Adjuvant therapy for colorectal cancer

Current Problems in I ' y '®

Sur Volume 34

Number 8

August 1997

Adjuvant Therapy for Colorectal Cancer Alfred M. Cohen, MD

Dr. Ridzuan Farouk, MCh

Chief, Colorectal Service Department of Surgery Professor of Surgery Cornell University Medical College Memorial Sloan-Kettering Cancer Center New York, New York

Fellow, Colon and Rectal Surgery Cornell University Medical College Memorial Sloan-Kettering Cancer Center New York, New York

Leonard k. Gunderson, MD Chair, Department of Radiation Oncology Mayo Clinic and Mayo Foundation Professor of Oncology Mayo Medical School Rochester, Minnesota

David Kelsen, MD Attending, Solid Tumor Service Department of Medicine Professor of Medicine Cornell University Medical College Memorial Sloan-Kettering Cancer Center New York, New York

Fabrizio Michelassi, MD Professor and Chief Section of General Surgery University of Chicago Chicago, Illinois

Leonard Saltz, MD Assistant Attending Solid Tumor Service Department of Medicine Cornell University Medical College Memorial Sloan-Kettering Cancer Center New York, New York

Richard B. Arenas, MD Department of Surgery University of Chicago Chicago, Illinois

Richard k. Schilsky,MD

Bruce D. Minsky, MD Associate Attending, Radiation Oncology Service Department of Radiation Oncology Associate Professor of RadiationOncology Cornell University Medical College Memorial Sloan-Kettering Cancer Center New York, New York

Heidi Nelson, MD Consultant, Division of Colon and Rectal Surgery Cornell University Medical College Memorial Sloan-Kettering Cancer Center New York, New York

Professor of Medicine Director, Cancer Research Center University of Chicago Chicago, Illinois

Christopher G. Willet, MD Department of Radiation Oncology Cox Cancer Center Massachusets General Hospital Boston, Massachusetts

Mosby A Times Mirror Company

Current Problems in

Sur

ry

Adjuvant Therapy for Colorectal Cancer Contents Foreword In Brief Background and Resultsof SurgicaJResection Staging Surgery for Colon Cancer Surgery for Rectal Cancer Patterns of Failure

Colon Cancer AdjuvantTherapy 5-Fluorouracil 5-Fluorouracil Plus Levamisole 5-Fluorouracil Plus Leucovorin InvestigationalApproaches

Rectal Cancer AdjuvantTherapy Postoperative Adjuvant Therapy Preoperative Adjuvant Therapy Postoperative Adjuvant Therapy After Local Excision

Adjuvant Therapy for LocallyAdvanced Rectal Cancer External Beam Radiation Therapy Chemotherapy Plus External Beam Radiation Therapy Intraoperative Radiation Therapy

604 605 611 611 612 614 618 623 623 625 627 629 634 635 642 649 652 653 657 660

References

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Curr Probl Surg, August 1997

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Foreword Carcinoma of the large bowel is the second most common cause of cancer death in males and females combined. The place of surgical resection in the treatment and cure of patients with carcinoma of the large bowel is well established. Because many patients with colorectal carcinoma have disease that is surgically incurable at the time of presentation, the use of adjuvant chemotherapy and x-ray therapy have both played a role, either alone or together, in their clinical management. In this issue of Current Problems in Surgery, Dr. Alfred Cohen and his distinguished colleagues have cooperatively written a monograph on "Adjuvant Therapy for Colorectal Cancer." This is an excellent summary of the state of the art in the treatment of patients with this generally aggressive disease. This is a monograph written by a team of oncologists from internal medicine, radiation therapy, and surgery. This team approach to writing the monograph demonstrates the therapeutic interdependency of these clinical disciplines. Readers will find this monograph highly informative and current. We are indebted to this talented group of clinical scientists for this splendid contribution.

