High-dose methotrexate and 5-fluorouracil in patients with advanced colorectal carcinoma. A randomized study of two pretreatment intervals. Am J Clin Oncol 1989;12:335. De Marco LC, Arena F, Desner M, Shevde N, Allen S, Weiselberg L, Attas L, Vinciguerra V . Low dose leucovorin and 5-FU modulation with prior methotrexate (L-FUSE-ME) for metastatic colorectal carcinoma. Proc Am Soc Clin Oncol 1988;7:104. Bruckner H, Cohen J. MTX/5-FU trials in gastrointestinal and other cancers. Semin Oncol 1983;10:32. Heim ME, Schuster D, Flechtner H, Worst P, Queisser W. Sequential high-dose methotrexate, 5-fluorouracil and folinic acid does not improve responses in advanced colorectal cancer. Onkologie 1989;12:161. Plotkin D, Ray M, Chien P. Sequential methotrexate-5-fluorouracil in advanced breast and colorectal cancer: a non-randomized pilot study. Proc Am Soc Clin Oncol 1988;7:25. Anonymous. Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 1994 May;12(5):960969. Richards F II, Capizzi RL, Muss H, et al. 5-fluorouracil (5-FU), high dose folinic acid and methotrexate for advanced colorectal cancer. A phase II trial of the Piedmont Oncology Association. Proc Am Soc Clin Oncol 1989;8:101. Sierra A, Colman L, White D, Dunning D. Sequential therapy with methotrexate and infusional 5-FU in advanced colorectal cancer. Proc Am Soc Clin Oncol 1988;7:105. Weinerman B, Shah A, Fields A, et al. A randomized trial of continuous systemic infusion vs. bolus therapy with 5-fluorouracil in metastatic measurable colorectal cancer. Proc Am Soc Clin Oncol 1990;9:103. Impact of second and Third Line Fu-Based chemotherapy on The Survival of Patients with advanced colorectal Cancer. Sobrero A, Labianca R, Zaniboni A, Frassineti G.L, Aschele C, Testore F, Guiliani R, Rizzato S, Ravaioli A, Arnoldi E, Barni S, Pessi M.A, Gugliemi A, Turci D, Grossi F, from GISCAD, IOR and collaborating centers, Italy Ame Soc Clin Oncol (ASCO) 1999; 915 Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Superiority of sequential methotrexate, fluorouracil, and leucovorin to fluorouracil alone in advanced asymptomatic colorectal carcinoma: a randomized trial. J Clin Oncol 1989;7:1437. Bruckner H, Cohen J. MTX/5-FU trials in gastrointestinal and other cancers. Semin Oncol 1983;10:32. Glimelius B, Hoffman K, Graf W, Pahlman L, Sjoden PO. Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer. The Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Cancer 1994;73:556562. Impact of Second and Third Line FU-Based Chemotherapy on The Survival of Patients with Advanced Colorectal Cancer. A. Sobrero, R. Labianca, A. Zaniboni, G.L. Frassineti, C. Aschele, F. Testore, R. Guiliani, S. Rizzato, A. Ravaioli, E. Arnoldi, S. Barni, M.A. Pessi, A. Guglielmi, D. Turci, F. Grossi, from, GISCAD, IOR and collaborating centers, Italy. Proc Am Soc Clin Oncol 915.

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1509

Phase II Study of Three-Hour-Interval Sequential MTX and 5-FU with Leucovorin Rescue in Patients with Advanced Colorectal Cancer.Y Yadama, Y Matsumura, Y Shimada, K Shirao, K Muro, K Sugano, K Haruyama. PROC AM SOC CLIN ONCOL 1173, . INTACC-02: 5 Fluorouracil (5FU)+6-S-Leucovorin (6-S-LV)+Levamisole (LEVA) Vs Methotrexate (MTX)+5FU+LEVA: An Italian Intergroup Study of Adjuvant Therapy for Resected Colon Cancer. R Lionetto.,# PROC AM SOC CLIN ONCOL 1118, . Blanke CD, Kasimis B, Schein P, Capizzi R, Kurman M Phase II study of trimetrexate, fluorouracil, and leucovorin for advanced colorectal cancer.; J Clin Oncol 1997 Mar;15(3):91520. A Phase II Trial of Trimetrexate (TMTX), 5-Fluorouracil (5FU), and Leucovorin (LCV) in Patients (PTS) with Previously Treated Unresectable or Metastatic Colorectal Cancer (CRC). Charles D. Blanke, J. Cassidy, H. Gerhartz, R.D. James, B. Kasimis, Proc Am Soc Clin Oncol 947. Behrens BC, Sickle-Santanello B, Martin E. Protracted venous 5-fluorouracil infusion and weekly cisplatin in metastatic colorectal cancer. Proc Am Soc Clin Oncol 1989;8:126. Diaz-Rubio E, Milla A, Jimeno J, et al. Lack of clinical synergism between cisplatin and 5-fluorouracil in advanced colorectal cancer. Results of a randomized study. Proc Am Soc Clin Oncol 1988;7:110. Iyer PR, Moran EM, Kaneshiro CA, Ottenheimer EJ III, El Sayad NI, Blitzer JB, Charter RA. Chemotherapy with cis-platinum and 5FU in metastatic colorectal cancer. Proc Am Soc Clin Oncol 1988;7:114. Kemeny N, Israel K, Niedzwiecki D, et al. Randomized study of continuous infusion fluorouracil verus fluorouracil plus cisplatin in patients with metastatic colorectal cancer. J Clin Oncol 1990;8:313. Labianca R, Pancera G, Cesana B, et al. Cisplatin 1 5-fluorouracil versus 5-fluorouracil alone in advanced colorectal cancer. A randomized study. Eur J Cancer Clin Oncol 1988;24:1579. Loehrer PJ Sr, Kubilis P, Hui S, et al. A prospective randomized trial of fluorouracil versus fluorouracil plus cisplatin in the treatment of metastatic colorectal cancer: a Hoosier Oncology Group Trial. J Clin Oncol 1988;6:642. Lokich J, Cantrell J, Ahlgren J, Phillips J. A phase III trial of protracted infusional 5FU vs PIF plus weekly bolus cisplatin in advanced measurable colon cancer (MAOP Protocol 5286). Proc Am Soc Clin Oncol 1989;8:104. LoRusso P, Pazdur R, Redman SG, Kinzie J, Vaitkevicius V. Low-dose continuous infusion 5-fluorouracil and cisplatin: phase II evaluation in advanced colorectal carcinoma. Am J Clin Oncol 1989;12:486. Petrelli NJ, Madejewicz S, Rustum Y, et al. Combination chemotherapy of cisplatin and 5-fluorouracil for advanced colorectal adenocarcinoma. Cancer Chemother Pharmacol 1989;23:57. Whitehead RP, Fleming T, Macdonald JS, Ahmann F, Inamasu M. A phase II study of 5-fluorouracil plus cisplatin for metastatic colorectal adenocarcinoma: a Southwest Oncology Group (SWOG) study. Proc Am Soc Clin Oncol 1989;8:128. Pandya KJ, Petrelli NJ, Lefkopoulou M, Haller D. Phase II evaluation of mitomycin, vincristine, platinum, and 5-fluorouracil or PF in advanced large bowel cancer. An Eastern Cooperative Oncology Group (ECOG) study. Proc Am Soc Clin Oncol 1989;8:104. Chiarion Sileni V, Figoli F, Gulisano M, et al. 120 hours 5-fluorouracil continuous infusion plus cisplatinum and folinic acid in metastatic colon cancer. Proc Am Soc Clin Oncol 1988;7:109. Scheithauer W, Depisch D, Schiessel R, et al. High dose leucovorin, 5-fluorouracil and cisplatin for treatment of metastatic colorectal cancer. Proc Am Soc Clin Oncol 1988;7:108. Scheithauer W, Depisch D, Kornek G, et al. Randomized comparison of fluorouracil and leuco-vorin therapy versus fluorouracil, leucovorin, and cisplatin therapy in patients with advanced colorectal cancer. Cancer 1994;73:15621568. Diaz-Rubio E, Marty M, Etra JM, et al. Multicentric phase II study with oxaliplatin (L-OHP) in 5-FU refractory patients with advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol 1995;14:209. Evaluation of Oxaliplatin Dose-Intensity with The Bimonthly 48th Leucovorin (LV) and 5-Fluorouracil (5FU) Regimens (FOLFOX) in Pretreated Metastatic Colorectal Cancer. A. De Gramont, F. Maindrault-Goebel, C. Louvet, T. Andre, E. Carola, V. Gilles-amar, M Mabro, V. Izrael, M. Krulik. For the, GERCOR, # PROC AM SOC CLIN ONCOL 1018, . A. Abad, M. Navarro, J. Sastre, A. et al. Biweekly Oxaliplatin (OXA) Plus Weekly 48 H Continuous Infusion (CI) 5FU (TTD Regimen) in First Line Treatment of Advanced Colorectal Cancer (ACC) (Preliminary Results) # Proc Am Soc Clin Oncol 1056. E.Van Cutsem, J. Szanto, A. Roth, Y. et al. Evaluation of the Addition of Oxaliplatin (OXA) to The Same Mayo or German 5FU Regimen in Advanced Refractory Colorectal Cancer (ARCRC ). # PROC AM SOC CLIN ONCOL 900. Evolution of Severe Sensory Neuropathy with Oxaliplatin Combined to The Bimonthly 48th Leucovorin (LV) and 5-Fluorouracil (5FU) Regimens (FOLFOX) in Metastatic Colorectal Cancer. V. Gilles-Amar, M.L Garcia, A. Sebille, f. Maindrault-Goebel, C. Louvet, K. Beerblock, M. Krulik, A. De Gramont, for the GERCOR,#PROC AM SOC CLIN ONCOL 944, .

