Etiology
The essential element of the etiology of colorectal cancer is a process of genetic change in the epithelial cells of the colonic mucosa.[ref: 16] These changes are discussed more fully in the Chapter 33.1 that address the molecular biology of this disease. Epidemiologic factors have provided initial evidence about the specific factors that initiate the process of carcinogenesis in the large bowel mucosa.[ref: 17] Chief among the factors that can initiate colorectal cancer development are a predisposition to mutagen effects, fecal mutagens, meat intake, bile acids, altered vitamin and mineral intake, and fecal pH.
Predisposition to Mutagen Effects
There is an interaction between mutagen exposure and genetic constitution. Metabolic pathways may be altered by polymorphisms in genes responsible for detoxifying mutagens. [ref: 18] Protection from the effects of mutagen-induced DNA damage is achieved by a range of detoxification enzymes. Examples are reduced glutathione S-transferase (GSH transferase), DT-diaphorase, and N-acetyltransferase. [ref: 19] Differences among individuals can account for susceptibility to mutagens from the diet. An example is a polymorphism in N- acetyltransferase, an enzyme that catalyzes the formation of mutagenic products from heterocyclic amines, which can play a role in colorectal cancer development.[ref: 20] Heterocyclic amines are substances formed in cooked meats. Differences in N-acetyltransferase activity classify individuals as slow or fast acetylators. Risk for colorectal cancer development increases with the level of red meat consumption in fast acetylators but not in slow acetylators. [ref: 21] Individuals with risk factors for colorectal cancer have significantly lower levels of GSH transferase activity in their blood lymphocytes.[ref: 22] Strategies to enhance the expression of detoxifying enzymes are available. [ref: 23]
Fecal Mutagens
Mutagenic compounds such as fecapentaenes, 3-ketosteroids, and heterocyclic amines in the stool may be produced by the interaction of digestion and food products. [ref: 24] These compounds produce reactive molecules that may form bulky adducts to DNA. One of the chief influences of diet is the production of fecal mutagens by certain diets. Changes in the fecal microflora indicate that changes in diet may alter mutagenic activity by altering extracellular superoxide formation.[ref: 25] For instance, a change in a lactovegetarian diet to a diet with increased fiber intake caused a dilution of mitogenic activity within the stool. [ref: 26] Other factors may moderate the effects of fecal mutagens. Intake of antioxidants reduces the mutagenicity of compounds in the stool. Changes in intestinal transit time owing to fiber intake affects the exposure of the mucosa to mutagens. In addition to mutagenic compounds such as fecapentaenes, the presence of other products of digestion such as 3-ketosteroids, which are products of cholesterol metabolism, may act as tumor promoters or initiators.
Meat Intake
Armstrong and Doll (1975) described the high correlation of meat intake and mortality from colorectal cancer. Among the risk factors are the intake of red meats and the compounds that result from cooking meats at high temperatures. [ref: 27] In a study of meat preparation, it was observed that the association between red meat and colorectal cancer could be due to heterocyclic amines present in cooked meat. [ref: 28] This mechanism has been implicated in the high incidence of colorectal cancer in New Zealand. [ref: 29] The method of red meat preparation and frequency of intake can be correlated with the prevalence of distal colorectal adenomas. Subjects who ate browned, fried red meat more than once per week had an OR of 2.2 for distal colorectal adenomas, as compared with those who ate lightly browned red meat one time or less per week. [ref: 30] In Western countries, fried meat is the main source of exposure to heterocyclic amines. Nurses who consumed the highest ratio of red meat to white meat had a higher relative risk (RR) of colon cancer (OR 2.49, P <.001). [ref: 31]
Bile Acids
Normal bile acids that are related to the digestion of fat can induce intestinal mucosal hyperproliferation, which acts as a marker for neoplasia risk. [ref: 32] The presence of bile acids correlates with fat consumption, which is a known risk factor for colorectal cancer.[ref: 33] Bile acids have been shown to activate AP-1, a transcription factor associated with the promotion of neoplastic transformation in colonic cells. [ref: 34] They are also able to induce apoptosis, and variations in the epithelial apoptotic response to bile acids may correlate with risk. [ref: 35] Cholecystectomy can result in high levels of bile acids in the cecum and ascending colon and appears to increase the frequency of right-sided carcinoma. In a retrospective study of colorectal cancer patients, it was found that levels of the secondary bile acid deoxycholic acid were higher than normal and that the ratio between deoxycholic acid and cholic acid may be an indicator of risk. [ref: 36]

Clinical Trials and Future Directions Clinical trials have established combined-modality therapy as the treatment of choice in the postoperative adjuvant treatment of high-risk rectal cancer. [ref: 35,98,133] The most favorable results have been achieved with the use of continuous-infusion 5-FU during external-beam irradiation. [ref: 133] A recently completed randomized study was designed to test the potential benefit of leucovorin and levamisole as modulators of 5-FU when used with radiation therapy in the adjuvant treatment of rectal cancer. The initial results of this study are expected soon. The current national intergroup study is designed to assess further the value of leucovorin and levamisole as modulators of 5-FU and also to test the value of adding preirradiation and postirradiation protracted venous 5-FU infusion to the current standard regimen, in which protracted venous 5-FU infusion is used only during radiation therapy. [ref: 133] A second randomized intergroup study designed to compare preoperative and postoperative adjuvant radiation therapy and chemotherapy in patients with T3-4 rectal cancer is currently under way. This important clinical trial will provide the first scientific comparison of neoadjuvant (preoperative) versus adjuvant (postoperative) treatment of rectal cancer. One of the most important recent advances in the field of oncology resulted from a randomized clinical trial that demonstrated that node-positive patients with completely resected colon cancer experienced improved survival when treated with adjuvant 5-FU and levamisole. [ref: 123] A current randomized clinical trial is attempting to build on these results by comparing 5-FU plus levamisole and radiation therapy versus 5-FU plus levamisole without radiation therapy in selected patients with resected colon cancer at high risk for local recurrence after surgical resection. Although results of treatment with IORT in patients with locally advanced rectal cancer suggest a possible improvement in outcome, scientific evidence is lacking. A European trial in which patients with locally advanced rectal cancer will be randomly assigned to receive or not to receive IORT is being planned and should provide definitive information as to whether this aggressive form of treatment is of value.