Samuel A. Wells, Jr., MD Editor-in-Chief

604

Curr Probl Surg, August 1997

In Brief The cure rate for patients with colorectal cancer depends on early diagnosis, successful operation, and appropriate use of adjuvant therapy. Longterm strategies of prevention through diet or nutritional supplements and screening of not only the high-risk subsets but the entire population may ultimately affect the mortality rate for patients with this disease inWestern countries.At present, however, successful operative resection has the greatest impact on the cure of patients with established disease. For patients with colon cancer, the surgical management involves local-regional control by resection of the primary tumor and the regional lymph nodes based on wellestablished surgical principles. The major surgical issue under investigation is the role of laparoscopic-assisted colectomy in these patients. For patients with rectal cancer, there has been a wide variation in the ability to control local-regional disease, apparently based on the surgical technique. A small subset of patients with early cancer are amenable to local excision and radiation therapy, a situation very similar to breast cancer treatment. Patients with transmural or node-positive rectal cancer appear to be best treated operatively by radical resection. This procedure maximizes tumor clearance at the lateral margins and improves the local control rate. Patients with node-positive colon cancer have a high incidence of systemic micrometastases, and randomized trials have demonstrated approximately a one third reduction in cancer-related mortality from the use of adjuvant chemotherapy. This issue of Current Problems in Surgery reviews both regional and systemic chemotherapy and future directions in clinical trials. Although in selected specialty centers the local-regional recurrence rate after radical resection for rectal cancer is less than 10%, results from a wide variety of centers throughout the United States indicate a 20% to 25% local relapse rate in patients with transmural or node-positive rectal cancer. In addition, in patients with node-positive cancer the presence of systemic micrometastatic disease exceeds 50%. For patients with extraperitoneal rectal cancer (below the peritoneal reflection), overall local control and overall survival are maximized by the use of combined chemoradiation therapy. The questions of which chemotherapy drug combination and the sequence of operation, chemotherapy, and radiation therapy regarding overall cancer control and patient functional outcome with sphincter-preserving surgery is the basis of current clinical trials. Curr Probl Surg, August 1997

605

After 2 decades of nonproductive studies of adjuvant chemotherapy for colorectal cancer, large clinical trials over the past decade conclusively demonstrate a survival benefit when patients with node-positive colon cancer receive adjuvant chemotherapy. One-year treatment with 5-fluorouracil (5FU) and levamisole reduces the cancer-related mortality by approximately one third. Recently completed trials in Europe and the United States indicate that identical benefit is obtained with a 6-month course of 5FU modulated with leucovorin. A recent multicenter trial from Germany suggests a survival benefit with routine monoclonal antibody 17-1A. A current trial is exploring the potential incremental benefit of such immunotherapy in addition to conventional adjuvant chemotherapy. Data suggest the benefit in patients with node-negative colon cancer is minimal, and adjuvant chemotherapy should be offered only to highly selected high-risk patients with node-negative cancer. Indicators of increased risk include obstruction or perforation, high grade, aneuploidy, and certain molecular markers. Adjuvant therapy is generally advised for patients with rectal cancer who have transmural extension and positive lymph nodes. Patients with upper rectal and rectosigmoid tumors should be treated under the colon guidelines. In almost all instances, adjuvant therapy involves combined systemic chemotherapy and pelvic radiation therapy. The exact sequence and choice of agents remain uncertain. Randomized clinical trials with surgery alone arms demonstrate a 50% reduction in local failure rates and approximately a 20% improvement in the overall survival rate with postoperative chemoradiation therapy. The most common combined modality strategy is operation followed by 2 months of chemotherapy, 6 weeks of chemoradiation, and then 2 additional months of chemotherapy. The concurrent chemoradiation should be either infusional 5FU or bolus 5FU and leucovofin. Preoperative radiation or chemoradiation, operation, and postoperative chemotherapy is the preferred sequence for locally advanced, tethered, or fixed rectal cancers. Because retrospective studies indicate that preoperative radiation appears to be well tolerated and perhaps is associated with better local control, combined with the observation that postoperative radiation therapy adversely affects late bowel function, two randomized trials comparing the preoperative with the postoperative sequences for the patients with more common resectable transmural rectal cancer are ongoing. Outcomes will be not only overall survival but also local failures and late bowel function. A small subset of patients with early rectal cancer may be treated by full-thickness local excision either transanally or through a posterior proctotomy. Patients with low-grade exophyfic T1 lesions require no further therapy. The remainder of patients are at risk for mural or nodal local and distant failure and should receive postoperative chemoradiation. 606

Curr Probt Surg, August 1997

Patients with locally advanced rectal cancer remain a therapeutic challenge. Radical resection followed by high-dose pelvic radiation is associated with a 50% local failure pattern. High-dose preoperative chemoradiation results in a 75% resectability rate but a persistent 30% to 40% local failure rate despite negative margins. Despite the absence of randomized trials, data from the major centers with intraoperative radiation facilities indicate that the strategy of preoperative chemoradiation, radical resection, and intraoperative radiation boosting reduces the local failure rate to 10%, with approximately a 50% longterm survival. Intraoperative radiation boosting is feasible with electron beam, high-dose rate iridium- 192, iodine- 125 suture seeds, or iridium- 192 afterloading systems. The high-dose rate iridium- 192 system is probably the most realistic for widespread use, at least in major medical centers.