1510 SECTION 29 / Neoplasms of the Alimentary Canal

Darnowski JW, Handschumacher RE. Enhancement of fluorouracil therapy by the manipulation of tissue uridine pools. Pharmacol Ther 1989;41:381. ODwyer PJ, Paul AR, Peter R, Weiner LM, Comis RL. Biochemical modulation of 5-fluorouracil by PALA: phase II study in colorectal cancer. Proc Am Soc Clin Oncol 1989;8:107. Ardalan B, Singh G, Silberman H. A randomized phase I and II study of short-term infusion of high-dose fluorouracil with or without N-(phosphonacetyl)-L-aspartic acid in patients with advanced pancreatic and colorectal cancers. J Clin Oncol 1988;6:1053. Kemeny N, Schneider A, Martin DS, Colofiore J, Sawyer RC, Derby S, Salvia B. Phase I trial of N-(phosphonacetyl)-L-aspartate, methotrexate and 5-fluorouracil with leucovorin rescue in patients with advanced cancer. Cancer Res 1989;49:4636. Casper ES, Vale K, Williams LJ, Martin DS, Young CW. Phase I and clinical pharmacological evaluation of biochemical modulation of 5-fluorouracil with N(phosphonacetyl)-L-aspartic acid. Cancer Res 1983;43:2324. Jodrell DI, Oster W, Kerr DJ, Canney PA, Yosef H, Steward WP, Kaye SB, Cassidy J. A phase I-II study of N-(phosphonacetyl)-L-aspartic acid (PALA) added to 5fluorouracil and folinic acid in advanced colorectal cancer. Eur J Cancer 1994;30A:950955. Pase II study of fluoouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. Leichman CG, Fleming TR, Muggia FM, Tangen CM, Ardalan B, Doroshow JH, Meyers FJ, Holcombe RF, Weiss GR, Mangalik A, et al. J Clin Oncol 1995 Jun;13(6):13031311. Kohne-Wompner CH, Wilke H, Weiss J, Hiddemann W, Gropp C, Schmitz-Hauubner U, Lohrmann HP, Bodenstein H, Preusser P, Urbanitz D, Hotz J, Preib J, Knuth A, Schwark J, Bade J, Kohler B, Schmoll HJ. 5-FU, folinic acid 6 dipyridamole in advanced and progressive colorectal cancer: a randomized multicenter phase II trial. Proc Am Soc Clin Oncol 1990;9:123. Leong L, Doroshow J, Akman S, Carr B, Margolin K, Morgan R, Raschko J, Somlo G. Phase II trial of 5-FU and high dose folinic acid with cis-platin and dipyridamole in advanced colorectal cancer. Proc Am Soc Clin Oncol 1989;8:99. Creemers GJ, Lund B, Verweij J. Topoisomerase I inhibitors: topotecan and irenotecan. Cancer Treat Rev 1994;20:7396. Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AT, Lim GA. Plant antitumor agents: I. The isolation and structure of camptothecin, a novel alkaloid leukemia and tumor inhibitor from camptotheca accuminata. J Am Chem Soc 1966;88:38883890. Jenks S. Camptothecins resurface as promising drugs. J Natl Cancer Inst 1994;86:11181120. Hsiang YH, Liu LF. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 1988;48:17221726. Abigerges D, Chabot GG, Armand JP, Herait P, Gouyette A, Gandia D. Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 1995;13:210221. Rowinsky EK, Grochow LB, Ettinger DS, Sartorius SE, Lubejko BG, Chen TL, Rock MK, Donehower RC. Phase I and pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-(4-(1-piperidino)-1-piperidino)carbonyloxycamptothecin (CPT-11) administered as a ninety-minute infusion every 3 weeks. Cancer Res 1994;54:427436. Cunningham D, Pyrhonen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Lancet Randomized trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. 1998 Oct 31;352(9138):1413-8. Randomized trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C. Lancet 1998 Oct 31;352(9138):1407-12. Weekly 24-Hours Infusion Irinotecan (CPT-11) in 5-FU Pretreated Metastatic Colorectal Cancer. T M. Lfler, C Drge, T-U Hausamen. #PROC AM SOC CLIN ONCOL 922, . LB Saltz, PK Locker, N Pirotta, GL Elfring, LL Miller Weekly Irinotecan (CPT-11), Leucovorin (LV), and Fluorouracil (FU) Is Superior to Daily x5 LV/FU in Patients (PTs) with Previously Untreated Metastatic Colorectal Cancer (CRC).. , for the CPT-11 CRC Study Group. #PROC AM SOC CLIN ONCOL 898, . CPT-11 + 5FU/LFA Biweekly Regimen in Advanced Colorectal Carcinoma (ACC). A Phase I/II Study. Comella P, Catalano G, Casaretti R, De Lucia L, De Vita F, Avallone A, Gravina A, Orditura M, Comis S, Faranda A, Comella G. #PROC AM SOC CLIN ONCOL 1078, . A Randomized Phase III Trial comparing Irinotecan (IRI) + 5FU/Folinic Acid (FA) to the Same Schedule of 5FU/FA in Patients (pts) with Metastatic Colorectal Cancer (MCRC) as Front Line Chemotherapy (CT). JY Douillard, D Cunningham, AD Roth, JR Germa, RD James, P Karasek, P. Jandik, T Iveson, J Carmichael, G Gruia, M Dembak, D Sibaud, P. Rougier. # PROC AM SOC CLIN ONCOL 899, . Phase I/II Study of Escalating Doses of Systemic Irinotecan (CPT-11) with Hepatic