External Radiation Therapy A shrinking-field technique should be used, with initial radiation therapy fields designed to treat the primary tumor volume and regional lymph nodes. Smaller fields then can be used to treat the primary tumor bed to higher doses, as clinically indicated. The width of posteroanterior (PA) portals (Fig. 54-3A and Fig. 54-3B) should cover the pelvic inlet with a 2-cm margin. The superior margin is usually 1.5 cm above the level of the sacral promontory. In patients who have had an anterior resection, the usual inferior margin is below the obturator foramina. If the pelvis is treated, lateral fields should be used for a portion of treatment to avoid as much small bowel as possible. Bladder distention and prone position are useful techniques for displacing the small bowel out of the pelvis. The posterior field margin for lateral fields is critical because the rectum and perirectal tissues lie just anterior to the sacrum and coccyx. Accordingly, the posterior field margin should be at least 1.5 to 2 cm behind the anterior bony sacral margin (Fig. 54-3A, Fig. 54-3B and Fig. 54-4). The entire sacral canal should be included in patients with locally advanced disease to avoid sacral recurrence from tumor spread along nerve roots (Fig. 54-5). In patients with rectal cancer, internal iliac and presacral nodes are at risk for metastatic involvement. These lymph node chains are not a standard part of the dissection for rectal cancer. Accordingly, they should be included in the initial radiation therapy volume treated to 45 Gy. External iliac nodes are not a primary lymph node drainage site and are not included unless pelvic organs with external iliac drainage (i.e., prostate, upper vagina, bladder, uterus) are involved by direct extension. Irradiation of the perineum after abdominoperineal resection appears to be effective in decreasing the rate of perineal recurrence. In surgical series, the risk of perineal recurrence after abdominoperineal resection ranges from 8% to 30%. At the Mayo Clinic, the perineal failure rate was 2% at 5 years for patients undergoing postoperative adjuvant radiation therapy for whom the perineum was included within the radiation therapy field for the initial 40 Gy. In contrast, if the entire perineum was not treated, the perineal failure rate was 23% at 5 years (P = 0.01). Although these results were not drawn from a randomized trial, multivariate analysis showed that perineal treatment with radiation was the only significant factor associated with perineal failure. Temporary, acute, moderate to moderately severe perineal discomfort occurs in all patients whose perineums are included within irradiation fields. This can be mitigated with the use of a three-field technique (PA and laterals, with wedges on the laterals, heels posterior). The incidence of chronic complications has not increased as a result of perineal inclusion. Radiopaque markers can be used to outline the extent of the perineal scar at the time of simulation for posterior and lateral fields (Fig. 54-6). Anteriorly, the lower third of the rectum abuts the posterior vaginal wall or prostate, and these structures should be included in patients with distal lesions. In female patients, this can be verified by placing a contrast-soaked tampon in the vagina during radiation therapy simulation. Bolus applied to the perineal scar during the PA treatment ensures adequate dosage to this site. The dose to the large fields, which include the tumor bed and regional lymph nodes, should be 45 Gy given over 5 weeks. After this, the use of a boost field to the primary tumor bed and immediately adjacent lymph nodes should be considered. Boost fields are defined by methods such as barium enema studies, CT scan, and clip placement. Doses greater than 50.4 Gy generally should not be administered unless there is complete shift of the small bowel out of the final boost field. If radiation therapy is used for locally advanced extrapelvic colon cancer, the tumor bed should be covered with a 3- to 5-cm margin. Adjuvant radiation therapy for colon cancer should not be given except in the context of a formal prospective clinical trial. Sphincter Preservation Endocavitary Radiation Therapy Endocavitary radiation therapy produces high rates of local control and long-term survival in appropriately selected patients with rectal cancer. The indications for this technique have been described by Papillon (Table 54-4). In assessing the suitability of a patient for this technique, intrarectal ultrasonography is helpful to determining tumor confinement to the rectal wall. The treatment is performed on an outpatient basis. Local anesthesia in the anal canal occasionally is necessary for introducing the 3-cm-diameter applicator into the rectum. The radiation oncologist verifies the position of the applicator and coverage of the lesion. A lead apron and gloves are worn by the radiation oncologist, who holds the applicator firmly in place during the x-ray exposure. The treatment regimen usually consists of four 30-Gy treatments separated by intervals of approximately 2 weeks. A short-focal-distance (contact) x-ray unit is used at 50 kVp at a dose rate of approximately 10 Gy per minute. If the size of the tumor exceeds the diameter of the applicator, several overlapping fields must be used. Most reports indicate that endocavitary radiation therapy for rectal cancer results in high rates of disease control. For 207 patients treated by Papillon [ref: 136] with 5-year follow-up, the locoregional failure rate was 11%. Overall, 11% of the patients died of cancer and 13% died of intercurrent disease. Distant metastasis was found in only 3% of all patients. In the largest experience in the United States, Sischy and colleagues [ref: 167] reported similar excellent results. At the Cleveland Clinic, 62 patients were treated between 1973 and 1984; the median follow-up was 30 months. [ref: 101] Local recurrence developed in 11 patients (18%). In 3 of these 11, local recurrence was associated with distant metastasis. The other 8 patients were rendered disease free by other treatment at a median of 20 months after recurrence. Only 3 patients in the entire series died of cancer. Similar favorable results with endocavitary irradiation have been reported from the Mayo Clinic, where the projected local control rate at 5 years was 89% among 20 patients treated with curative intent. Local Excision With or Without Postoperative Radiation Therapy In 1961, Jackman reported results in 211 patients with rectal cancer treated with sphincter-sparing procedures. With follow-up ranging from 8 to 18 years, 8 patients (4%) experienced local recurrence. A later report described 234 patients treated mostly with local excision. [ref: 13] Forty-nine (21%) subsequently had local recurrence. The 5-year probability of local recurrence was approximately 11% for patients with in situ disease and 27% for patients with invasive disease. Hager and associates described results of local excision of cancer of the rectum in 95 patients. Fifty-nine low-risk patients, who had a wide margin of healthy tissue at the time of local excision, were divided into those with invasion of tumor into the submucosa (group 1) and those with invasion into the muscularis propria (group 2). Local recurrence was observed in 3 (8%) of 39 patients in group 1 and 3 (15%) of 20 patients in group 2. The 5-year survival rate was 90% in group 1 and 58% in group 2. These data strongly suggest that patients with early lesions with minimal invasion (i.e., those similar to patients in group 1) may be treated successfully with surgery alone without the use of further adjuvant therapy. Thirty-six percent of patients were considered high risk, as defined by incomplete removal of tumor; at a median follow-up of 45 months, 24% had experienced local progression, and 39% had died of cancer. It is clear that there is a wide range in incidence of local recurrence after limited surgical procedures for rectal cancer. Interpretation of the data is made difficult by the variation in selection criteria. To minimize local recurrence, postoperative radiation therapy has been used at some institutions. Rich and colleagues described results of treating 17 patients by limited surgery and postoperative radiation therapy. With a short median follow-up of 26 months in surviving patients, 1 (6%) had local failure. In another study, the local failure rate was 21% after local excision and postoperative radiation therapy. These results are not clearly better than those that may have been expected with local excision alone. In the absence of randomized studies, it is not possible to clearly identify which patients, if any, may benefit from postoperative adjuvant treatment after local excision. Results of Therapy Rectal Cancer Preoperative Irradiation Low-dose preoperative irradiation using 5 Gy in 1 fraction to 25 Gy in 10 fractions has been compared with surgery alone in several randomized prospective trials. None of these studies showed improved survival with preoperative radiation therapy (Fig. 54-7). Retrospective subgroup analysis did suggest a possible effect of preoperative treatment in two of these trials. In the Princess Margaret trial, patients with rectal cancer were randomly assigned to receive surgery either alone or with preoperative radiation therapy of 5 Gy given in one fraction. Although survival for all patients in the trial was virtually identical (Fig. 54-7), retrospective subgroup analysis of patients with Dukes' stage C cancer suggested a survival advantage for preoperatively irradiated patients. Based on this observation, the authors recommended that "this form of preoperative irradiation become routine." This conclusion is not justified for several reasons. If, for the entire group of patients, survival was virtually identical in the two groups, an apparent positive impact of preoperative irradiation on survival in some subgroups must be balanced by an apparent negative impact in other groups. Unfortunately, analysis of subgroups complementary to the Dukes' stage C patients was not presented. Moreover, no reliable technique is currently available to identify Dukes' stage C patients preoperatively. Although useful for generating hypotheses, retrospective subgroup analysis is generally an invalid statistical technique for reaching conclusions about treatment efficacy. The Veterans Administration study group found better survival among preoperatively irradiated patients (20 to 25 Gy) who underwent abdominoperineal resection. The hazard of retrospective subgroup analysis is illustrated by a later Veterans Administration trial, which strongly suggested that the original evaluation favoring the preoperatively irradiated patients resulted from an imbalance in prognostic factors rather than from any effect of treatment. Analysis of a trial conducted by the Stockholm Rectal Cancer Study Group suggested a clinically measurable effect of low-dose preoperative radiation therapy at high dose per fraction, when compared with surgery alone. In this trial, the patients were randomly assigned to receive 25 Gy in five fractions preoperatively or to receive surgery alone. Survival rates through 5 years of follow-up were virtually identical. Postoperative mortality was 8% in the preoperatively irradiated patients and only 2% in patients treated with surgery alone (P < 0.01). Among the patients who underwent curative surgery, the incidence of pelvic recurrence at 5 years was approximately 18% in the preoperatively irradiated group and approximately 31% in the surgical control group (P < 0.01). Although preoperative radiation therapy, as used in this study, appeared to provide improved local control, the overall benefit to patients was questionable in view of the lack of survival benefit and increased morbidity seen with the preoperative regimen. The most recent test of the value of low-dose preoperative radiation therapy was a Radiation Therapy Oncology Group (RTOG) trial in which patients with rectal cancer initially were randomly assigned to receive either 5 Gy preoperatively or immediate surgery. After surgery, all patients in both arms who were found to have tumor penetration beyond the rectal wall or involved nodes received 45 Gy to the pelvis. No differences in local recurrence, survival, or freedom from distant metastases were found between the two groups. In view of these data, low-dose preoperative radiation therapy should no longer be used in patients with rectal cancer. Retrospective studies suggest that higher doses of preoperative radiation therapy may be associated with improved survival and decreased pelvic recurrence. Moderate doses (30 to 40 Gy) of preoperative radiation therapy have been formally tested in several randomized prospective trials. At the Rotterdamsch Radio-Therapeutisch, patients with rectal cancer were randomly assigned to preoperative irradiation (34.5 Gy in 15 fractions to a pelvic and paraaortic field) or to operation alone. Freedom from local recurrence and survival were not significantly different in patients with T2 lesions. For patients with clinical evidence of T3 or T4 disease, 97% of those in the preoperative radiation therapy group subsequently had potentially curative resections, compared with only 68% in the operation-only group (P < 0.05). Irradiated patients with T3 or T4 tumors also had better 5-year rates of survival (P< 0.005) and freedom from local recurrence (P = 0.08). A larger randomized trial, using the same preoperative dose-fractionation scheme and field design, was conducted by the European Organization for Research and Treatment of Cancer. Although local recurrence was significantly lower among patients given preoperative radiation therapy (Fig. 54-8, A), survival was not affected (Fig. 54-8, B). In the second randomized trial of neoadjuvant radiation therapy conducted by the Veterans Administration Surgical Oncology Group, a preoperative dose of 31.5 Gy in 18 fractions to a pelvic and paraaortic field was compared with surgery alone in patients with rectal cancer. The 5-year survival rate was 50% in both arms of the study. Overall recurrence (distant and local) was also virtually identical, although a detailed analysis of patterns of failure was not