Curr Probl Surg, August 1997

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tended medical school at . The Johns Hopkins University School of Medicine and completed his surgical training at The Massachusetts General Hos )ital. He then spent 21/~ years in the surgery branch of the National Cancer Institute. Dr. Cohen was on the faculty of Harvard University and The Massachusetts General Hospital until he accepted his current position at the Memorial Sloan-Kettering Cancer Center. Dr. Cohen is Chief of the Colorectal Service, Department of Surgery, and leader of the Colorectal Cancer Disease Management Team at the Memorial Sloan-Kettering Cancer Center. He is also Professor of Surgery at Cornell University Medical College. He has clinical interest in all aspects of colorectal cancer. In addition to his clinical activities, Dr. Cohen has investigated the use of radiolabeled monoclonal antibodies in the diagnosis and therapy of colorectal cancer.

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Bruce D. Minsky, MD, attended medical school at the University of Massachusetts and completed his residency at the Harvard Joint Center for Radiation Therapy. He is currently an attending physician in the Department of Radiation Oncology at Memorial Sloan-Kettering Cancer Center and Associate Professor of Radiation Oncology at Cornell University Medical College. His primary clinical and research interests are in the field of gastrointestinal oncology, and he serves as the principal investigator of an number of institutional and national clinical trials in this field.

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Heidi Nelson, MD, is Associate Professor and Surgical Consultant at the Mayo Medical School and Mayo Foundation in Rochester, Minnesota After receiving her MD degree from the University of Washington, she completed her training in general surgery at the Oregon Health Sciences University, in colon and rectal surgery at the Mayo Clinic, and in immunology research at the University of Washington. Dr. Nelson's clinical and basic research programs in colorectal cancer include locally advanced primary recurrent cancer, laparoscopic colectomy, and immune-based cancer therapies.

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Leonard L. Gunderson, MD, is Chair of Radiation Oncology at Mayo Clinic and Professor of Oncology at Mayo Medical School. He received his undergraduate training at Montana State University, his MS degree in anatomy from the University of North Dakota, and his MD degree from the University of Kentucky. He pursued a surgery internship at the University of Utah and specialty training in radiation oncology at Latter 608

Curr Probl Surg, August 1997

Day Saints Hospital. He has served on the staffs of LDS Hospital (1974-75), Massachusetts General Hospital and Harvard Medical School (1976-80), and Mayo Clinic (1981-present). Dr. Gunderson's major scientific interests include combined modality treatment for gastrointestinal malignancies and soft tissue sarcomas and the integration of intraoperative irradiation in the combined modality treatment of locally advanced primary or recurrent malignancies in a variety of sites.

Fabrizio Michelassi, MD, is Professor and Chief of General Surgery at the University of Chicago. Dr. Michelassi graduated from the University of Pisa School of Medicine, trained in surgery at New York University, and was research fellow in surgery at the Massachusetts General Hospital. He has written extensively on the surgical treatment of colorectal cancer, periampullary and pancreatic cancer, gastric cancer, and inflammatory bowel disease. Dr. Michelassi's research interests include the genetic expression and pathologic features of gastrointestinal cancers.

Leonard Saltz, MD, graduated from the Yale University School of Medicine and completed his internal medicine training and his fellowship in Medical Oncology and Hematology at the New York Hospital-Cornell University Medical Center. He is currently an assistant attending physician at Memorial Sloan-Kettering Cancer Center (New York) and Assistant Professor of Medicine at Cornell University Medical College. Dr. Saltz's primary research interest is the development of new chemotherapeutic agents and new combined modality strategies for the treatment of colorectal cancer.