Arterial Infusion of Floxurdine (FUDR) and Dexamethasone (D), with or Without Cryosurgery for Patients with Unresectable hepatic Metastases from Colorectal Cancer. IG Ron, NE Kemeny, B Tong, D Sullivan, Y Fong, L Saltz, P Paty. #PROC AM SOC CLIN ONCOL 908, . Phase II study of hepatic arterial flozuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma. Kemeny N, Conti JA, Cohen A, Campana P, Huang Y, Shi WJ, Botet J, Pulliam S, Bertino JR; J Clin Oncol 1994 Nov;12(11):2288-95. (HAI)1180-74-4A. Miniinvasive Access to Perform Hepatic Arterial Infusion for Colorectal Liver Metastasis. C. Zanon, M. Grosso, S. Miraglia, R. Clara, I. Chiappino, R. Martinotti, D. Ottaviani, L. Evangelists, S. Zai, M. Bortolini, E. Milani and O. Alabiso. Oncology Dept., Molinette Hosp, Turin and *Oncology Dept. Univ Piemonte Orientale, Novara, Italy. #PROC AM SOC CLIN ONCOL 1180, . Alternating Hepatic Arterial Infusion and Systemic Chemotherapy for Liver Metastases from colorectal Cancer: A Phase II Trial Using Intermittent Percutaneous Hepatic Arterial Access. Mehmet S. Copur, A. Matamoros, M. Capadano, T. Goertzen, T. McCowan, R.Brand, J.C. Lynch, M. Tempero #PROC AM SOC CLIN ONCOL 955, . Combination of Irinotecan with Leucovorin and 5-FU in Advanced Colorectal Carcinoma-A Phase II Study. ASK Durrani, A Benhammouda, MA Gil-Delgado, F Guinet, D Castaing, R Adams, EC Antoine, D Coeffic, H Bismuth, D Khayat. #PROC AM SOC CLIN ONCOL 1083, . Efficacy and Feasibility of Intra-Arterial Hepatic Chemotherapy (IaHC) with a Percutaneous transaxillary Placement of Arterial Device. #PROC AM SOC CLIN ONCOL 1146, . Escalating Dose Irinotecan (CPT-11) Immediately Prior or After 5-Fluorouracil (5FU) 48 Hours Infusion+Leucovorin (LV): Pharmacokinetic and Pharmacodynamic Interactions in Chemotherapy-Nave Metastatic Colorectal Cancer Patients. A. Falcone, R. Danesi, G. Allegrini, G. Masi, A. Di Paolo, M. Lencioni, E. Pfanner, S. Comis. #PROC AM SOC CLIN ONCOL 924, . Oxaliplatin (L-OHP) and Irinotecan (CPT11) Phase I/II Studies: Results in 5 FU Refractory (FR) Colorectal Cancer (CRC) Patients (pts). E. Wasserman, S. Kalla, J.L. Misset, F. Goldwasser, N. Bedairia, M.A. Bensamine, M. Marty, E. Cvitkovic. # PROC AM SOC CLIN ONCOL 913, . Oxaliplatin (Ox) After Irinotecan (Iri): Antitumor Activity and Clinical Benefit of 3rd and Higher-Line Chemotherapy with Ox for Patients (pts) with Metastatic Colorectal Cancer (MCC) After Failure of Iri. A Kretzschmar, J Mezger, P C. Thuss-Patience, C.C. Kaufmann, M Wilhelm, H Krning, H. Schumacher, B Drken, P Reichardt.#PROC AM SOC CLIN ONCOL 995, . Results of the Intergroup [Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG)] Prospective Randomized Study of Surgery Alone Versus Continuous Hepatic Artery Infusion of FUDR and Continuous Systemic Infusion of 5FU After Hepatic Resection for Colorectal Liver Metastases. M.M. Kemeny, S. Adak, S. Lipsitz, B. Gray, J. MacDonald, AB Benson III. #PROC AM SOC CLIN ONCOL 1012, . Randomized Study of Hepatic Arterial Infusion (HAI) and Systemic chemotherapy )Sys) Versus SYS Alone as Adjuvant Therapy After Resection of Hepatic Metastases from Colorectal Cancer. N. Kemeny, A. Cohen, Y. Huang, W. Shi, L. Blumgart, A. Turnbull, D. Sullivan, J. Stockman, Y. Fong. #PROC AM SOC CLIN ONCOL 1011, . Phase II Study of Tomudex in chemotherapy Pretreated Patients with Advanced Colorectal Cancer. N. Horikoshi, K. Aiba, M. Kurihara, Y. Sakata, Y. Mitachi, N. Kikkawa, A. Wakui, for the Tomudex Cooperative Study Group. #PROC AM SOC CLIN ONCOL 988, . Preliminary Results of a Multicentre Randomized Trial Comparing 3 chemotherapy Regimens (de Gramont, Lokich and Raltitrexed) in Metastatic Colorectal Cancer. TS Maughan, RD James, D Kerr, C McArdle, JA Ledermann, M Seymour, C Johnston and RJ Stephens on behalf of the British MRC Colorectal Cancer Working Party. #PROC AM SOC CLIN ONCOL 1007, . A Syndrome (SDR) Characterized by Fatigue, Fever and Flu-Like (FFF) Symptoms Associated with Raltitrexed (R) Therapy. P. Osterlund, I Elomaa, T. Alauhtala, A. Orpana, H. Joensuu. #PROC AM SOC CLIN ONCOL 1135, . Genomic Study of Patients with Advanced Colorectal Cancer Treated with Raltitrexed (Tomudex). D.C. Farrugia, H. Ford, D. Cunningham, D. McVicar, G.W. Aherne, A. Hardcastle, K. McCarthy, F. Mitchell, P.V. Danenberg, #PROC AM SOC CLIN ONCOL 1029, . Preliminary Data of A Randomized Three-Arm Phase II Study in Relapsed or Metastatic Colorectal Cancer with Bolus (BI) Vs Continuous (CI) Vs ChronoModulated Infusion (CHI) of 5-FU + Folinic Acid + Tomudex. Facchini G,Tortoriello A, Gravina A, Libutti M, Perone V , Di Martino N, Crovella F, Carbone I, Pezzullo L, Sarnella G, Iaffaioli RV. #PROC AM SOC CLIN ONCOL 1086, . Raltitrexed (Tomudex) Plus 5-Fluorouracil (5-FU): Improved Palliation as Second Line Therapy in Patients with Metastatic Colorectal Cancer. J. Bertino, G.K. Schwartz, N. Kemeny, L. Saltz, D.K. Kelsen, W. Tong, J. Barazzuol, C. Lowery, M. Smith. #PROC AM SOC CLIN ONCOL 949, . Tomudex (Raltitrexed) Plus Oxaliplatin as First-Line Chemotherapy in Metastatic Colorectal Cancer (MCRC) Patients: A Promising Combination. J.F. Seitz, J.Y. Douillard, B. Paillot, E. Gamelin, E. Franois, T. Conroy, J.L. Raoul, R. Brunet, F. Bertheault Cvitkovic, S. Nasca, M. Ychou, J. Jacob, M. Smith, A. Fandi, #PROC AM SOC CLIN ONCOL 986, . Phase II trial of uracil and tegafur plus oral leucovorin: an effective oral regimen in

the treatment of metastatic colorectal carcinoma. Pazdur R, Lassere Y, Rhodes V, Ajani JA, Sugarman SM, Patt YZ, Jones DV Jr, Markowitz AB, Abbruzzese JL, Bready B, et al. J Clin Oncol 1994 Nov; 12(11):2296-300. Randomized Comparative Study of ORZEL (Oral Uracil/Tegafur (UFTTM) Plus Leucovori (LV) Versus Parenteral 5-Fluorouracil (5-FU) Plus LV in Patients with Metastatic Colorectal Cancer. J. Carmichael, T. Popiela, D. Radston, S. Falk, M. Fey, A. Oza, T. Skovsgaard, C. Martin.#PROC AM SOC CLIN ONCOL 1015, . A Phase III Trial of XIPROC AM SOC CLIN ONCOL 1016, . (Need to reprint this article) Mini-Meta-Analysis of Toxicity of Full Dose Mayo Regimen (FUFA) from Two Randomized Controlled Trials (RCTs): A Concern About Dose. M. Vincent, F. Whiston, A. Tomiak. #PROC AM SOC CLIN ONCOL 930, . Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors. Rustum YM, Harstrick A,Cao S, Vanhoefer U, Yin MB, Wilke H, Seeber S. J Clin Oncol 1997 Jan;15(1):389-400. 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Proc Am Soc Clin Onc 1024 Moertel CG, Fleming JR, McDonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tomey DC, Glick JM, Veeder MP, Maillard JA. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352. Brown ML, Nayfield SG, Shibley LM. Adjuvant therapy for stage III colon cancer: economics returns to research and cost-effectiveness of treatment. J Natl Cancer Inst 1994;86:424430.

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Reynolds T. Dutch trial casts doubt on colorectal adjuvant therapy. J Natl Cancer Inst 1995;87:476479. Adjuvant 5FU Plus Levamisole Improves Survival in Stage II and III Colonic Cancer, But Not in Rectal Cancer. Interim Analysis of The Netherlands Adjuvant Colorectal Cancer Project (NACCP). F.A.N. Zoetmulder,B.G. Taal, H. Van Tinteren #PROC AM SOC CLIN ONCOL 1021, . Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM< Ungerleider JS, Emerson WA, Tormey DC, Glick JH, et al Intergroup study of fluorouracil plus levimisole as adjuvant therapy for stage II/Dukes B2 colon cancer. J Clin Oncol; 13(12):2936-43 1995 UI: 96101611 Mamounas E, Wieand S, Wolmark N, Bear HD, Atkins JN, Song K, Jones J, Rockette H Comparative efficacy of adjuvant chemotherapy in patients with Dukes B versus Dukes C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04) [see comments. J Martenson, C Willett, D. Sargent, J. Donohue, R. Goldberg, T.Wasserman, L. Gunderson, R. Myerson, P. Thomas, B. Fisher, A. Benson, III. Coordinated by the North Central Cancer Treatment Group, Rochester, MN. A Phase III Study of Adjuvant Radiation Therapy (RT), 5-Flouorouracil (5-FU), and Levamisole (LEV) Vs 5-FU and LEV in Selected Patients with Resected, High Risk Colon Cancer: Initial Results of Int 0130. Proc Am Soc Clin Onc, ; 904 Meta-analysis Group In Cancer. Efficacy of intravenous continuous infusion of flurouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998 Jan;16(1):301-8 Scheithauer W, Kornek G, Rosen h, Sebesta C, Marcell A, Kwasny W, Karall M, Depisch D. Combined intraperitoneal plus intravenous chemotherapy after curative resection for colonic adenocarcinoma. Eur J Cancer 1995 Nv;31A(12):1981-6 Penna C, Nordlinger B. Locoregional chemotherapy for adjuvant treatment of colorectal adenocarcinoma. 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1512 SECTION 29 / Neoplasms of the Alimentary Canal