reported. No benefit from low-dose preoperative radiation therapy has been observed in randomized prospective studies. Most randomized studies with higher doses of preoperative radiation suggest better local tumor control but not improved survival. Postoperative Adjuvant Therapy The advantage of postoperative adjuvant therapy of rectal cancer is that it allows consideration of pathologic factors in the selection of patients for this treatment. In trials of preoperative radiation therapy, 22% to 37% of patients randomly assigned to surgery alone had tumors that were limited to the bowel wall and therefore were at low risk for recurrence. [ref: 24,127,153] An additional 8% to 14% were found to have distant metastasis at surgery. [ref: 24,53,127,153] A postoperative approach allows the physician to use pathologic information to exclude 30% to 50% of patients who are unlikely to benefit from adjuvant therapy. A retrospective comparison of adjuvant postoperative irradiation with surgery alone in patients at high risk for local recurrence was performed at Massachusetts General Hospital. [ref: 78] For patients with gross extension of tumor beyond the rectal wall, metastatically involved lymph nodes, or both, the incidence of local failure was lower after postoperative adjuvant radiation therapy. Other retrospective studies suggested that local failure could be decreased by as much as 20% with the use of postoperative radiation therapy after resection of modified Astler-Coller B2-B3 and C1-C3 (equivalent to T3-4 or node-positive) tumors. [ref: 19,55,78,161,176,192] However, results from these retrospective studies have not been consistently corroborated by prospective studies. In an RTOG study, for example, patients with tumors that penetrated the rectal wall and those with positive nodes received postoperative radiation therapy to a dose of 45 Gy. The rate of local recurrence was 31% among patients who received 5-Gy preoperative radiation therapy and 34% among those who did not. [ref: 159] The 31% to 34% rate of local recurrence is not different from what would have been expected without the use of adjuvant therapy. In a study from the National Surgical Adjuvant Bowel and Breast Project, there was a modest nonsignificant difference in patients who were treated with postoperative radiation therapy, compared with surgery alone (16% and 25% local recurrence, P = 0.06). [ref: 44] Two separate randomized studies of postoperative radiation therapy (50 Gy) versus no adjuvant treatment in patients at high risk for local recurrence also failed to demonstrate a significant benefit for either local control or survival among patients who received postoperative radiation therapy. [ref: 11,173] Although results of adjuvant postoperative radiation therapy without chemotherapy have been disappointing, randomized prospective clinical trials have provided scientific evidence that improved survival and local tumor control after combined adjuvant postoperative radiation therapy and chemotherapy can be achieved in patients with T3-4 or node-positive tumors. The Gastrointestinal Tumor Study Group randomly assigned patients postoperatively to four groups: no further therapy; methyl-CCNU and 5-FU; pelvic radiation therapy (40 to 48 Gy); or pelvic radiation therapy (40 to 44 Gy), methyl-CCNU, and 5-FU. [ref: 50] Overall survival was significantly better among patients receiving chemotherapy plus irradiation than among those who had no adjuvant therapy. [ref: 35] Local recurrence rates were 24% in control patients, 27% in chemotherapy patients, 20% in irradiated patients, and 11% in patients who received the combination therapy. The results of this study suggest that both chemotherapy and radiation therapy are required for adjuvant treatment to have a favorable impact on local control; neither modality alone had a significant impact on local control. The value of adjuvant postoperative radiation therapy and chemotherapy in T3-4 and node-positive patients was confirmed by a randomized North Central Cancer Treatment Group (NCCTG) study. After complete surgical resection, the patients were randomly assigned to receive either postoperative pelvic radiation therapy or sequential postoperative chemotherapy (methyl-CCNU and 5-FU) and pelvic radiation therapy. Disease-free survival, overall survival, freedom from local recurrence, and freedom from distant recurrence were significantly improved in patients who received radiation therapy and chemotherapy. [ref: 98] The results of the Gastrointestinal Study Group and the NCCTG trials provided clear evidence that a combination of adjuvant postoperative chemotherapy and radiation therapy improves local control and survival in high-risk rectal cancer patients who have undergone complete surgical resection. A subsequent randomized NCCTG trial was undertaken to assess the contribution of the relatively toxic drug methyl-CCNU [ref: 16] to adjuvant therapy and to determine whether continuous infusion of 5-FU during radiation therapy resulted in better outcome than bolus administration of 5-FU. An improvement in survival (Fig. 54-9) was observed in patients who received continuous-infusion 5-FU [ref: 133]; details of the regimen are shown in Figure 54-10. Methyl-CCNU did not improve survival. A Gastrointestinal Tumor Study Group randomized study also found that methyl-CCNU did not improve survival. [ref: 51] Methyl-CCNU is no longer used in the adjuvant treatment of rectal cancer. The National Surgical Adjuvant Bowel and Breast Project conducted a clinical trial to assess the contribution of radiation therapy to adjuvant combined-modality treatment. Patients were randomly assigned to receive one of two chemotherapy regimens and either pelvic irradiation or no irradiation. Initial results from this study showed no difference in survival for patients who did or did not receive radiation therapy. The local recurrence rates were 6.7% and 11.3%, respectively (P = 0.045). [ref: 154] Although this difference was particularly in view of the potential toxicity associated with pelvic irradiation. [ref: 94] Longer follow-up is needed to assess definitively the findings of this study. Further clinical trials may be needed to evaluate definitively the contribution of radiation therapy to adjuvant treatment when used in conjunction with modern chemotherapy. Several randomized studies support the use of combined adjuvant postoperative radiation therapy plus chemotherapy in patients with T3-4 and node-positive rectal cancer. Currently, postoperative adjuvant combined-modality therapy is preferable to preoperative radiation therapy on the basis of evidence from randomized prospective studies that have consistently demonstrated a survival benefit for this approach and because a postoperative approach to adjuvant therapy allows exclusion of patients who would achieve little benefit from such treatment. Preoperative radiation therapy should not be used in patients with resectable rectal cancer unless a clear advantage of this approach, relative to postoperative adjuvant treatment, is demonstrated in a randomized clinical trial. Locally Advanced Rectal Cancer External-beam radiation therapy alone or in combination with chemotherapy provides palliation and modest prolongation of life but has only minimal curative potential in patients with locally advanced rectal cancer. At the Mayo Clinic, 65 patients with locally unresectable carcinoma of the large bowel were treated with external-beam radiation therapy (35 to 40 Gy) with or without 5-FU in a randomized prospective study. [ref: 120] Survival free of progression, median duration of symptomatic control, and overall survival were better in patients who received 5-FU and radiation therapy. Several papers have described results of treating patients with postoperative radiation therapy after subtotal resection of large bowel cancer. [ref: 2,19,55,162,181] At the Mayo Clinic, 17 patients received postoperative radiation therapy with doses of 40 to 60 Gy. Local failure was observed in 76% of patients, and the 5-year survival rate was 24%. The minimum follow-up among surviving patients was 5 years. [ref: 162] Other investigators have reported lower local failure rates (15% to 32%) but similar overall survival. [ref: 2,19,55,181] The reason for the wide range of results for local control is not clear but may relate to the manner in which local failure was defined and to the short duration of follow-up in some series. [ref: 162] Preoperative irradiation with doses of 45 Gy or more has been used in patients presenting with unresectable colon and rectal cancer. [ref: 34,39,135,169] Resectability rates after preoperative radiation therapy vary widely, ranging from about 50% to 75%. After resection, local failure occurs in approximately 36% to 45% of patients, so long-term local control is achieved in only 25% to 35% of these patients. Intraoperative radiation therapy (IORT) may improve these results. In most cases, patients who are considered for combined radical operation and IORT are given preoperative chemotherapy and external-beam radiation therapy. Theoretically, preoperative irradiation may provide tumor shrinkage, improve resectability, and potentiate IORT effects. Typically, between 45 and 55 Gy in 1.8-Gy fractions over 5 to 6 weeks is given, often in conjunction with 5-FU-based chemotherapy. After completion of external-beam radiation therapy and a 3- to 5-week recovery period, patients are reevaluated for metastatic disease and prepared for operation. Usually, aggressive surgical resection and IORT are performed only in patients without distant metastases. At operation, exploration is performed initially to detect the presence or absence of metastatic disease. If no evidence of metastatic disease is detected, tumor resection is performed. An attempt is made to perform a complete resection. Areas of suspected or known residual disease are evaluated jointly by the surgeon and the radiation oncologist to determine the feasibility of IORT. Sites of adherence or residual disease are then fitted with a suitably sized translucent cone designed specifically for delivery of the electron beam. The IORT dose is selected according to the amount of disease subsequent to surgical resection and ranges from 10 to 20 Gy. The two largest groups of patients in whom IORT has been used are patients with locally recurrent rectal cancer and those with primary unresectable disease. Details of therapy with external-beam radiation therapy, surgical resection, and IORT at the Mayo Clinic have been reported [ref: 65] and recently have been updated for 116 patients with recurrent colorectal cancer. [ref: 66] At 5 years, the survival rate was 18%, and the local failure rate was 40%. In an analysis of 106 patients treated with palliative surgical resection alone, palliative resection with external radiation therapy, palliative resection with IORT with or without external-beam radiation therapy, or palliative resection with brachytherapy, the use of IORT was associated with significantly improved survival (Fig. 54-11). [ref: 171] These results must be interpreted with caution because they are not from a randomized clinical trial. Prognostic factors that were related significantly to survival included the amount of residual tumor after surgical resection, the use of IORT, the symptomatic status of the patient, the degree of fixation of tumor to surrounding structures, and the performance status of the patient (Table 54-5). Results from patients with a history of pelvic irradiation before local recurrence are less satisfactory. In a Mayo Clinic series, survival at 5 years was only 13%, and local control at 4 years was 34%. [ref: 69] Thirty-nine patients with locally recurrent rectal or rectosigmoid cancer were treated at Massachusetts General Hospital with preoperative external-beam irradiation followed by IORT. [ref: 187] Nine patients did not receive IORT because it was not technically feasible, the tumor was unresectable or metastatic, or the tumor was completely resected with negative margins. For all 39 patients, the 5-year survival rate was 29%, and the disease-free survival rate was 21%. Five-year local control and disease-free survival rates in the 30 patients who received IORT were 26% and 19%, respectively. Local control was related to the degree of surgical resection performed before IORT. Local control was 62% and 18% in patients who had complete and partial resections, respectively. Four patients received no or minimal preoperative irradiation because of a history of prior pelvic irradiation. Of these 4 patients, 3 had local failure; 3 died of cancer and 1 of intercurrent disease. Currently, patients with locally recurrent rectal cancer who have a history of pelvic irradiation are not considered candidates for IORT at the Massachusetts General Hospital. [ref: 187] Twenty-six patients received external-beam radiation therapy and IORT for localized pelvic recurrence of large bowel cancer at Rush-Presbyterian Hospital. [ref: 97] The 3-year relapse-free and overall survival rates were 15% and 25%, respectively. Local failure occurred in 11 of 18 patients with gross disease after surgery and in 4 of 8 patients with microscopic disease. The local failure rate was higher in patients who received external-beam radiation therapy doses of less than 40 Gy (11 of 15 patients, 73%) than in those who received more than 40 Gy (4 of 11 patients, 36%). Like the group at the Massachusetts General Hospital, these investigators no longer use IORT when a full course of external-beam pelvic radiation therapy is not possible. External-beam radiation therapy with IORT has also been used in the treatment of primary locally advanced rectal cancer. [ref: 65,66,186] At the Massachusetts General Hospital, the actuarial overall disease-free survival rate at 5 years was 32% for patients with incompletely resected tumors and 53% for patients treated with adjuvant IORT (i.e., patients with completely resected tumors). Local control at 5 years was 60% for patients who underwent partial surgical resection and 88% for patients who received adjuvant IORT. At the Mayo Clinic, local control and survival rates at 5 years for 56 patients with primary locally advanced disease were 82% and 42%, respectively. [ref: 66]