Chief of the Gastrointestinal Oncology Service in the Department of Medicine at Memorial SloanKettering Cancer Center and Professor of Medicine at Cornell Medical College. Dr. Kelsen's major interests are in clinical and laboratory investigation of human gastrointestinal cancers. His clinical interests involve multimodality therapy for highrisk patients with primary malignancies, and the development of new agents in the treatment of patients with more advanced disease that can then be carried to the adjuvant setting. His laboratory interests focus on the molecular biology of patients with upper gastrointestinal-tract malignancies, particularly gastric and esophageal cancers. He is currently principal investigator or co-principal investigator for several U.S. National Intergroup trials for patients with gastrointestinal tumors. Curr Probl Surg, August 1997

609

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Christopher G. Willett, MD, graduated from Tufts University School of Medicine and completed a residency in Radiation Oncology at The Massachusetts General Hospital. Dr. Willett has specialized in the use of intraoperative radiation therapy and the care of patients with gastrointestinal neoplasms at the Massachusetts General Hospital.

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Richard B. Arenas, MD, is Assistant Professor of Surgery at The University of Chicago. Specializing in surgical oncology, Dr. Arenas maintains his clinical activities within the Gastrointestinal and Breast Oncology Services. A medical graduate of The Robert Wood Johnson Medical School in New Jersey, he completed his residency in surgery at The Hospital of Saint Raphael in New Haven, Connecticut, and at the University of Medicine and Dentistry of New Jersey-University Hospital in Newark, New Jersey. Before his faculty appointment at The University of Chicago, Dr. Arenas served as a Fellow in Surgical Oncology. His research interests include the molecular genetics of colorectal cancer and specifically the effects of tumor suppressor gene therapy in colorectal tumorigenesis.

Ridzuan Farouk, MCh, underwent his medical training at the Welsh National School of Medicine in Cardiff. He received his fellowships in surgery from the Royal Colleges in Glasgow and Edinburgh in 1990 and 1992, respectively. Mr. Farouk took up a lectureship in surgery at the University of Edinburgh that was funded by the Medical Research Council, United Kingdom, to complete a thesis on ambulatory aspects of anorectal motility in patients with pelvic floor disorders culminating in the degree of MCh awarded by the University of Wales. In 1994, he moved to the University of Hull as a lecturer in surgery and in 1996 was awarded the intercollegiate fellowship in general surgery. Currently he is completing a clinical fellowship at the section of Colon and Rectal Surgery at the Mayo Clinic.

Richard L. Schilsky, MD, is Professor of Medicine, Director of the University of Chicago Cancer Research Center, and Chairman of the Cancer and Leukemia Group B. After receiving his medical degree from the University of Chicago and completing a residency at the University of Texas-Southwestern Medical Center, Dr. Schilsky became a clinical associate at the National Cancer Institute in Bethesda, Maryland. Since joining the faculty of the University of Chicago, he has continued his research with a focus on the pharmacokinetics of novel anticancer drugs. Dr. Schilsky's clinical interests include new drug development and the treatment of advanced colorectal cancer. 610

Curr Probl Surg, August 1997

Adjuvant Therapy for Colorectal Cancer Background and Resultsof Surgical Resection

Staging l ~ h e staging of colorectal cancer has been based for several decades on modifications of the system first introduced by Dukes 1in 1930. The Dukes' system defined the stage (A through C) by the greatest depth of tumor invasion. Several modifications were proposed over the years, but it was not until 1967 that Turnbull and colleagues2 added a stage D for the presence of metastatic disease. The Astler-Coller staging system was introduced in 1954 and refined in 1978. In its most recent form, this staging system incorporates the depth of invasion, lymph node involvement, and distant metastasis. 3 In the modifiedAstler-Coller system, stage A tumors are limited to the mucosa and stage B tumors invade into the muscularis propria (B 1), subserosa (B2), and into the adjacent structures (B3). Tumors with nodal involvement are identified as C 1 to C3 based on the extent of primary invasion into the bowel wall. Tumors with distant metastasis, either by lymphatic or hematogenous spread, are designated as stage D. In 1987, theAmerican Joint Committee on Cancer and the International Union against Cancer introduced the TNM staging system for cancer of the colon and rectum (Table 1).4'5 The stage of the tumor considers tumor invasion (T), lymph node involvement (N), and distant metastasis (M).With this system the extent of tumor invasion is designated as T 1 t h r o u g h T4, the latter depicting the extent of spread to adjacent structures. Nodal involvement is subdivided into N1 (<4 nodes), N 2 (>4 nodes), and N 3 (nodes along a vascular trunk) based on information from the National Surgical and Adjuvant Breast and Bowel Project (NSABP) and the Gastrointestinal Tumor Study Group (GITSG) trials suggesting that the number of metastatic lymph nodes is a statistically significant and independent prognostic variable. 6.7 The presence of distant metastasis is defined as M1. Critics of the current TNM staging system for colorectal cancer believe that despite a systematic attempt to define lesions more precisely, it does not take into account other prognostic factors. The histologic grade has been shown to correlate with survival with poorly differentiated or anaplastic tumors, presenting a greater risk for failure. The presence of vascular or lymphatic invasion has been identified as a poor prognostic factor in several studies carefully controlling for other factors such as stage. 8.9 The tumor morphology and Curr Probl Surg, August 1997