P Thirion, M. Buyse, N. Wolmark, E Haddad, P. Piedbois, for the Meta-Analysis group In Cancer. Survival Impact of Chemotherapy in Patients with Colorectal Metastases confined to the liver: A Meta-Analysis of 1, 458 Non-Operable Patients Randomized in 22 Trials, Proc. Am Soc Clin Onc, , 1019 Zalcberg J, Kerr D, seymour L, Palmer M. Haematological and non-haematological toxicity after 5-fluorouracil and leucovorin in patients with advanced colorectal cancer in significantly associated with gender increasing age and cycle number. Tomudex International Study Group. Eur J Cancer 1998 Nov;34(12):1871-5 de Gramont A, Louvet C, Andre T, Tournigand C, Krulik M. A review of GERCOD trials of biomonthly leukovorin plus 5-fluorouracil 48-h continuous infusion in advanced colorectal cancer: evolution of a regimen. (GERCOD). Eur J Cancer 1998 Apr;34(5):619-26 F.A.N. Zoetmulder, B.G. Taal, H. Van Tinteren on behalf of the, NACCP.#PROC AM SOC CLIN ONCOL , 1021; S. Cascinu, V . Catalano, L. Latini, G. Catalano, R. Mattioli, E.T. Menichetti, R. Trivisonne, R. Bascioni, U. Torresi, V . Pieroni, R.R. Silva, G De Signoribus, #PROC AM SOC CLIN ONCOL , 923: Jager E, Klein O, Wchter B, Muller B, Braum Y, Knuth A. High dose 5-fluorouracil (f-FU) and folinic acid in advanced colorectal cancer resistant to standard dose 5-FU treatment: result of a phase II study. Eur J Cancer 1995 Sep;31a(10):1717 Comella P, Palmieri G, Lourusso V, Catalano G, Nicollela D, Ianniello GP, casaretti R, Montella M, Frasci G, Perna M, Comella G. Double biochemical moddulation of 5-fluorouracil by methotrexate and levo-folinic acid in the treatment of advanced digestive tract malignancies. Eur J Cancer 1996 Sep;32A(10):1719-26 RD James on behalf of the AXIS collaborators. , MRC . Intraportal 5FU (PVI) and Peri-Operative Radiotherapy (RT) in the Adjuvant Treatment of Colorectal Cancer (CRCa)-3681 Patients Randomised in the UK Coordinating Committee on Cancer Research (UKCCCR) AXIS Trial. #PROC AM SOC CLIN ONCOL , 1013; H. Nakazato, K. Ito, H. Takagi, S Saji, A. Koike, S. Baba, M. Mai, Y. Ohashi, J. Sakamoto. The study group of immunochemotherapy with PSK for Colon Cancer, Nagoya, Aichi, Japan. #PROC AM SOC CLIN ONCOL , 942; Jessup JM, Stewart AK, Menck HR. The National Cancer Data Base report on patterns of care for adenocarcinoma of the rectum, 1985-95. Cancer 1998 Dec 1;83(11):240818. D. Jonker. J. Maroun, W. Kocha. Survival Benefit of Chemotherapy in Metastaic Colorectal Cancer: A Meta-Analysis of Randomized Controlled Trials. #PROC AM SOC CLIN ONCOL , 1019; P Thirian, M. Buyse, N. Wolmark, E Haddad, P. Piebois, for the, Meta-Analysis Group In Cancer. Survival Impact of Chemotherapy in Patients with Colorectal Metastases Confined to the liver: A Meta-Analysis of 1,458 Non-Operable Patients randomized in 22 Trials. #PROC AM SOC CLIN ONCOL , 912; Conti JA Kemeny NE, Saltz LB, Hauang Y, Tong WP, Chou TC, Sun M, Pulliam S, Gonzalez C. Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 1996 Mar;14(3):709-15 Cunningham D, Pyrhonen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998 Oct 31;352(9138):1413-8 Rougier P, Van utsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navaro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C. Randomised trial of irinotecan versus fluorouracil by continous infuson after fluorourail failure in patients with metastatic colorectal cancer. Lancet 1998 Oct 31;352(9138):1407-12 M. Michael, M.J. Moore, D. Hedley, A. Oza, R. feld,R Goel, J. Maroun, J. Jolivet, A. Fields. Irinotecan CPT-11) as Palliative Therapy in Refractory Advnced Colorectal Cancer (CRC). #PROC AM SOC CLIN ONCOL , 934; LB Saltz, PK Locker, N Pirotta, GL Elfring, LL Miler. , for the CPT-11 CRC Study Group. Weekly Irinotecan (CPT-11), Leucovorin (LV), and Fluorouracil (FU) Is Superior to Daily X5 Lv/FU in patients (PTS) with previusly Untreated Metastatic colorectal Cancer (CRC). #PROC AM SOC CLIN ONCOL , 898; Thomas M. Lofler, Cornelia Droge, Torsten- Udo Hausamen. Epartment of Medicine, Div. Of Medical Oncology Stadtische Kliniken Dortmund, Dortmund, Germany. Weekly 24-Hour Infusion Iriontecan (CPT-11) in 5FU Pretreated Metastatic Colorectal ancer. #PROC AM SOC CLIN ONCOL , 922; Comella P. Catalano G, Casaretti R, De Lucia L, De Vita F, Avallone a,Gravina A, Orditura M, Comis S, Faranda A, Comella G. CPT-11 + 5FU/LFA Biweekly Regimen in Advanced Colorectal Carcinoma (ACC). A phase I/II Study. #PROC AM SOC CLIN ONCOL , 1078; JY Douillard, D Cunningham, AD Roth, JR Germa, D James, P Karasek, P. Jandik, T iveson, J Carmichael, G Gruta, M Dembak, D Sibaud, P. Rougier. A Randomized Phase III Trial Comparing Irinotecan (IRI) + 5FU/Folinic Acid (FA) to the Same Schedule of 5FU/FA in Patients (pts) with Metastatic Colorectal Cancer (MRRC) as Front Line Chemotherapy (CT). #PROC AM SOC CLIN ONCOL , 899; G Ron, NE Kemeny, B Tong, D Sulivan, Y Fong, L Saltz, P Paty. . Phase I/II Study of Escalating Doses of Systemetic Irinotecan (CPT-1) with Hepatic Arterial Infusion of Floxuridine (FUDR) and Dexamethasone (D), with or Without Cryosurgery for Patents with Unresectable Hepatic Metastases from Colorectal Cancer. #PROC AM SOC CLIN ONCOL , 908; Kemeny N, Conti JA, Cohen A, Campana P, Huang Y, Shi WJ, Botet J, Pulliam S,