Although the addition of IORT to external-beam radiation therapy and
surgical resection may result in improved local control and possibly
improved survival, long-term follow-up demonstrates an overall
survival rate of less than 20%. Methods for achieving better local
control and preventing distant metastasis are needed. Modulation of
5-FU activity by levamisole [ref: 113,123] or leucovorin [ref:
40,99,116, 132,139,143] or by specialized delivery methods such as
continuous infusion [ref: 133] may provide improved systemic and local
disease control. Investigation of these and other innovative treatment
methods within the context of prospective clinical trials provides the
best hope for improving outcomes in the future. A randomized clinical
trial is planned in Europe to compare external-beam radiation therapy
with and without IORT in patients with locally recurrent and primary
locally advanced disease. Results from this study should provide a
definitive assessment as to whether IORT should have a continuing role
in the treatment of selected patients with colorectal cancer.

Rectal Cancer

Preoperative Irradiation

Low-dose preoperative irradiation using 5 Gy in 1 fraction to 25 Gy in
10 fractions has been compared with surgery alone in several
randomized prospective trials. [ref: 74,127,153] None of these studies
showed improved survival with preoperative radiation therapy
(Fig. 54-7). Retrospective subgroup analysis did suggest a possible
effect of preoperative treatment in two of these trials. In the
Princess Margaret trial, patients with rectal cancer were randomly
assigned to receive surgery either alone or with preoperative
radiation therapy of 5 Gy given in one fraction. Although survival for
all patients in the trial was virtually identical (Fig. 54-7),
retrospective subgroup analysis of patients with Dukes' stage C cancer
suggested a survival advantage for preoperatively irradiated patients.
Based on this observation, the authors recommended that "this form of
preoperative irradiation become routine." [ref: 153]

This conclusion is not justified for several reasons. If, for the
entire group of patients, survival was virtually identical in the two
groups, an apparent positive impact of preoperative irradiation on
survival in some subgroups must be balanced by an apparent negative
impact in other groups. Unfortunately, analysis of subgroups
complementary to the Dukes' stage C patients was not presented.
Moreover, no reliable technique is currently available to identify
Dukes' stage C patients preoperatively. Although useful for generating
hypotheses, retrospective subgroup analysis is generally an invalid
statistical technique for reaching conclusions about treatment
efficacy. [ref: 52,166] The Veterans Administration study group found
better survival among preoperatively irradiated patients (20 to 25 Gy)
who underwent abdominoperineal resection. [ref: 74] The hazard of
retrospective subgroup analysis is illustrated by a later Veterans
Administration trial, which strongly suggested that the original
evaluation favoring the preoperatively irradiated patients resulted
from an imbalance in prognostic factors rather than from any effect of
treatment. [ref: 75]

Analysis of a trial conducted by the Stockholm Rectal Cancer Study
Group suggested a clinically measurable effect of low-dose
preoperative radiation therapy at high dose per fraction, when
compared with surgery alone. [ref: 23] In this trial, the patients
were randomly assigned to receive 25 Gy in five fractions
preoperatively or to receive surgery alone. Survival rates through 5
years of follow-up were virtually identical. Postoperative mortality
was 8% in the preoperatively irradiated patients and only 2% in
patients treated with surgery alone (P < 0.01). Among the patients who
underwent curative surgery, the incidence of pelvic recurrence at 5
years was approximately 18% in the preoperatively irradiated group and
approximately 31% in the surgical control group (P < 0.01). Although
preoperative radiation therapy, as used in this study, appeared to
provide improved local control, the overall benefit to patients was
questionable in view of the lack of survival benefit and increased
morbidity seen with the preoperative regimen.

The most recent test of the value of low-dose preoperative radiation
therapy was a Radiation Therapy Oncology Group (RTOG) trial in which
patients with rectal cancer initially were randomly assigned to
receive either 5 Gy preoperatively or immediate surgery. After
surgery, all patients in both arms who were found to have tumor
penetration beyond the rectal wall or involved nodes received 45 Gy to
the pelvis. No differences in local recurrence, survival, or freedom
from distant metastases were found between the two groups. [ref: 159]
In view of these data, low-dose preoperative radiation therapy should
no longer be used in patients with rectal cancer.

Retrospective studies suggest that higher doses of preoperative
radiation therapy may be associated with improved survival [ref:
49,92,93,148,169] and decreased pelvic recurrence. [ref:
48,148,169,170] Moderate doses (30 to 40 Gy) of preoperative radiation
therapy have been formally tested in several randomized prospective
trials.

At the Rotterdamsch Radio-Therapeutisch, patients with rectal cancer
were randomly assigned to preoperative irradiation (34.5 Gy in 15
fractions to a pelvic and paraaortic field) or to operation alone.
[ref: 17] Freedom from local recurrence and survival were not
significantly different in patients with T2 lesions. For patients with
clinical evidence of T3 or T4 disease, 97% of those in the
preoperative radiation therapy group subsequently had potentially
curative resections, compared with only 68% in the operation-only
group (P < 0.05). Irradiated patients with T3 or T4 tumors also had
better 5-year rates of survival (P< 0.005) and freedom from local
recurrence (P = 0.08).

A larger randomized trial, using the same preoperative
dose-fractionation scheme and field design, was conducted by the
European Organization for Research and Treatment of Cancer. [ref: 54]
Although local recurrence was significantly lower among patients given
preoperative radiation therapy (Fig. 54-8, A), survival was not
affected (Fig. 54-8, B).

In the second randomized trial of neoadjuvant radiation therapy
conducted by the Veterans Administration Surgical Oncology Group, a
preoperative dose of 31.5 Gy in 18 fractions to a pelvic and
paraaortic field was compared with surgery alone in patients with
rectal cancer. [ref: 75] The 5-year survival rate was 50% in both arms
of the study. Overall recurrence (distant and local) was also
virtually identical, although a detailed analysis of patterns of
failure was not reported.

No benefit from low-dose preoperative radiation therapy has been
observed in randomized prospective studies. Most randomized studies
with higher doses of preoperative radiation suggest better local tumor
control but not improved survival.

Postoperative Adjuvant Therapy

The advantage of postoperative adjuvant therapy of rectal cancer is
that it allows consideration of pathologic factors in the selection of
patients for this treatment. In trials of preoperative radiation
therapy, 22% to 37% of patients randomly assigned to surgery alone had
tumors that were limited to the bowel wall and therefore were at low
risk for recurrence. [ref: 24,127,153] An additional 8% to 14% were
found to have distant metastasis at surgery. [ref: 24,53,127,153] A
postoperative approach allows the physician to use pathologic
information to exclude 30% to 50% of patients who are unlikely to
benefit from adjuvant therapy.