611

TABLE 1. TNM staging system for colorectal cancer

Primary Tumor (T) Tx TO Tis T1 T2 T3 T4

Primary t u m o r cannot be assessed No evidence of primary t u m o r Carcinoma in situ Tumor invades submucosa Tumor invades muscularis propria Tumor invades through muscularis propria into subserosa, or into nonperitonealized pericolic or perirectal tissues Tumor perforates visceral peritoneum or directly invades other organs or structures

Lymph Nodes (N) Nx NO N1 N2 Na

Regional lymph nodes cannot be assessed No regional lymph node m e t a s t a s i s M e t a s t a s i s in I to 3 pericolic or perirectal lymph nodes M e t a s t a s i s in 4 or more pericolic or perirectal lymph nodes M e t a s t a s i s in any lymph node along course of a major named vascular trunk

Distant Metastasis (M) Mx Mo M1

Presence of distant m e t a s t a s i s cannot be assessed No distant m e t a s t a s i s Distant m e t a s t a s i s

Stage Grouping Stage O

Tis

No

Mo

Stage I

T1 T2 Ta

NO No No

Mo Mo Mo

No N1 N2 N3 Any N

Mo Mo Mo Mo M1

Stage II Stage III

Stage IV

T4 Any Any Any Any

T T T T

histologic type may be a factor as well with ulcerative or mucinous type lesions, suggesting a worse outcome. The interrelation of these other factors helps to explain the variations in predicted outcome observed within each stage. 8'9 In addition, despite accumulating data on the molecular biology of colorectal cancer, current staging systems fail to include potentially significant prognosticators involving cell biology and molecular genetic features. The incorporation of these other variables into future staging systems will require further understanding about the biology of colorectal tumorigenesis.

Surgery for Colon Cancer Surgery remains the mainstay of treatment for cancer of the large bowel. Based on the knowledge of loco-regional tumor spread, wide resection of 612

Curr Probl Surg, August 1 9 9 7

the primary lesion en bloc with the draining lymph node basin is the standard procedure. Oncologic principles for resection are based on histologic studies of the spread of colorectal cancer. Because colorectal tumors have been shown to invade the submucosa of the intestinal wall for a distance from the primary tumor, a margin of 5 cm has traditionally been considered necessary to reduce the incidence of local recurrence. The "5 cm rule" is based on examination of pathologic specimens that have shown that distal microscopic intramural spread can occur as far as 4 cm from the primary tumor. 1° In addition, because colorectal tumors metastasize to locoregional lymph nodes along the vascular arcades of the large bowel, resection specimens for colon cancer should include the site-specific blood supply. For left colonic lesions based around the inferior mesenteric pedicle, the prognostic significance of high mesenteric node metastasis was emphasized by Grinnell, H who demonstrated poorer outcomes in patients with metastasis at this level. Several other studies could not demonstrate a clinical benefit with high ligation of the mesenteric trunk, suggesting that patients with lymphatic spread at the mesenteric root are at greater risk for disseminated disease. 12,13 Relapse after resection for colon cancer occurs in 20% to 40% of patients after curative s u r g e r y . 14-16 The tumor stage remains the most important predictor for relapse. Recurrences of 50% or greater occur with tumors with transmural invasion, especially in the presence of lymph node metastasis. Other predictors for recurrence include the degree of anaplasia, 15'17"18margins of resection, 19and the presence of perforation at the initial operation. 18Obstruction has not been shown conclusively to affect the long-term outcome. Despite some studies that have demonstrated a poor prognosis in patients with obstructing lesions, 18 others have shown that obstruction does not have a negative predictive value when the tumor stage is also considered. 2°Anastomotic recurrences have been reported in as many as 2% to 15% of all curative resections, 21 comprising approximately 10% of cases with loco-regional failure, The presence of an anastomotic recurrence despite wide margins of resection suggests that tumor behavior is a major cause of local failure. 22 The results of curative resection for colon cancer can be reviewed in the context of node-positive and node-negative disease (Table 2). Excellent 5year survival rates of greater than 80% can be achieved with operation alone for node-negative cancers limited to the bowel wall (T~-T2). 16,23,24Transmural invasion (T3-T4) in the absence of lymph node metastasis is curable in 60% to 80% of patients at 5 y e a r s . 16'23'24 For node-positive disease the 5year survival rate decreases to approximately 50% at 5 years. 6'16'23Involvement of the pericolic fat or contiguous structures further decreases the surCurr Probl Surg, August 1997