Bertino JR. Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorctal carcinoma. J Clin Oncol 1994 Nov;12(11):2288-95 C. Zanon, M. Grasso, S. Miraglia, R. Clara, I Chiappino, R. Martinotti, D. Ottaviani, L. Evangelisti, S. Zai, M Bortolini, E. Milani and O. Alabiso. Oncology Dept Molinette Hosp. Turin and *Oncology Dept. Univ Piemonte Orientale, novara, italy. Miniinvasive Access to perform Hepatic Arterial Infusion (HAI) for Colorectal Liver Metastasis. #PROC AM SOC CLIN ONCOL , 1180; Mehmet S. Copur, A. Matamoros, M. Capadano, T. Goertzen, T. McCowan, R. Brand, J.C. Lynch, M. Tempero. Niversity of Nebraska Medical Center, Omaha, NE. Alternating Hepatic Arterial Infusion and systemic Chemotherapy for liver Metastases from Colorectal Cancer: A Phase II rial Using Intermittent Percutaneous Hepatic Arterial Access. #PROC AM SOC CLIN ONCOL , 955; ASK Durrani, A Benhammouda, MA Gil-Delgado, F Guinet, D Castaing, R Adams, EC Antoine, D Coeffic, H Bismuth, D Khayet Combination of Irinotecan with Leucovorin and 5-FU in Advanced Colorectal Carcinoma- A Phase II Study. #PROC AM SOC CLIN ONCOL , 1083; Monica Ronzoni, Luisa Somma, Luca Aldrighetti, Marco Stella, Massimo Venturini, Eugenio Villa. Radiology S. Raffaele Hospital, Milan, Italy. Efficacy and Feasibility of Intra- Arterial Hepatic Chemotherapy (IAHC) with a Percutaneous Transaxillary Placement of Arterial Device. PROC AM SOC CLIN ONCOL , 1146; A. Falcone, P. Denesi, G. Allegrini, G. Masi, A. Di Paolo, M. Lencioni, E. Pfanner, S. Comis. Escalating Dose Irinotecan (CPT-11) mmediately Prior or After 5-Fluorouracil (5-FU) 48 Hours Infusion+Leucovorin (LV): Pharmacokinetic and Pharmacodynamic Interactions in Chemotherapy-Nave Metastatic Colorectal Cancer Patients. #PROC AM SOC CLIN ONCOL , 924; Van Cutsem E, Pozzo C, Starkhammar H, Dirix L, Terzoli E, Cognetti F, Humblet , Garufl C, Filez L, Gruia G, Cote C, Barone C. A Phase II study of irinotecan alternated with five days bolus of 5-fluorouracil and leucovorin in first-line chemotherapy of metastatic colorectal cancer. Ann Oncol 2998 Nov;9(11):1199-204 E. Wasserman, S. Kalla, J.L. Misset, F. GoldWasser, N. Bedairia, M.A. Bensamine, M. Marty, E. Cvitkovic. Hop. P. Brousse Villejuif. 2 Hop. St Louis Paris. Oxaliplatin (L-OHP) and Irinotecan (CPT11) Phase II Studies: Results in 5 FU Refractory (FR) Colorectal Cancer (CRC) Patients (PTS). #PROC AM SOC CLIN ONCOL , 913; Durand-Zaleski I, Roche B, Buyse , Carlson R, OConnell MJ, Rougier P, Chang AE,Sondak VK,Kemeny MM, Allen-MersTG, Fagniez PL, Le Bourgeois JP, Piedbois P. Economic implications of hepatic arterial infusion chemotherapy in treatment of nonrsectable colorectal liver metastases. Meta-Analysis Group in Cancer###. Hartmann Jt, Schmoll E, Bokemeyer C, Fety R, Lucas C, iroux B, Schmoll HJ. Phase I pharmacological of intra-arterial infused fotemustine for colorectal liver metastases. Eur J Cancer 1998 Jan;34(1):87-91 Cunningham D, Zalcberg JR, Rath U, Olver I, Van Cutsem E, Svensson C, Seitz JF, Harper P, Kerr D, Perez-MangaG, et al. Advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopena. The Tomudex Colorectal Cancer Study Group. Tomudex(ZD1694): results of a randomised trial in Thymidylate Synthase inhibition, dead end?. Eur J Cancer 1995 Nov;31(12):1945-54 Herrmann R. Tomudex (ZD1694): results of a randomised trial in Thymidylate synthase inhibition, a dead end?. Eur J Cancer 1995 Nov;31A(12):1919-20 Farrugia DC, Norman AR, Cunningham D. Single agent infusional 5-fluorouracil is not effective second-line therapy after raltitrexed (Tomudex) in advanced colorectal cancer. Eur J Cancer 1998 Jun;34(7):987-91 Sulkes A, Benner SE, Canetta RM. Uracil-ftorafur: an oral fluoropyrimidine active in colorectal cancer. J Clin Oncol 1998 Oct;16(10):3461-75 Kohne CH, Schoffski P, Wilke H, Kaufer C, Anderson R, Ohl U, Klaasen U, Westerhausen M, Hiddemann W, Schott G, Harstick A, Bade J Horster A, Schubert U, Hecker H, Dorken B, Schmoll HJ. Effective biomodulation by leukovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: results of a randomized trial in patients with advanced colorectal cancer. J Clin Oncol 1998 Fe;16(2):418-26 de Gramont A. Bosset JF, Milan C, Rougier P, Bouche , O Etienne PL, Morvan F, Louvet C, Guillot T, Francois E, Bedenne L. Randomized trial comparing monthly low-dose leukovorin and fluorouracil bolus with bimonthly high-doseleukovorin and fluorouracil bolus plus continuous infusion for advanced. J Clin Oncol 1997 feb;15(2):808-15 T. Price, D Cunningham, T. Hickish, D. Tait, A. Norman, P.J. Ross,G. Middleton, H.E.R. For, K. Sumpter. Royal Marsden Hospital, London and Surrey, UK; Royal Bournemouth and Poole Hospitals,UK. Phase III study of chronomodulated Vs Protracted Venous Infusional 5-Fluorouracil Both Combined with Mitomycin in First Line Therapy for Advanced Colorectal Carcinoma. PROC AM SOC CLIN ONCOL , 1008; Yadama, Matsumura, Shimada, Shirao, Muro Kei, Sugano, Haruyama. Phase II study of Three-Hour-Interval Sequential MTX and 5-FU with Leucovorin Rescue in Patients with Advanced Colorectal Cancer. PROC AM SOC CLIN ONCOL , 1999; 1173 Rita Lionetto., Unit of Clinical Epidemiology and Trials National Institute for Cancer Research, Genova, Italy. Intacc-02: 5 Fluorouracil (5FU)+6-S-Leucovorin (6S-L-V)+ Levamisole (LEVA) Vs Methotreate (MTX)+5FU+LEVA: An Italian Intergroup Study of Adjuvant Therapy for Resected Colon Cancer. PROC AM SOC CLIN ONCOL . 1118;

Blanke CD, Kasimis B, Schein P, Cappizzi R, Kurman M. Phase II Study of trimetrexate, Fluorouracil, and leucovorin for advanced colorectal cancer. J Clin Oncol 1997 Mar; 15(3):915-20 Charles D. Blanke, J. Cassidy, H. Gerhartz, R.D. James, B. Kasimis. East Orange VA Hospital, East Orange, NJ. A Phase II Trial Of Trimetrexate (TMTX), 5-Fluoroucil (5FU), and Leucovorin (LCV) in Patients (PTS) with Previously Treated Unresectable or Metastatic Colorectal Cancer (CRC). PROC AM SOC CLIN ONCOL , 947; C.P Spears, C. Vergon, M. Polonsky. Pasadena, CA; M. Masterson, N. Habboubi. Gustavsson, B.G. and the Nordic Biomodulation Group. Phase I/II Sequential Trimetrexate/ Split-Dose Fluorouracil Therapy in Advanced Colorectal Cancer.Blank CD et al J clin Oncol 15:915-920, 1997 C.P. Spears, C. Vergon, M. Polonsky. Huntington Cancer Center, Pasadena, CA; M. Masterson, N. Habboubi. U.S. Bioscience, West Conshohocken, PA; G. Carlsson, B.G. Gustavsson, Sahlgrenska Institute of Surgery, Goteborg, Sweden; and the Nordic Biomodulation Group. Cont J etal J Clin Oncol 12:695-700, 1994 CJA Punt, HJ Keizer, J Douma, J Schuller, T Skovsgaard, CHH ten Napel, H Lochs, EW Muller, N Habboubi, DJT Wagner. Dept. Of Medical Oncology, University Hospital Nijmegen, The Netherlands, USBioscience USA; on behalf of the European TNTX Study Group. Multicenter Randomized Trial of 5-Fluorouracil (5FU) and Leucovorin (LV) with Or Without Trimetrxate (TMTX) as First Line Treatment in Patients (pts) with Advanced Colorectal Cancer (ACC) Becouarn Y, Ychou M, Ducreux M, Borel C, Bertheault-Cvitkovic F, Seitz JF, Nasca S, Nguyen TD, Paillot B, Raoul JL, Duffour J, Fandi A, Dupont-Andre G, Rougier P. Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers. J Clin Oncol 1998 Aug;16(8):2739-44 de Gramont A, Vignoud J, Tournigand C, Louvet C, Andre T, Varette C, Raymond E, Moreau S, Le Bail N, Krulik M. Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 1997 Feb;33(2):214-9 Raymond E, Chaney SG, Taamma A, Cvitkovic E. Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol 1998 Oct;9(10):1053-71 A. De Garmont, F. maindrault-Goebel, C. Louvet, T. Andre, E. Carola, V. GillesAmar,M. Mabro, V. Izrael, M. Krulik. For the, GERCOR. Evaluation of Oxaliplatin Dose-Intensity with The Bimonthly 48h Leucovorin (LV) and 5-Fluorouracil (5FU) Regimens (FOLFOX) in Pretreated Metastatic Colorectal Cancer. PROC AM SOC CLIN ONCOL , 1018; A. Abad, M. Navarro, J Sastre, A. Cervantes, A. Anton, E. Marcuello, A. Carrato, E. Aranda, B. Massuti, M. Guillot, M. Garcia, E. Diaz-Rubio, L. MounedjiBoudiaf, F. Llados. Sanofi Winthrop, Barcelona, Spain. Biweekly Oxaliplatin (OXA) Plus Weekly 48 H Continous Infusion (CI) 5FU (TTD Regimen) in First Line Treatment of Advanced Colorectal Cancer (ACC) (Preliminary Results). PROC AM SOC CLIN ONCOL , 1056; E. Van Cutsem, J. Szanto, A. Roth, Y. Humblet, C.H. Kohne, J. Wils, M. Lorenz, M. Borner, P. Schoffski, I. Tabah-Fisch. Univ. Hosp. Gasthuisberg, Evaluation of the Addition of Oxaliplatin (OXA) to The Same Mayo or German 5FU Regimen in Advanced Refractory Colorectal Cancer. PROC AM SOC CLIN ONCOL , 1999; 900 V. Gilles-Amar, M.L. Garcia, A. Sebille, F. Maindrault-Goebel, C. Louvet, K. Beerblock, M. Krulik, A. De Gramont, for the, GERCOR hopital St-Antoine, 75012 Paris, France. Evaluation of Severe Sensory Neuropathy with Oxaliplatin Combined to The Bimonthly 48h Leucovorin (LV) and 5-Fluorouracil (5FU) Regimens (FOLFOX) in Metastatic Colorectal Cancer. PROC AM SOC CLIN ONCOL , 944; Bertheault-Cvitkovic F, Jami A, Ithazaki M, Brummer PD, Brienza S, Adam R, Kunstlinger F, Bismuth H, Misset JL, Levi F. Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer. J Clin Oncol 1996 Nov;14(11):2950-8 Falcone A, Danesi R, Dargenio F, Pfanner E, Bruneti I, Del Tacea M, Nethersell AB, Cont PF. Intravenous azidothymidine with fluorouracil and leucovorin: a phase I-II stdy in previously untreated metastatic colorectal cancer patients. J Clin Oncol 1996 Mar;14(3):729-36 Labianca R Cascinu s, fontini , Barni S, Fiorentini G, Comella G, Zaniboni A, Gottardi O, Arnoldi E, Oliani C, Duro M, Pavanato G, Martignoni G, Raina A, Piazza E, Dallavalle G, Valsecchi R, Pancera G, Luporini G. High-versus low-dose levoleucovorin as a modulator of 5-fluorouracil in advanced colorectal cancer: a GISCAD phase III study. Italian Group for the Study of Digestive Tract Cancer. Ann Oncol 1997 Feb;8(2):169-74 Albrecht Kretzschmar, Jorg Mezger, Peter C. Thuss-Patience, C.C. Kaufmann, Martin Wilhelm, Hans Kroning, H. Schumacher, Bernd Dorken, peter Reichardt. Diakonie- Krankenhaus, Schwab. Hall. Oxaliplatin (OX) After Irinotecan (Iri): Antitumor Activity and Clinical Benefit of 3rd and Higher-Line Chemotherapy with OX for Patients (PTS) with Metastatic Colorectal Cancer (MCC) After Failure of Iri. PROC AM SOC CLIN ONCOL , 995; . Patt YZ, Hoque A, Lozano R, Pozdur R, Chase J, Carraco H, Chuang V, Delpassand Es, Ellis L, Curley S, Roh M, Jones DV Jr Colorectal cancer refractory to systemic fluorouracil and leucovrin. N. Horikoshi, K. Aiba, M. Kurihara, y. Sakata, Y. Mitachi, n. Kikkawa, A. wakui, A. Wakui, for thetomudex Cooperative Study Group. Tohoku Univ., Sendai, Japan. Phase II study of Tomudex in Chemotherapy Pretreated Patients with Advanced Colorectal Cancer. PROC AM SOC CLIN ONCOL , 988;