A retrospective comparison of adjuvant postoperative irradiation with
surgery alone in patients at high risk for local recurrence was
performed at Massachusetts General Hospital. [ref: 78] For patients
with gross extension of tumor beyond the rectal wall, metastatically
involved lymph nodes, or both, the incidence of local failure was
lower after postoperative adjuvant radiation therapy. Other
retrospective studies suggested that local failure could be decreased
by as much as 20% with the use of postoperative radiation therapy
after resection of modified Astler-Coller B2-B3 and C1-C3 (equivalent
to T3-4 or node-positive) tumors. [ref: 19,55,78,161,176,192] However,
results from these retrospective studies have not been consistently
corroborated by prospective studies. In an RTOG study, for example,
patients with tumors that penetrated the rectal wall and those with
positive nodes received postoperative radiation therapy to a dose of
45 Gy. The rate of local recurrence was 31% among patients who
received 5-Gy preoperative radiation therapy and 34% among those who
did not. [ref: 159] The 31% to 34% rate of local recurrence is not
different from what would have been expected without the use of
adjuvant therapy. In a study from the National Surgical Adjuvant Bowel
and Breast Project, there was a modest nonsignificant difference in
patients who were treated with postoperative radiation therapy,
compared with surgery alone (16% and 25% local recurrence, P = 0.06).
[ref: 44] Two separate randomized studies of postoperative radiation
therapy (50 Gy) versus no adjuvant treatment in patients at high risk
for local recurrence also failed to demonstrate a significant benefit
for either local control or survival among patients who received
postoperative radiation therapy. [ref: 11,173]

Although results of adjuvant postoperative radiation therapy without
chemotherapy have been disappointing, randomized prospective clinical
trials have provided scientific evidence that improved survival and
local tumor control after combined adjuvant postoperative radiation
therapy and chemotherapy can be achieved in patients with T3-4 or
node-positive tumors. The Gastrointestinal Tumor Study Group randomly
assigned patients postoperatively to four groups: no further therapy;
methyl-CCNU and 5-FU; pelvic radiation therapy (40 to 48 Gy); or
pelvic radiation therapy (40 to 44 Gy), methyl-CCNU, and 5-FU. [ref:
50] Overall survival was significantly better among patients receiving
chemotherapy plus irradiation than among those who had no adjuvant
therapy. [ref: 35] Local recurrence rates were 24% in control
patients, 27% in chemotherapy patients, 20% in irradiated patients,
and 11% in patients who received the combination therapy. The results
of this study suggest that both chemotherapy and radiation therapy are
required for adjuvant treatment to have a favorable impact on local
control; neither modality alone had a significant impact on local
control.

The value of adjuvant postoperative radiation therapy and chemotherapy
in T3-4 and node-positive patients was confirmed by a randomized North
Central Cancer Treatment Group (NCCTG) study. After complete surgical
resection, the patients were randomly assigned to receive either
postoperative pelvic radiation therapy or sequential postoperative
chemotherapy (methyl-CCNU and 5-FU) and pelvic radiation therapy.
Disease-free survival, overall survival, freedom from local
recurrence, and freedom from distant recurrence were significantly
improved in patients who received radiation therapy and chemotherapy.
[ref: 98]

The results of the Gastrointestinal Study Group and the NCCTG trials
provided clear evidence that a combination of adjuvant postoperative
chemotherapy and radiation therapy improves local control and survival
in high-risk rectal cancer patients who have undergone complete
surgical resection. A subsequent randomized NCCTG trial was undertaken
to assess the contribution of the relatively toxic drug methyl-CCNU
[ref: 16] to adjuvant therapy and to determine whether continuous
infusion of 5-FU during radiation therapy resulted in better outcome
than bolus administration of 5-FU. An improvement in survival
(Fig. 54-9) was observed in patients who received continuous-infusion
5-FU [ref: 133]; details of the regimen are shown in Figure 54-10.
Methyl-CCNU did not improve survival. A Gastrointestinal Tumor Study
Group randomized study also found that methyl-CCNU did not improve
survival. [ref: 51] Methyl-CCNU is no longer used in the adjuvant
treatment of rectal cancer.

The National Surgical Adjuvant Bowel and Breast Project conducted a
clinical trial to assess the contribution of radiation therapy to
adjuvant combined-modality treatment. Patients were randomly assigned
to receive one of two chemotherapy regimens and either pelvic
irradiation or no irradiation. Initial results from this study showed
no difference in survival for patients who did or did not receive
radiation therapy. The local recurrence rates were 6.7% and 11.3%,
respectively (P = 0.045). [ref: 154] Although this difference was
particularly in view of the potential toxicity associated with pelvic
irradiation. [ref: 94] Longer follow-up is needed to assess
definitively the findings of this study. Further clinical trials may
be needed to evaluate definitively the contribution of radiation
therapy to adjuvant treatment when used in conjunction with modern
chemotherapy.

Several randomized studies support the use of combined adjuvant
postoperative radiation therapy plus chemotherapy in patients with
T3-4 and node-positive rectal cancer. Currently, postoperative
adjuvant combined-modality therapy is preferable to preoperative
radiation therapy on the basis of evidence from randomized prospective
studies that have consistently demonstrated a survival benefit for
this approach and because a postoperative approach to adjuvant therapy
allows exclusion of patients who would achieve little benefit from
such treatment. Preoperative radiation therapy should not be used in
patients with resectable rectal cancer unless a clear advantage of
this approach, relative to postoperative adjuvant treatment, is
demonstrated in a randomized clinical trial.

Locally Advanced Rectal Cancer

External-beam radiation therapy alone or in combination with
chemotherapy provides palliation and modest prolongation of life but
has only minimal curative potential in patients with locally advanced
rectal cancer. At the Mayo Clinic, 65 patients with locally
unresectable carcinoma of the large bowel were treated with
external-beam radiation therapy (35 to 40 Gy) with or without 5-FU in
a randomized prospective study. [ref: 120] Survival free of
progression, median duration of symptomatic control, and overall
survival were better in patients who received 5-FU and radiation
therapy.

Several papers have described results of treating patients with
postoperative radiation therapy after subtotal resection of large
bowel cancer. [ref: 2,19,55,162,181] At the Mayo Clinic, 17 patients
received postoperative radiation therapy with doses of 40 to 60 Gy.
Local failure was observed in 76% of patients, and the 5-year survival
rate was 24%. The minimum follow-up among surviving patients was 5
years. [ref: 162] Other investigators have reported lower local
failure rates (15% to 32%) but similar overall survival. [ref:
2,19,55,181] The reason for the wide range of results for local
control is not clear but may relate to the manner in which local
failure was defined and to the short duration of follow-up in some
series. [ref: 162]

Preoperative irradiation with doses of 45 Gy or more has been used in
patients presenting with unresectable colon and rectal cancer. [ref:
34,39,135,169] Resectability rates after preoperative radiation
therapy vary widely, ranging from about 50% to 75%. After resection,
local failure occurs in approximately 36% to 45% of patients, so
long-term local control is achieved in only 25% to 35% of these
patients. Intraoperative radiation therapy (IORT) may improve these
results.

In most cases, patients who are considered for combined radical
operation and IORT are given preoperative chemotherapy and
external-beam radiation therapy. Theoretically, preoperative
irradiation may provide tumor shrinkage, improve resectability, and
potentiate IORT effects. Typically, between 45 and 55 Gy in 1.8-Gy
fractions over 5 to 6 weeks is given, often in conjunction with
5-FU-based chemotherapy. After completion of external-beam radiation
therapy and a 3- to 5-week recovery period, patients are reevaluated
for metastatic disease and prepared for operation. Usually, aggressive
surgical resection and IORT are performed only in patients without
distant metastases.

At operation, exploration is performed initially to detect the
presence or absence of metastatic disease. If no evidence of
metastatic disease is detected, tumor resection is performed. An
attempt is made to perform a complete resection. Areas of suspected or
known residual disease are evaluated jointly by the surgeon and the
radiation oncologist to determine the feasibility of IORT. Sites of
adherence or residual disease are then fitted with a suitably sized
translucent cone designed specifically for delivery of the electron
beam. The IORT dose is selected according to the amount of disease
subsequent to surgical resection and ranges from 10 to 20 Gy. The two
largest groups of patients in whom IORT has been used are patients
with locally recurrent rectal cancer and those with primary
unresectable disease.

Details of therapy with external-beam radiation therapy, surgical
resection, and IORT at the Mayo Clinic have been reported [ref: 65]
and recently have been updated for 116 patients with recurrent
colorectal cancer. [ref: 66] At 5 years, the survival rate was 18%,
and the local failure rate was 40%. In an analysis of 106 patients
treated with palliative surgical resection alone, palliative resection
with external radiation therapy, palliative resection with IORT with
or without external-beam radiation therapy, or palliative resection
with brachytherapy, the use of IORT was associated with significantly
improved survival (Fig. 54-11). [ref: 171] These results must be
interpreted with caution because they are not from a randomized
clinical trial. Prognostic factors that were related significantly to
survival included the amount of residual tumor after surgical
resection, the use of IORT, the symptomatic status of the patient, the
degree of fixation of tumor to surrounding structures, and the
performance status of the patient (Table 54-5). Results from patients
with a history of pelvic irradiation before local recurrence are less
satisfactory. In a Mayo Clinic series, survival at 5 years was only
13%, and local control at 4 years was 34%. [ref: 69]

Thirty-nine patients with locally recurrent rectal or rectosigmoid
cancer were treated at Massachusetts General Hospital with
preoperative external-beam irradiation followed by IORT. [ref: 187]
Nine patients did not receive IORT because it was not technically
feasible, the tumor was unresectable or metastatic, or the tumor was
completely resected with negative margins. For all 39 patients, the
5-year survival rate was 29%, and the disease-free survival rate was
21%. Five-year local control and disease-free survival rates in the 30
patients who received IORT were 26% and 19%, respectively. Local
control was related to the degree of surgical resection performed
before IORT. Local control was 62% and 18% in patients who had
complete and partial resections, respectively. Four patients received
no or minimal preoperative irradiation because of a history of prior
pelvic irradiation. Of these 4 patients, 3 had local failure; 3 died
of cancer and 1 of intercurrent disease. Currently, patients with
locally recurrent rectal cancer who have a history of pelvic
irradiation are not considered candidates for IORT at the
Massachusetts General Hospital. [ref: 187]

Twenty-six patients received external-beam radiation therapy and IORT
for localized pelvic recurrence of large bowel cancer at
Rush-Presbyterian Hospital. [ref: 97] The 3-year relapse-free and
overall survival rates were 15% and 25%, respectively. Local failure
occurred in 11 of 18 patients with gross disease after surgery and in
4 of 8 patients with microscopic disease. The local failure rate was
higher in patients who received external-beam radiation therapy doses
of less than 40 Gy (11 of 15 patients, 73%) than in those who received
more than 40 Gy (4 of 11 patients, 36%). Like the group at the
Massachusetts General Hospital, these investigators no longer use IORT
when a full course of external-beam pelvic radiation therapy is not
possible.