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TABLE 2. Five-year survival after curative resection for colon cancer

Stage Node-negative disease TI_2 NoM o T3NoM o T4NoM o Node-positive disease T2N1M o T3N1M o T4N1M o

5-year survival (%) 82 - 97 73 - 80 63 74 48 - 60 30 - 40

vival rate to 38% to 50%, and the presence of more than four metastatic lymph nodes predicts a survival rate of only 20% to 3 0 % . 6'16'24'25 Much of the data on the results of operation alone for colorectal cancer are based on the results of several large randomized studies such as the GITSG and the North Central Cancer Treatment Group (NCCTG) comparing the results of operation alone with operation and postoperative adjuvant therapy. 24'26

Surgery for Rectal Cancer The staging of rectal cancer is similar to that for colon cancer, and it is based on TNM criteria. In the distal two thirds of the rectum (without a serosa), however, a T3 tumor is transmural. Pathologic staging remains the most accurate method to establish the extent of disease. There is a need for better clinical staging in the preoperative setting. Modalities such as digital examination and proctosigmoidoscopy, pelvic computed tomography, and endorectal ultrasonography are able to stage node-negative disease with a 90% accuracy; however, the specificity for the detection of nodal metastasis drops off to approximately 60%. 27`28 Reseetable Rectal Cancer. The resection of rectal cancer is based on the same oncologic principles guiding resections for colorectal cancers. Yet, because of anatomic and functional implications, the length of distal margins and the magnitude of lymph node clearance assumes special importance. A distal margin of 5 cm was once thought to be necessary to avoid local recurrence of rectal cancer. With the extension of sphincter-sparing procedures to rectal cancers of the middle rectal ampulla and to selected ones of the lower one third, a 2 cm distal margin is now accepted as satisfactory. With this margin, several studies have demonstrated no compromise in local recurrence or survival ratesY -32In 1986, the NSABP reported a review of sphincter-sparing procedures for rectal cancers? ° No significant difference in disease-free survival could be ascertained in the group of patients with resections to within 2 cm versus those greater than 3 cm. Only 614