CHAPTER 103 / Adenocarcinoma of the Colon and Rectum 1513

Maughan TS, James RD, Kerr D, McArdele C, Lederman JA, seymour M, Johnston C and Stephens RJ British MRC Preliminary results of a Multicentre Randomised Trial Comparing 3 Chemotherapy Regimens (de Gramont, Lokich and Raltitrexed) in Metastatic Colorectal cancer. PROC AM SOC CLIN ONCOL , 1007; Farrugia D.C, Ford H., Cunningham D, McVicar D, Aherne G.W., a hardcastle, McCarthy K., Mitchell F, Dananberg P.V, Jackman A.L, Dananberg K. University of Southern Clifornia, Los Angeles, CA. Genomic study of Patients with Advanced Colorectal Cancer Treated with Raltitrexed (Tomudex) PROC AM SOC CLIN ONCOL , 1029; Facchini G, tortoriello a, Gravina A, Libutti M, Perone V , Di Martino N, Crovella F, Carbone I, Pezzullo L, Sarnella G, Iaffaioli RV. Oncologia Medica, Univ. Caliari; INT Napoli; ASLNA 1 and CE 1; Chir. App. Dig, Univ.II Napoli; Chir. Gen, Osp,. Oliveto Citra (SA); Chir. Gen, Osp. Cerreto Sannita (BN); CHIR. GEN, OSP. Pellegrini Napoli. Preliminary Data of a randomised Three-Arm Phase II Study in Relapsed or Metastatic Colorectal Cancer with Bolus (BI) Vs Continuous (CI) Vs Chrono-Modulated Infusion (CHI) of 5-FU + Folinic Acid + Tomudex. PROC AM SOC CLIN ONCOL , 1086; Zalcberg JR, Cunningham D, Van Cutsem E, Schornagel J, Adenis A, Green M, Iveson A, Azab M, Seymour I. ZD1694: a Novel thymidylate Synthase inhibitor with substantial activity in the treatment of patients with advanced clorectal cancer. Tomudex Colorectal study Group. J clin Oncol 1996 Mar;14(3):716-21 Bertino J, Schwartz G.K, Kemeny N., Saltz L, Kelsen D.K, Tong W, Barazzuol J, Lowery C, Smith m.. UK> Raltitrexed (Tomudex) Plus 5-Fluorouracil (5-FU): Improved Palliation as Second Line Therapy in patients with Metastatic Colorectal Cancer. PROC AM SOC CLIN ONCOL , 949; P. Osterlund, I. Elomaa, T. Alaluhtala, A. Orpana, H. Joensuu. Dept Of Oncology Helsinki University central hospital, helsinki, Finland. PROC AM SOC CLIN ONCOL , 1999; 1135 J.F. Seitz, J.Y. Douillard, B. Paillot, . Gamelin, E. rancois, T. Conroy, J.L. Raoul, R. Brunet, F. Berheault Cvitkovic, S. Nasca, M. Ychou, J. Jacob, m. Smith, A. andi,for the French Federation Nationale des centre de lutte Contre le Cancer. Zeneca Pharmaceuticals, Cergy, France. Tomudex (Raltitrexed) Plus Oxaliplatin as First-Line Chemotherapy in Metastatic Colorectal Cancer(MCRC) Patients: A Promising Combination. PROC AM SOC CLIN ONCOL , 986; Pazdur R, Lassere Y, Rhodes V , Ajani JA, Sugarman SM, Patt YZ, Jones DV Jr,. Phase II trial of uracil and tegafur plus oral leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma. J Clin Oncol 1994 Nov;12(11);2296-300 Carmichael J, Popiela D, Radston Falk S, Fey M, Oza A, Skovsgarrd T, Martin C. Bristol Meyers Squaibb Company, Waterloo, Belgium, on behalf of investigation from 47 sites. Randomized Comparative Study of ORZEL (Oral Uracil/Tegafur (UFT) Plus Leucovorin (LV) Versus Parenteral 5-Flurouracil (5-FU) Plus LV in Patients with Metastatic Colorectal Cancer. PROC AM SOC CLIN ONCOL , 1999;1015 Jean Maroun, Charles weo Oncology, Memphis,TN. A Phase III Trial of XI Advanced/Metastatic C. PROC AM SOC CLIN ONCOL , 1999; 1016 Vincent M, Whiston F, Tomiak A. London Regional Cancer Centre, london, ON, Canada. Mini-Meta-Analysis of Toxicity of Full Dose Mayo Regimen (FuFA) from Two Randomized Controlled Trials (RCTs): A Concern About Dose. PROC AM SOC CLIN ONCOL , 930; Rustum YM, Harstrick A, Cao S, Vanhoefer U, Yin MB, Wilke H, Seeber S. Thymidylate Synthase inhibitors in cancer therapy: direct and indirect inhibitors. J Clin Oncol 1997 Jan;15(1):389-400 Punt CJ. New drugs in the treatment of colorectal carcinoma. Cancer 1998 Aug 15;83(4):679-89 Rothenberg ML, Eckardt JR, Kuhn JG, Burris HA 3rd, Nelson J, Hilsenbeck SG, Rodriguez GI, Thurman AM, Smith LS, Eckhardt SG, Weiss GR, Elfring GL, Rinaldi DA, Schaaf LJ, Von Hoff DD. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 1996 Apr;14(4):1128-35 Rougier P, Bugat R, Douillard JY, Culine S, Sue E, Brunet P, Becouran Y, Ychou M, Marty M, Extra JM, Bonneterre J, Adenis A, Seitz JF, Ganem G, Namer m, Conroy T, Negrier S, Merrouche Y, Burki F, Mousseau m, Herait P, Mahjoubi M. Phase II study of Irinotecan in the treatment of advanced colorectal cancer in chemotherapy-nave patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 1997 Jan;15(1):251-60 Vanhoefer U, Harstrick A, Kohne CH, Achterrath W, Rustum YM, Seeber S,Wilke H. Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first-line chemotherapy in patients with advanced colorectal cancer. J Clin Oncol Mar;17(3):907-13 Scheithauer W, Kornek GV, Raderer M, Valencak J, Weinlander G, Hejna M, Haider K, Kwasny W, Depisch D. Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer. J Clin Oncol Mar;1793):902-6 Pitot HC, wender DB, OConnel MJ, Schroeder G, Goldberg RM, Rubin J, Mailliard JA, Knost JA, Ghosh C, Kirschling RJ, Levitt R, Windschitl He. Phase II trial of irinotecan in patients with metatstatic colorectal carcinoma. J Clin Oncol 1997 Aug;15(8):2910-9