External-beam radiation therapy with IORT has also been used in the
treatment of primary locally advanced rectal cancer. [ref: 65,66,186]
At the Massachusetts General Hospital, the actuarial overall
disease-free survival rate at 5 years was 32% for patients with
incompletely resected tumors and 53% for patients treated with
adjuvant IORT (i.e., patients with completely resected tumors). Local
control at 5 years was 60% for patients who underwent partial surgical
resection and 88% for patients who received adjuvant IORT. At the Mayo
Clinic, local control and survival rates at 5 years for 56 patients
with primary locally advanced disease were 82% and 42%, respectively.
[ref: 66]

Although the addition of IORT to external-beam radiation therapy and
surgical resection may result in improved local control and possibly
improved survival, long-term follow-up demonstrates an overall
survival rate of less than 20%. Methods for achieving better local
control and preventing distant metastasis are needed. Modulation of
5-FU activity by levamisole [ref: 113,123] or leucovorin [ref:
40,99,116, 132,139,143] or by specialized delivery methods such as
continuous infusion [ref: 133] may provide improved systemic and local
disease control. Investigation of these and other innovative treatment
methods within the context of prospective clinical trials provides the
best hope for improving outcomes in the future. A randomized clinical
trial is planned in Europe to compare external-beam radiation therapy
with and without IORT in patients with locally recurrent and primary
locally advanced disease. Results from this study should provide a
definitive assessment as to whether IORT should have a continuing role
in the treatment of selected patients with colorectal cancer.

Colon Cancer

No randomized prospective trials have examined the value of
postoperative adjuvant radiation therapy for colon cancer. However,
several retrospective studies suggest that this would be a fruitful
avenue for research. [ref: 18,38,95,96,165,185,189] In view of the
positive results with adjuvant systemic therapy in high-risk colon
cancer patients, [ref: 100,121,123] a randomized trial comparing
radiation therapy, 5-FU, and levamisole versus 5-FU and levamisole
alone after resection in patients with high-risk colon cancer has been
undertaken. Currently, adjuvant radiation therapy for colon cancer
should not be used except in the context of a prospective clinical
trial.

Chemotherapy

Until recently, the results of most studies of chemotherapy for
advanced disease or adjuvant therapy have been disappointing. [ref:
64,125] However, several recent clinical trials have demonstrated a
clear role for chemotherapy in well-defined settings. A Mayo
Clinic/NCCTG study suggested improved outcome in patients with Dukes
stage C disease in overall and disease-free survival with adjuvant
levamisole therapy with or without 5-FU. [ref: 100] A subsequent
intergroup confirmatory trial verified the value of 5-FU and
levamisole for node-positive patients. [ref: 121,123] For patients
with metastatic colorectal cancer, trials of 5-FU and leucovorin have
demonstrated improved response rates and, in some cases, improved
quality of life and better survival when compared with single-agent
5-FU therapy. [ref: 40,99,132, 139,143] In a small study at the
Roswell Memorial Park Institute, [ref: 103] patients with metastatic
disease were randomly assigned to receive either 5-FU alone,
methotrexate plus 5-FU, or leucovorin plus 5-FU. [ref: 139] Response
rates were 11%, 5%, and 48%, respectively. Survival was not altered
significantly. However, a larger Mayo Clinic/NCCTG study showed
improved survival for patients receiving regimens containing 5-FU plus
leucovorin. [ref: 132]

Sequelae of Therapy

The most common form of acute toxicity during adjuvant pelvic
radiation therapy for rectal cancer is diarrhea. Approximately 24% of
patients develop severe or life-threatening diarrhea (according to the
National Cancer Institute Common Toxicity Criteria) when pelvic
radiation therapy is used in combination with protracted infusion of
5-FU. [ref: 133] The maximal frequency of other severe or worse
toxicities is 3% when pelvic radiation therapy is used with concurrent
protracted venous infusion of 5-FU.

The risk of functionally significant long-term toxicity after pelvic
radiation therapy and chemotherapy appears to be higher than
previously appreciated. This was suggested by a study in which
assessment of bowel function was undertaken in a group of patients who
either had or had not received postoperative radiation therapy and
chemotherapy after anterior resection for rectal cancer. The two
groups of patients were well balanced for factors that had a potential
impact on bowel function, such as level and type of anastomosis.
Consistently worse bowel function, by multiple measures, was found
among the patients who had received radiation therapy and
chemotherapy. For example, 56% reported at least occasional fecal
incontinence, compared with only 7% of those who did not receive
adjuvant treatment (P < 0.001). [ref: 94]

A large retrospective analysis of patients who received radiation
therapy for high-risk, completely resected colon cancer or for
incompletely resected colon cancer found that acute enteritis
resulting in hospitalization or a break from treatment occurred in 16
(8%) of 203 patients. Long-term toxicity requiring surgery was
observed in 9 patients (4.4%). Nonsurgical complications, such as
chronic abdominal pain, were not assessed. [ref: 185] The paucity of
data with regard to serious nonsurgical complications and the
potential for significant toxicity requiring surgical intervention
underscore the importance of avoiding adjuvant therapy for large bowel
cancer outside the setting of a clinical trial.

Endocavitary radiation therapy for rectal cancer generally is well
tolerated. Approximately 35% of patients have minor rectal bleeding
after treatment. Rectal urgency occurs in about 20% of patients. These
symptoms usually resolve. Ulcers develop in about 75% of patients
after endocavitary radiation therapy, but this condition is usually
asymptomatic and resolves in most patients. [ref: 101]

Severe treatment-related toxicity can occur in patients with locally
advanced disease who undergo IORT. Immediate complications include
pelvic abscess and delayed perineal wound healing. [ref: 171] Common
long-term sequelae of IORT include neurotoxicity in approximately 32%
of patients, hydronephrosis in about 63% of patients when a ureter is
included in the radiation therapy field, and small bowel obstruction
in about 12% of patients. [ref: 164,171] Neurotoxicity appears to
depend on the site irradiated. If the pelvic sidewall is included
within the field, the incidence of neuropathy approaches 50%, but if
the field is limited to the presacrum, the incidence is less than 10%.
[ref: 164] In one series, the risk of severe complications in a group
of patients with locally recurrent rectal cancer was 30% with surgery
alone; 14% with external-beam radiation therapy; 45% with surgery,
external-beam radiation therapy, and IORT; and 60% with surgery and
brachytherapy. [ref: 171] The significant risk of complications
associated with aggressive treatment underscores the need for
prospective clinical trials to assess definitively the value of IORT.

No form of treatment has clearly been demonstrated to be of value in
the management of the complications of radiation therapy. Therefore,
prevention of complications is of critical importance. Methods for
minimizing the volume of normal tissue within the radiation therapy
field should be used (see Radiation Therapy Techniques). Randomized
trials testing two pharmacologic agents, olsalazine and
cholestyramine, for prevention of treatment-related diarrhea showed
that these agents are associated with unacceptable toxicity. [ref:
26,111,112] Sucralfate is a more promising drug. A European clinical
trial has suggested that this agent may decrease both acute and
long-term toxicity after pelvic irradiation. [ref: 72] A confirmatory
randomized trial is in progress.

Anatomy

Rectum

The rectum begins at the point where the large bowel loses its mesentery, which is at the level of the body of the third sacral vertebra. Peritoneum covers the upper portion of the rectum laterally and anteriorly near its junction with the sigmoid colon and only anteriorly near the peritoneal reflection. The peritoneum is reflected anteriorly onto the seminal vesicles and bladder in the male and onto the upper vagina and uterus in the female, leaving the lower half of the rectum without a peritoneal covering. The location of the peritoneal reflection is important in patients undergoing sphincter-preservation procedures. Electrocoagulation of anterior tumors above the peritoneal reflection is considered unsafe because of the risk of perforation. However, location above the peritoneal reflection does not contraindicate management of selected tumors by endocavitary radiation therapy.
The three transverse folds of the rectum, two on the left and one on the right, apportion it into thirds. The middle transverse fold lies approximately 11 cm from the anal verge and provides a landmark for the peritoneal reflection. The portion of the rectum below the middle valve is the rectal ampulla; if the ampulla is resected, stool frequency often is increased markedly. This morbidity is an important factor to consider in choosing between a "radical" sphincter-sparing procedure, such as coloanal anastomosis, and a "conservative" sphincter-sparing procedure, such as endocavitary irradiation.
The principal route of lymphatic drainage for carcinomas of the rectum follows the superior rectal vessels, which empty into the inferior mesenteric nodes. Lymphatic drainage of the middle and lower rectum also occurs along the middle rectal vessels, terminating in internal iliac nodes. The lowest part of the rectum and the upper part of the anal canal share a plexus that drains to lymphatics that accompany the inferior rectal and internal pudendal blood vessels and ultimately drain to internal iliac nodes. Carcinomas of the lower rectum and those that extend into the anal canal occasionally may metastasize to superficial inguinal nodes through connections to efferent lymphatics draining the lower anus (Fig. 54-1).