Curr Probl Surg, August 1 9 9 7

in cases of poorly differentiated cancers did margins less than 5 cm appear to jeopardize the cure rate. 33 The dual lymph node drainage of rectal cancers along the inferior mesenteric and the middle rectal vessels was offered as the rationale for extended lymphatic resection with complete abdomino-iliac lymphadenectomy and removal of the periaortic tissue from the duodenum to the iliac bifurcation. This extended lymphatic resection suggests slight increases in survival in several studies with additional benefits in loco-regional control for rectal cancer. 34,35Enker and colleagues 35reported an exceptional 5-year survival rate of 70% with extended lymphadenectomy, suggesting a technical advantage for wide anatomic resection for node-positive disease. Pelvic lymphadenectomy and concomitant hypogastric vessel resection have shown modest increases in the disease-free survival rate of 6%. 36 These putative improvements in survival with extended lymphadenectomy have been achieved at the expense of higher morbidities in urinary and sexual dysfunction. In addition, other studies such as the series from St. Mark's Hospital failed to demonstrate any advantage, especially in Dukes' C cancers. 37 Extended lymphadenectomy has not conclusively been proven superior to conventional lymph node resection. Instead, the presence of hypogastric and periaortic nodal disease indicates concomitant widespread metastatic disease that is unlikely to be amenable to curative resection. Wide resection of the distal colon, rectum, mesorectum and, when necessary, the anus is important to minimize local recurrences. Compromise of the lateral margin and mesorectum has been implicated in higher incidences of local recurrence. Quirke and colleagues 38 in a review of 14 patients with tumor at the lateral margin noted a recurrence rate of 85% at 2 years. Cawthorne and colleagues 39 demonstrated that tumor infiltration at the lateral margin, although failing to predict local recurrence, did correlate independently with a poor prognosis. 39The dismal results obtained from extended pelvic wall dissection (12% at 5 years) suggest that involvement of the lateral margins is an indication of advanced disease. 36 Heald and Ryall, 4° in a series of 115 patients who underwent resection for cure, demonstrated a reduction in loco-regional recurrence (3.6% at 5 years) by total removal of the visceral rectal mesentery or mesorectum. Furthermore, a significant number of these patients did not undergo abdominoperineal resection, confirming the feasibility of sphincter-preservation with total mesorectal excision. Cawthorne and colleagues 39independently predicted survival by the extent of mesorectal invasion regardless of lymph node metastasis. The 5-year survival rates in the presence of disease 4 mm or less was 55% versus 25% for infiltration greater than 4 mm. Both of these studies suggested the necessity for total mesorectal excision with Curr Probl Surg, August 1997

615

TABLE 3. Five-year survival rate after curative resection for rectal cancer

Dukes' stage A B C

Survival (%) 86 - 94 61 - 87 33 - 58

resection along defined anatomic planes to achieve safe margins and, subsequently, acceptable local control and survival rates. Tumor stage is the most powerful predictor for long-term survival (Table 3). In a review of patients treated solely by operation at the Lahey Clinic, Murray 4~ reported an overall 5-year survival rate of 57% for 200 patients after abdominoperineal resection. Dukes' stage-related survival rates were 86% (A), 65% (B), 33% (C), and 0% (D), demonstrating a significant decrease in the survival rate for patients with node-positive cancer.41A retrospective analysis of 250 patients with rectal cancer and a minimal followup of 5 years revealed survival rates of 69% for Dukes' B 1, 56% for Dukes' B 2, and 43 % with lymph node metastasis (C).9 Heald and colleagues4° confirmed this reduction in a series of patients undergoing curative resection by either abdominoperineal resection or anterior resection. A similar decrease in disease-free survival was noted in patients with node-positive cancer (58%) despite complete excision of the mesorectum. In a retrospective analysis of 99 cases of rectal cancer resected for cure according to the Astler-Coller system, Athlin and colleagues42 found that some patients with transmural invasion (B2) responded similarly to patients with node-positive disease. Inaccurate pathologic staging for lymph node metastasis could explain these similar outcomes in stage B2 and C cancers. This was suggested by Herrera and colleagues, 43 who found a substantial number (78%) of small (<5 mm) metastatic lymph nodes within Dukes' C specimens. Such results raise concern regarding the accuracy of pathologic staging for lymph nodal metastasis, especially in the advent of preoperative radiation, which has been shown to reduce the tumor burden significantly in perirectal lymphatic tissue. But whether discrepancies in survival rates between stages are related to tumor biology or to staging inadequacies, it is clear that operation alone cannot cure rectal cancer once transmural invasion or lymph node metastasis has been established. Local Excision. The excellent results obtained with the resection of early rectal cancers (T 1-T2) suggest that local excision may be feasible in certain favorable cases. Local excision is preferable to destructive procedures such as fulguration and endocavitary radiation simply because of the preservation of the pathologic specimen. Preoperative assessment is mandatory to 616