1514 SECTION 29 / Neoplasms of the Alimentary Canal

Giovanni Brandi, Jean Dabar, Guido BiProc Am Soc Clin Oncol , Pierre Raiband, Chantal Bridonneau, Barbara Poggi, Annamaria Pisi, Stefano Tamberi, Silvia Comis, sante Tura. Medical Direction Rhone-Poulenc Rorer, origgio, Milano, Italy. Role of the zgut Flora (IBF) in the Intestinal Toxicity from CPT-11 in Mice. PROC AM SOC CLIN ONCOL , 1068; Riethmuller G, Holz E, Schlimok G, Schmiegel W, Raab R, Hoffken K, Gruber R, Funke I, #Pichlmaier H, Hirche H, Buggisch P, Witte J, #Pichlmayr R. Monoclonal antibodytherapy for resected Dukes C colorectal cancer: seven-year outcome of a multicenter randomized trial. J clin Oncol 1998 May;16(5):1788-94 Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 1994 may;12(5):960-9 A Sobrero, R. Labianca, A Zaniboni, G.L. Frassineti, C. Aschele, F Testore, R.Giuliani, S. Rizzato, A. Ravaioli, E. Arnoldi, S. arni, M.A. Passi, A Guglielmi, D. Turci, F. Grossi, from, GISCAD, IOR and callaborating centers, Italy. Impact of Second and Third Line FU-Based Chemotherapy on The Survival of Patients with Advanced Colorectal Cancer. PROC AM SOC CLIN ONCOL , 915; Levi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acidin metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet 1997 Sep 6;350(9079):681-6 Oconnel MJ, Nagorney DM, Bernath AM, Schroeder G, Fitzgibbons RJ, Mailliard JA, Burch P, Bolton JS, Colon-Otero G, Krook JE. Sequential intrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver. Cocconi G, Cunningham D, Van Cutsem E, Francois E, Gustavsson B, Van Hazel G, Kerr D, Possinger K, Hietschold SM. 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A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer: a Mayo Clinic/North Central Cancer Treatment Group study. Cancer 1989;63:10261030. Moertel C, Fleming T, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352358. Wadler S, Goldman M, Lyver A, Wiernik PH. Phase I trial of 5-fluorouracil and recombinant alpha 2a-interferon in patients with advanced colorectal carcinoma. Cancer Res 1990;50:2056. Ajani JA, Rios AA, Ende K, Abbruzzese JL, Edwards C, Faintuch JS, Saks S, Gutterman JU, Levin B. Phase I and II studies of the combination of recombinant human interferon-gamma and 5-fluorouracil in patients with advanced colorectal carcinoma. J Biol Response Mod 1989;8:140. Kemeny N, Kelsen D, Derby S, Sammarco P, Adams L, Murray P. Combination of 5-fluorouracil plus recombinant alpha interferon in advanced colorectal cancer. Proc Am Soc Clin Oncol 1990;9:109. Pazdur R, Abbruzzese J, Faintuch J, Ajani J, Patt Y, Jackson D, Markowitz A, Winn R, Gutterman J, Levin B. Phase II study of recombinant interferon alpha and 5fluorouracil in patients with advanced colorectal carcinoma. Proc Am Soc Clin Oncol 1990;9:117. Yalavarthi P, Murthy S, Budd GT, Andresen S, Koletsky A, Avashia J, Gibson V, Sergi J, Bukowski RM. Phase I/II trial of 5FU, leucovorin and rhuifin-alpha-2a in metastatic colorectal cancer: possible decrease in myelosuppression. Proc Am Soc Clin Oncol 1990;9:125. Marshall ME, Tangen CM, Berenberg JL, Balcerzak SP, Brown T, MacDonald JS. Treatment of advanced colorectal cancer with 5-fluorouracil, leucovorin and Roferon-A: a Southwest Oncology Study Group study. Cancer Biother 1994;9:301306. Dion PW, Bright-See EB, Smith LL, Bruce WR. The effect of dietary ascorbic acid and alpha-tocopherol on fecal mutagenicity. Mutat Res 1982;102:27. Baker AR. Local procedures in the management of rectal cancer. Semin Oncol 1980;7:385. 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Dube S, Heyen F, Jenicek M. Adjuvant chemotherapy in colorectal carcinoma: results of a meta-analysis.. Dis Colon Rectum 1997 Jan:40(1):35-41 Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, et al. Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes B2 colon cancer. J Clin Oncol 1995 Dec:13(12):2936-43 Figueraedo A, Fine S, Maroun J, Walker-Dilks C, Wong S. Adjuvant therapy for stage III colon cancer after complete resection. Provincial Gastrointestinal Disease Site Group. Cancer Prev Control 1997 Oct;1(4):304-19 Portal Vein chemotherapy for colorectal cancer: a meta-analysis of 4000 patients in 10 studies. Liver Infusion Meta-analysis Group. J Natl Cancer Inst 1997 Apr 2;89(7):497-505 Evans JT, Mittleman A, Chu M, Holyoke ED. Pre- and postoperative uses of CEA. Cancer 1978;42:1419. G. Steele, U of Chicago, Chicago, Il; J. Tepper U. Of North Carolina, Chaple Hill, NC; J. Herndon, Duke U.,Durham,NC;R Mayer, Dana-Farber Cancer Institute, Boston, MA. Failure and Salvage After Sphincter Treatment for Distal Rectal Adenocarcinoma-A CALGB Coordinated Intergroup Study. PROC AM SOC CLIN ONCOL 903 , A903. Mohiuddin M, Chen E, Ahmad N. Combined liver radiation and chemotherapy for palliation of hepatic metastases from colorectal cancer. J Clin Incol 1996 Mar:14(3):722-8 Beart RW Jr, Moertel CG, Wieand HS, et al. A randomized trial of 5-fluorouracil by portal vein infusion as surgical adjuvant therapy for colorectal cancer. 42nd Annual Cancer Symposium of the Society of Surgical Oncology and 35th Annual Meeting of the Society of Head and Neck Surgeons, San Francisco, May 1989, pp 2124 (abstract 204). Donohue JH, Williams AS, Cha , Windschitl HE, Witzig TE, Nelson H, Fitzgibbons RJ Jr, Wieand HS, Moertel CG Perioperative blood transfusion do not affect disease recurrence of patients undergoing curative resection of colorectal carcinoma: a Mayo/ North Central Cancer Treatment Group study. J Clin Oncol; 13(7):1671-8 1995 UI: 95325885 Vermorken JB, Claessen AM, van Tinteren H, Gall HE, Ezinga R, Meijer S, Scheper RJ, Meijer CJ, Bloemena E, Ranson JH, Hanna MG Jr, Pinedo HM Active specific immunotherapy for stage II and stage II human colon cancer: a randomized trial. Lancet Jan 30;353(9150):345-50 Riethmuller G, Schneider-Gadicke E, Schlimok G, Schmiegel W, Raab R, Hoffken K, Gruber R, Pichlmaier H, Hirche H, Pichlmayr R, et al Randomized trial of monoclonal antibody for adjuvant therapy of resected DukesC colorectal carcinoma. German Cancer Aid 17-1A Study Group. Lancet 1994 May 14; 343 (8907):1177-83 Kemeny N, Huang Y Cohen AM, Shi W, Conti JA, Brennan MF, Bertino JR, Turnbull AD, Sullivan D, Stockman J, Blumgart LH, Fong Y Hepatic arterial infusion of chemotherapy after resection of hepatic metastasis from colorectal cancer. N Engl J Med; 341(270;2039-48 UI: 20061996 Nordlinger B, Vallant JC, Guiguet M, Balladur P, Paris F, Bachellier P, Jaeck D. Survival benefit of repeat liver resections for recurrent colorectal metastases:. Association Francaise De Chirurgie. J Clin Oncol 1994 Jul;12(7):1491-6 OConnell MJ, Weiand H, Krook J, Martenson J, Macdonald J, Rich T, Haller D, Mayer R, Gunderson L. Improving adjuvant therapy for rectal cancer by combining protracted infusion fluorouracil with radiation tharapy after curative surgery. N Engl J Med 1994;331: 502-507 Tomudex (ZD1694): results of a randomized trial in Thymidylate Synthease inhibition, dead end?. Eur J Cancer 1995 Nov;31 (12):1945-54 Herrmann R. Tomudex (ZD1694): results of a randomised trial in Thymidylate synthase inhibition, a dead end?. Eur J Cancer 1995 No;31A(12):1919-20 Gonzalez-Baron M, eliu j, de la gandara I, Espinosa E, Colmenarejo A, MartinezMartinez B, Blanco E, Garcia-Giron C, Juarez F, Garrido P,etal. Efficacy of oral tegafur modulation by uracil and leucovorin in advanced colorectal cancer. A phase II Study. And their role in the treatment of colorectal cancer. Eur J Cancer 1998 Feb;34(3):296-306 M.M. Kemeny, S. Adak, S. Lipsitz, B. Gray, J. MacDonald, AB Benson III. Suny Stony Brook, Stony Brook, NY; ECOG Statistics Center, Boston, Mass; Royal Perth Hospital, Perth, Aus; St. Vincents Hospital, NYC, Northwestern U Medical Center, Chicago, IL. Results of the Intergroup [Eastern Coopertive Oncology Group (ECOG) and Southwest Oncology Group (SWOG)] Prospective Randomized Study of Surgery Alone versus Continuous hepatic Artery Infusion of FUDR and Liver Metastases. PROC AM SOC CLIN ONCOL , 1012; B. N. Kemeny, A. Cohen, Y. Huang, W. Shi, L. Blumgart, A. Turnbull, D. Sullivan, J. Stockman, Y. Fong. Memorial Sloan-Kettering Cancer Center (MSKCC), NYC, NY. Randomized Study of Hepatic Arterial Infusion (HAI) and Systemic Chemotherapy (SYS) Versus SYS Alone as Adjuvant Therapy After Resection Of Hepatic Metastases From Colorectal Cancer. PROC AM SOC CLIN ONCOL , 1011; (HAI) OConnell MJ, Nagorney DM Bernath AM, Schroeder G, Fitzgibbons RJ, Mailliard JA, Burch P, Bolton JS, olon-Otero G, Krok JE. Sequential inttrahepatic fluorodeoyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver A. Wein, C. Riedel, A. galland, B. Hanke, W. Brueckl, T. Reck, W. Hohenberger, E.G. Hahn. 2 University Erlangen, Surgical Clinic, erlangen, Germany. High Efficacy of Neoadjuvant Chemotherapy (CT) with 5-FU as 24-H-Infusion (INF),