Colon

The ascending and descending colon and the splenic and hepatic flexures lack a mesentery and are immobile because of their retroperitoneal location. Cancers that extend through the bowel wall on the posterior aspect may have compromised surgical margins.
The cecum lacks a true mesentery but may have some mobility because of short folds of peritoneum that are variably present. Surgical margins may be narrow when lesions extend posteriorly.
The lymphatic drainage of the colon follows the inferior mesenteric vessels for the left colon and the superior mesenteric vessels for the right colon. Additional lymph node groups can be at risk if adjacent organs or structures are involved by cancer. If tumors involve adjacent organs in the true or false pelvis, the iliac nodes may be at risk. Periaortic lymph nodes may be at risk when cancer invades the retroperitoneum.

Epidemiology

Adenocarcinoma of the large bowel occurred in an estimated 131,200 persons in the United States in 1997 and caused approximately 54,900 deaths. The incidences of large bowel cancer in males and females are approximately equal. Large bowel cancer risk and distribution may be affected by genetic factors, the presence of acquired conditions, screening, and environmental factors.
Acquired and genetic conditions that influence the risk of developing large bowel cancer include inflammatory bowel disease, polyposis syndromes, and hereditary nonpolyposis colorectal cancer. The risk of large bowel cancer is markedly increased in patients with inflammatory bowel disease, particularly ulcerative colitis. Genetic polyposis syndromes include familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, and familial juvenile polyposis.
These conditions are inherited in an autosomal dominant pattern with almost complete penetrance. Patients with familial adenomatous polyposis and Gardner syndrome have thousands of polyps in the large bowel and inevitably develop cancer at an early age if the large bowel is not surgically removed. These polyposis syndromes result from APC gene mutations on chromosome 5q. Peutz-Jeghers syndrome and juvenile polyposis are also associated with an increased risk of gastrointestinal neoplasia, including colon cancer.
The other major genetic condition associated with large bowel cancer is hereditary nonpolyposis colon cancer, which is inherited in an autosomal dominant pattern and includes Lynch syndromes I and II. Lynch syndrome I is characterized by a familial tendency to early-age onset of predominantly proximal large bowel cancer. Lynch syndrome II is similar, except that an increased risk of endometrial cancer, ovarian cancer, and other malignancies has also been observed. The influence of genetic factors in "sporadic" large bowel cancer is demonstrated by the fact that the incidence of colon cancer is two to three times that expected by chance in first-degree relatives of patients with large bowel cancer. A family history should be obtained from every colorectal cancer patient so that relatives who may benefit from early screening can be identified.
In the last 30 to 50 years, the site of colon and rectal cancer has shifted toward the right colon. Increased early detection of distal precancerous lesions (for example, by proctoscopy) has been suggested as a possible contributing factor.
The influence of environment is suggested by studies assessing cancer risk and dietary factors and by studies of immigrant populations. Immigrant Japanese populations acquire the higher large bowel cancer mortality rates of the host country within one generation. Seventh Day Adventists and Mormons follow dietary practices that increase their fiber consumption and decrease their meat consumption. Among Seventh Day Adventists, mortality rates from colon cancer are approximately 60% to 70% of those of the general population, and the incidence of colon and rectal cancer in the Utah Mormon population is approximately 60% of that in the non-Mormon population.
Epidemiologic evidence suggests a preventive role for dietary fiber in large bowel cancer. Burkitt called attention to the low incidence of large bowel cancer in developing nations, in which high-fiber diets are common. Other studies have shown an inverse correlation between fiber intake and risk of large bowel cancer. Although not all reports confirm this relation, a National Cancer Institute review found an inverse relation between dietary fiber intake and colon cancer in most studies.
Fecal bile acids promote carcinogenesis in an animal model, and fecal excretion of bile acids has been shown to be high in colon cancer patients. Cholecystectomy, which results in an increase in the amount of secondary bile acids that reach the colon, could result in an increased incidence of colon cancer if secondary bile acids have a role in colon carcinogenesis in humans. Although some studies lend support to the hypothesis that cholecystectomy increases the risk of colon cancer, others do not. A study of fecal bile acid physiology in a low-risk, high-fiber-intake population in Finland suggested a possible link between promotion of colon cancer by secondary bile acids and prevention of colon cancer by high-fiber intake.
Several studies indicate a positive association between fat intake and colon carcinogenesis. Armstrong and Doll found a strong association between mortality rates for colon cancer and total fat consumption. A possible carcinogenic effect of dietary cholesterol was suggested by Liu and co-workers. Dietary cholesterol has been hypothesized to be the fat-related substance that has cocarcinogenic properties.
Selenium appears to inhibit carcinogenesis in laboratory animals. Areas of the United States with high bioavailability of selenium have lower death rates from cancer in general and from cancer of the intestines and rectum in particular.

Patterns of Spread and Natural History

Discontinuous spread of colon and rectal cancer can occur by four mechanisms: peritoneal seeding, lymphatic spread, hematogenous spread, and surgical implantation. Peritoneal spread is rare in patients with rectal cancer because most of the rectum is below the peritoneal reflection.
Extension within the bowel usually occurs only for short distances. Black and Waugh found that only 4 of 103 patients had microscopic intramural spread farther than 0.5 cm from the gross lesion. Further evidence of the limited tendency for intramural spread was found in a study by Pollett and Nicholls, in which anastomotic recurrence, local control, and survival were almost identical in patients with longitudinal margins less than or greater than 2 cm.
Because primary venous and lymphatic channels originate in submucosal layers of the bowel, cancers limited to the mucosa are at little risk for dissemination. Lymph node involvement is found in almost 50% of patients and usually is orderly and predictable. Skip metastasis or retrograde spread occurs in only 1% to 3% of node-positive patients and is generally thought to be caused by lymphatic blockage.

Clinical Presentation

The most common presenting feature in patients with rectal and lower sigmoid cancer is melena. Abdominal pain is the most common presenting feature in patients with colon cancer. In taking a history from a patient with cancer of the large bowel, particular attention should be given to these features. Other presenting features of large bowel cancer include change in bowel habit, nausea, vomiting, weakness, and abdominal mass. Patients found incidentally to have microcytic anemia should be considered to have large bowel cancer until proved otherwise.

Diagnostic Workup

Diagnostic procedures for the evaluation of colon and rectal cancer include a detailed history, physical examination, and endoscopic, radiographic, and laboratory studies (Table 54-1). The history should include a review of symptoms commonly associated with large bowel cancer. In addition, a family history should be obtained. Particular attention should be given to familial tendencies toward large bowel cancer, endometrial cancer, ovarian cancer, and other malignancies that may indicate the presence of one of the genetic syndromes associated with large bowel cancer. Physical examination should result in a detailed description of the primary tumor and a screen for potential sites of metastatic disease. In patients with rectal cancer, a digital rectal examination and endoscopy should provide information regarding the location of the lesion (i.e., distance above the anal verge and which rectal walls are involved), whether it is exophytic or ulcerative, its size and mobility, and whether any palpable perirectal nodes are present. For colon and rectal tumors, attention should be given to palpation of any anterior extrarectal mass that may suggest peritoneal spread. In women, a complete pelvic examination, including rectovaginal examination, is important. Particular attention should be given to potential areas of metastatic spread, including inguinal lymph nodes (particularly with rectal lesions near the dentate line) and supraclavicular lymph nodes. Abdominal examination should screen for evidence of liver metastasis, abdominal mass, or ascites.
When a large bowel cancer is found or suspected, the rectum and colon should be examined with barium enema and proctosigmoidoscopy or with colonoscopy to rule out second primary large bowel cancers. Biopsy of any suspicious lesions should be performed at the time of endoscopy. For patients with rectal cancer, barium enema performed before resection, including a cross-table lateral view, can also assist greatly in planning radiation therapy. Intrarectal ultrasonography is useful in determining whether lesions are limited to the bowel wall and therefore amenable to sphincter preservation by techniques such as local excision or endocavitary radiation therapy.
Additional laboratory evaluation should include liver and renal function studies. If the results are abnormal, computed tomography (CT) or ultrasonography is indicated. The preoperative carcinoembryonic antigen (CEA) value is an independent prognostic factor in large bowel cancer, and its serial measurement postoperatively has been used in some medical centers to identify disease progression in asymptomatic patients. A National Institutes of Health Consensus Development Panel determined that serial CEA measurement is the most sensitive laboratory indicator of recurrent disease. However, most patients with recurrence have symptoms before the CEA value increases. In one study, CEA increased in only 25% of patients with recurrent disease. Moreover, patients found with this test to have recurrent disease are unlikely to be cured. A retrospective analysis by Moertel and colleagues of patients from a large clinical trial of adjuvant treatment for colon cancer reported that 1017 (84%) of 1216 patients had CEA monitoring. Among the 345 CEA-monitored patients with recurrence, only 2.9% were alive more than 1 year after recurrence, compared with 2.0% of patients with recurrence who were not monitored with CEA. The estimated cost of CEA monitoring for the 1017 patients was almost $1.5 million. This study must be interpreted carefully because it was retrospective and because CEA monitoring was not standardized. Nevertheless, the results were similar to those of studies employing more systematic monitoring of CEA.