Folinic Acid (FA) and Oxaliplatin in Patients (pts) with Primary Resectable liver Metastases of Colorectal Cancer. PROC AM SOC CLIN ONCOL , 1168; Punt CJ; New drugs in the treatment of colorectal carcinoma; Cancer 1998 Aug 15:83(4):679-89 Price T, Cunningham D, Hickish T, Tait D, Norman A, Ross P.J, Middleton G, FordH.E.R, Sumpter K. 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Postoperative radiation therapy for incompletely resected colorectal carcinoma. Int J Radiat Oncol Biol Phys 1989;17:1171. Doroshow JH, Multhauf P, Leong L, Margolin K, Litchfield T, Akman S, Carr B, Bertrand M, Goldberg D, Blayney D, Odujinrin O, DeLap R, Shuster J, Newman E. Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol 1990;8:491. Pahlman L, Sjoden PO. Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer. The Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Cancer 1994;73:556562. Sung M. Personal communication, 1986. DeCosse JJ, Cennerazzo WJ. A quality-adjusted time without symptoms or toxicity (Q-Twist) analysis of adjuvant radiation therapy and chemotherapy for resectable rectal cancer. 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1518 SECTION 29 / Neoplasms of the Alimentary Canal

LB Saltz, PK Locker, N Pirotta, GL Elfring, LL Miller. Weekly Irinotecan (CPT-11), Leucovorin (LV), and Fluorouracil (FU) Is Superior to Daily x5 LV/FU in Patients (PTs) with Previously Untreated Metastatic Colorectal Cancer (CRC). Memorial Sloan-Kettering Cancer Center NY, NY, and Pharmacia & UpJohn, Inc, Kalamazoo, MI, for the CPT-11 CRC Study Group. ASCO 898, 1999. Comella P, Catalano G, Casaretti R, De Lucia L, De Vita F, Avallone A, Gravina A, Orditura M, Comis S, Faranda A, Comella G. CPT-11 + 5FU/LFA Biweekly Regimen in Advanced Colorectal Carcinoma (ACC). A Phase I/II Study. Medical Oncology A, Natl. Tumor Inst. Naples; Med Onc,2nd Univ. Naples; Med. Oncol, General Hospital of Caserta. Rhne-Poulenc Rorer, Milan-Italy. ASCO 1078, 1999. JY Douillard, D Cunningham, AD Roth, et al. A Randomized Phase III Trial comparing Irinotecan (IRI) + 5FU/Folinic Acid (FA) to the Same Schedule of 5FU/FA in Patients (pts) with Metastatic Colorectal Cancer (MCRC) as Front Line Chemotherapy (CT). 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10 studies. Liver Infusion Meta-analysis Group J Natl Cancer Inst 1997 Apr 2;89(7):497-505 Bellemare S, Heyen F, Martin G, Dube S [Assessment of the quality of life during adjuvant chemotherapy of colorectal cancer] Ann Chir; 52(8):711-5 1998 UI: 99062849 Sheperd L, Moertel CG, Kocha WI, Pazdur R, Wieand HS, Rubin J, Vukov AM, Donohue JH, Krook JE, Figueredo A Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol; 16(1):295-300 1998 UI: 98101706 Goldberg RM, Hatfield AK, Kahn M, Sargent DJ, Knost JA, O connell MJ, Krook JE, Maillaard JA, Wiesenfeld M, Schaefer pl, Tirona MT, Moertl CG Prospectively randomized North General Cancer Treatment Group trial of intensivecourse fluorouracil combined with the 1-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer, J Clin Oncol; 15(110:3320-9 1997 UI: 98028491 Kemeny N, Huang Y Cohen AM, Shi W, Conti JA, Brennan MF, Bertino JR, Turnbull AD, Sullivan D, Stockman J, Blumgart LH, Fong Y Hepatic arterial infusion of chemotherapy after resection of hepatic metastasis from colorectal cancer. N Engl J Med; 341(270;2039-48 1999 UI: 20061996 Thomas M. Lfler, Cornelia Drge, Torsten-Udo Hausamen. Weekly 24-Hours Infusion Irinotecan (CPT-11) in 5-FU Pretreated Metastatic Colorectal Cancer. Department of Medicine, Div. Of Medical Oncology Stdtische kliniken Dortmund, Dortmund, Germany. ASCO 922, 1999. LB Saltz, PK Locker, N Pirotta, GL Elfring. Weekly Irinotecan (CPT-11), Leucovorin (LV), and Fluorouracil (FU) Is Superior to Daily x5 LV/FU in Patients (PTs) with Previously Untreated Metastatic Colorectal Cancer (CRC). ASCO 898, 1999. Comella P, Catalano G, Casaretti R, De Lucia L, De Vita F, Avallone A, Gravina A, Orditura M, Comis S, Faranda A, Comella G. CPT-11 + 5FU/LFA Biweekly Regimen in Advanced Colorectal Carcinoma (ACC). A Phase I/II Study. Medical Oncology A, Natl. Tumor Inst. Naples; Med Onc,2nd Univ. Naples; Med. Oncol, General Hospital of Caserta. Rhne-Poulenc Rorer, Milan-Italy. ASCO 1078, 1999. JY Douillard, D Cunningham, AD Roth,et al. A Randomized Phase III Trial comparing Irinotecan (IRI) + 5FU/Folinic Acid (FA) to the Same Schedule of 5FU/FA in Patients (pts) with Metastatic Colorectal Cancer (MCRC) as Front Line Chemotherapy (CT). ASCO 899, 1999. IG Ron, NE Kemeny, B Tong, D Sullivan, Y Fong, L Saltz, P Paty. Phase I/II Study of Escalating Doses of Systemic Irinotecan (CPT-11) with Hepatic Arterial Infusion of Floxurdine (FUDR) and Dexamethasone (D), with or Without Cryosurgery for Patients with Unresectable hepatic Metastases from Colorectal Cancer. Memorial Sloan-Kettering Cancer Center, New York, NY. ASCO 908, 1999. Kemeny N, Conti JA, Cohen A, Campana P, Huang Y, Shi WJ, Botet J, Pulliam S, Bertino JR. Phase II study of hepatic arterial flozuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma. J Clin Oncol 1994 Nov;12(11):2288-95. C. Zanon, M. Grosso, S. Miraglia, R. Clara, I. Chiappino, R. Martinotti, D. Ottaviani, L. Evangelists, S. Zai, M. Bortolini, E. Milani and O. Alabiso. Miniinvasive Access to Perform Hepatic Arterial Infusion (HAI) for Colorectal Liver Metastasis. Oncology Dept., Molinette Hosp, Turin and *Oncology Dept. Univ Piemonte Orientale, Novara, Italy. ASCO 1180, 1999. Mehmet S. Copur, A. Matamoros, M. Capadano, T. Goertzen, T. McCowan, R.Brand, J.C. Lynch, M. Tempero. Alternating Hepatic Arterial Infusion and Systemic Chemotherapy for Liver Metastases from colorectal Cancer: A Phase II Trial Using Intermittent Percutaneous Hepatic Arterial Access. University of Nebraska Medical Center, Omaha, NE. ASCO 955, 1999. ASK Durrani, A Benhammouda, MA Gil-Delgado, F Guinet, D Castaing, R Adams, EC Antoine, D Coeffic, H Bismuth, D Khayat. ombination of Irinotecan with Leucovorin and 5-FU in Advanced Colorectal Carcinoma-A Phase II Study. (1) Salpetriere Hospital, SOMPS, Paris, France, (2) Paul Brousse Hospital, CHB, Villejuif, France. ASCO 1083, 1999.