A preliminary report of a prospective randomized trial designed specifically to assess the value of CEA monitoring also suggests that this test is not beneficial when used as part of a broad-based screening program for recurrent disease. It seems unlikely that CEA monitoring is of benefit to broad groups of patients with large bowel cancer, given the extreme nature of the poor results observed in these studies. The very modest theoretic potential for benefit of postoperative CEA monitoring must be weighed against the potential for harm when, for example, asymptomatic patients are subjected prematurely to the distressing news that the disease has recurred and that there is no effective curative treatment.
Future studies may help to define whether CEA monitoring is of value in subgroups of patients, such as those most likely to develop potentially curable liver metastases.

Staging Systems

Dukes described a staging system based on the extent of disease penetration through the bowel wall and the presence or absence of nodal metastasis (Table 54-2). Dukes' staging has the disadvantage of not specifying the degree of tumor penetration through the wall of the bowel in node-positive patients. The Astler-Coller staging system allows specification of both tumor penetration and nodal involvement, and its subsequent modification also permits the specification of tumor adherence to surrounding organ structures. The Dukes, Astler-Coller, and modified Astler-Coller systems are postoperative pathologic staging systems and cannot be used preoperatively. The TNM system of the American Joint Committee can be used as a clinical (preoperative) or postoperative pathologic staging system.

Pathology

Most malignant tumors of the large bowel are adenocarcinomas, and most are moderately well differentiated histologically. Among patients who undergo operation for cure, approximately one third have lymph node metastasis. Retrograde lymph node involvement and skip metastasis are unusual, and both are associated with poor prognosis.

Molecular Biology

Several types of genetic alterations at the molecular level contribute to malignant transformation. One of the earliest changes is the loss of methyl groups in DNA.
Mutations in oncogenes are another common finding in colorectal neoplasia. For example, mutational activation of the ras gene is found in about 50% of colorectal carcinomas and advanced adenomas but in only 12% of early adenomas. Loss of genetic information is common in patients with colorectal cancer. Tumorigenesis associated with allelic loss is caused by the loss of function of tumor suppressor genes. Allelic deletions occurring in association with colorectal neoplasia are not distributed randomly but instead appear to occur most commonly at specific chromosomal locations. Allelic loss is particularly common on chromosomes 5, 17, and 18. Allelic loss at chromosome 18q contributes to colorectal neoplasia because of loss of DCC (deleted in colorectal carcinoma), one of several tumor suppressor genes. Another tumor suppressor gene, APC, has been identified on chromosome 5q.
The most commonly altered tumor suppressor gene in colon cancer is p53, which is located on chromosome 17q.
The p53 protein affects cellular proliferation and therapeutic response. Normal or wild-type p53 (wtp53) appears to limit tumor proliferation by at least two mechanisms. In some situations, p53 is involved in a reversible arrest in the G(1) phase of the cell cycle.
Expression of p53 can also lead to apoptosis, a physiologic irreversible process leading to cell death. Although p53 and other tumor suppressor genes are recessive, it appears that a point mutation in one allele is often followed by loss of the remaining wild-type allele. This is believed to be a late event in colorectal tumorigenesis.
P53-dependent apoptosis has significant implications for cancer therapy. Cells that express wtp53 typically undergo cell death by apoptosis in response to exposure to cytotoxic agents such as radiation, 5-fluorouracil (5-FU), etoposide, and doxorubicin. Cells that do not express wtp53 are resistant to these agents.
Colon cancer patients with mutations in the p53 gene appear to have a worse prognosis than those with wtp53. After exposure of cells to radiation, p53 interacts in a complex way with the products of other genes affecting cellular proliferation. An example is the relation between p53 and the MDM2 gene. The protein encoded by the p53 gene is induced by radiation. This, in turn, leads to a p53-dependent increase in the expression of the MDM2 gene. The MDM2 protein is able to bind to p53. If the MDM2 protein is present in sufficient quantities, this binding results in abrogation of p53-mediated arrest of the cell cycle at G(1).
Recently, a novel type of genetic alteration at DNA microsatellites (called microsatellite instability) has been described. Microsatellites are repeated sequences of DNA that occur abundantly and randomly throughout the human genome. Microsatellite instability has been identified in tumors from a subset of patients with sporadic colon cancer and in most patients with hereditary nonpolyposis colon cancer. At least in the latter group, microsatellite instability appears to be caused by a defect in one of several genes involved in DNA mismatch repair, including hMSH2, hMLH1, hPMS1, and hPMS2. [ref: 77] These same genes are now known to be the genetic susceptibility loci for hereditary nonpolyposis colon cancer.
The cause of the microsatellite instability in patients with sporadic colorectal cancer has not been clearly defined.

Prognostic Factors

Important prognostic factors for radiation oncologists include tumor penetration of the bowel wall and lymph node involvement. Both factors are associated with an increased risk of local recurrence and, accordingly, are helpful in selecting candidates for adjuvant radiation therapy. The absolute number and the proportion of lymph nodes involved are important predictors of outcome. The presence of both lymph node involvement and extension of disease beyond the bowel wall is more ominous than the presence of either alone. In patients with low rectal cancer who are being considered for sphincter-sparing treatment, the clinical mobility, size, and morphology of the lesion are predictors of outcome.
Techniques for analyzing pathologic genetic modifications at the molecular level, enzymatic activity influencing metabolism of chemotherapeutic agents, DNA ploidy, and cell kinetics have led to the identification of additional prognostic factors. In one study, for example, deletions on chromosome 18q (the site of the DCC gene) were associated with a trend toward lower rates of disease-free survival in patients with colorectal cancer (P = 0.08). Other studies have also suggested a worse prognosis for patients with deletions from 18q or 17q. The presence of microsatellite instability has been correlated with improved patient survival in sporadic colon cancer. The overexpression of p53 is associated with worse survival in patients with node-positive colorectal cancer. Thymidylate synthase, an important target of the chemotherapeutic drug 5-FU, was found in one study to have significantly higher activity in patients with advanced colorectal cancer whose tumors did not respond to 5-FU than in those with responsive tumors. Aneuploidy and high proliferative index (measured by adding the percentage of cells in S phase to those of cells in G(2) and M phase) are associated with worse survival in patients with colorectal cancers. Information from studies of this type may be useful in the selection of patients for adjuvant therapy.

General Management

Operative Considerations

Surgical resection is the initial treatment of choice for most patients. The objective is to remove the tumor and adjacent lymph nodes. Anterior resections are technically feasible in patients with tumors at least 6 to 8 cm above the anal verge and result in survival rates similar to those for abdominoperineal resection.
Surgical and pathology reports commonly refer to the longitudinal bowel margin. However, nodal and circumferential (radial) margins may be more important. If a tumor spreads beyond the bowel wall in anatomically immobile segments of the large bowel, the narrowest margin of resection typically is situated laterally, anteriorly, or posteriorly rather than along the length of the bowel. A study of whole-mount sections found that 40% of patients who underwent resection of a rectal carcinoma had a radial margin of 3 mm or less. In patients in whom postoperative irradiation may be part of the treatment, several surgical procedures assist in planning treatment and minimizing toxicity. Pelvic floor reconstruction and reperitonealization help to minimize the volume of small bowel in the pelvis. For patients in whom high-dose treatment to the pelvis is anticipated, complete exclusion of all small bowel from the pelvis can be achieved by use of an absorbable mesh sling. Primary closure of the perineal wound after abdominoperineal resection generally results in more rapid healing and prevents delays in instituting postoperative radiation therapy. A full description of the extent of the tumor and placement of clips demarcating the tumor bed and residual disease can assist in the design of radiation therapy fields.

Patterns of Failure After Curative Resection

Detailed information regarding anatomic sites of failure after operation for rectal cancer is available from the University of Minnesota reoperation series (Fig. 54-2). Seventy-four patients thought to be at high risk for local recurrence underwent elective or symptomatic second-look operations. Of these, 52 (70%) had metastatic or locally recurrent cancer. Locoregional recurrence in the pelvis or paraaortic nodes was the sole failure in 24 (46%) of these 52 patients and occurred as a component of failure in 48 (92%). Table 54-3 provides information about failure patterns in an unselected patient population. Patients with disease extension beyond the bowel wall, nodal involvement, or both have local recurrence rates of 20% to 70%. Distant metastasis occurs in approximately 30% of patients who undergo curative resection of rectal cancer, and the most common sites of involvement are liver, lung, and peritoneum.
Patterns of failure in colon cancer have been analyzed in autopsy, clinical, and reoperation series. Data from these series suggest that local failure is a significant problem after resection of colon cancer in selected patients. Local failure is highest among patients with tumors adhering to surrounding structures and those who have both tumor extension beyond the bowel wall and metastatically involved lymph nodes. In one retrospective study, the local recurrence rate among patients with these pathologic characteristics was 30% to 49%.
Approximately 20% of patients who undergo curative resection of colon cancer develop distant metastasis. The most common sites of distant metastasis are liver, lung, and peritoneum.

Radiation Therapy Techniques