Curr Probl Surg, August 1 9 9 7

determine the accessibility and depth of invasion of the lesion. The depth of invasion with other parameters such as tumor grade can predict the potential for perirectal lymph node involvement, a contraindication for local treatment. In general, well-differentiated lesions, no larger than 3 cm, located within 8 cm from the anal verge are amenable to local excision, especially if located on the posterior wall. If on excision the margins of the specimen are free of disease and the lesion is well or moderately differentiated, the procedure is sufficient if invasion is limited to the mucosa. If the tumor extends to the submucosa, a postoperative course of radiotherapy to the tumor bed and the lymph node basin is usually recommended because of the 5% to 25% incidence of nodal disease. If the lesion extends to the muscularis layer of the bowel wall, a more definitive resection must be performed. Keeping this in mind, the results after local excision are equivalent to those for patients who undergo a more radical resection, with most series reporting a 5-year survival rate in the range of 84% to 100% and 65% to 78% for lesions invading beyond the submucosa. 44 Locally Advanced Rectal Cancer. Fixation of the tumor at the time of operation represents an important prognostic variable. 45It may be difficult to determine whether fixation is caused by inflammatory adhesions or by direct tumor extension tethering the tumor to the surrounding pelvic structures. Those lesions reactively fixed by inflammation should respond no worse to curative resection than mobile resectable lesions except for at most, slight increases in the operative morbidity. Durdley and colleagues 46 reviewed 338 patients who had undergone potentially curative excision of the rectum before the advent of preoperative radiotherapy; 169 patients had fixed lesions, 124 (73%) by direct tumor invasion and 45 (27%) by inflammatory reaction. Survival rates and recurrence rates were compared to those of an equivalent group of patients with mobile lesions. Local recurrence (20%) and 5-year survival rates (65%) in the tethered group were comparable to those of the mobile group (15% and 69%, respectively). Both groups were superior to the group of malign antly fixed tumors (41.3 % and 28.5 %, respectively). These investigators concluded that patients with fixed tumors within the pelvis have a poor prognosis when contiguous tumor spread has occurred. Similarly, Bonfanti and colleagues 47determined that local recurrence increased substantially if there was microscopic evidence of neoplastic involvement in stuctures excised simultaneously. Spratt and Spjut, 48 in an examination of clinical and pathologic variables, demonstrated the lack of lymph node metastases in certain colorectal tumors despite relatively large sizes or extensive local invasion. In several series, the results after extended resections for colorectal cancer revealed tumor infiltration and stage predicted the outcome independently. However, Curr Probl Surg, August 1997

617

in the presence of node-positive disease, tumor infiltration was not significant. 49'5° In a series from Washington University, patients undergoing extended resection had a 76% actuarial 5-year survival rate in the presence of negative lymph nodes, whereas none of the patients with lymph node metastasis survived beyond 5 y e a r s . 49 Whether the resection is performed for primary or recurrent disease affects the prognosis. Hafner and colleagues 51 demonstrated that 43% of patients who underwent resection for primary disease versus 20% of patients who underwent resection for recurrence were alive at 5 years. At the time of operation it may be particularly difficult to ascertain whether fixation is due to malignant spread or to benign adhesions. This distinction assumes even more relevance when conversion to a pelvic exenteration is required to achieve en bloc resection of a fixed tumor. Attempts to separate contiguous structures at operation predispose the patient to extremely high local recurrence rates with decreased survival. In a retrospective review at Virginia Mason Hospital, Hunter and colleagues 5z demonstrated a 5-year survival rate of 23 % in patients undergoing limited resection with separation of adherent structures, substantially less than the en bloc resection group (61%). Sound surgical judgement would dictate that in the face of a tethered lesion, the surgeon must be prepared to extend his or her procedure radically to resect any tumor en bloc. For rectal cancers that have spread to the fixed pelvis or beyond, the opportunity for cure has been lost. Although removal of the primary tumor may entail a significant undertaking that will not cure the disease at this stage, the ability to palliate may still be important. The elimination of pain, fistulas, pelvic sepsis, hemorrhage, and malodorous tumor necrosis can potentially improve the quality of life for the patient and family.53 Brophy and colleagues 54 reported on 35 patients who underwent palliative pelvic exenteration. The two most common symptoms leading to operation were pain (12 patients) and bleeding (11 patients). Operation was performed with an acceptable mortality of 3% and with an 88% increase in the quality of life and reduction in presenting symptoms. The important consideration for palliative exenteration is to perform surgery with a realistic goal in mind, keeping within an acceptable morbidity and mortality rate. Nevertheless, patient selection can be the greatest challenge.

Patterns of Failure Rectosigmoid and lntraperitoneal Rectum Issues. In the past 20 years, numerous studies have examined the patterns of failure in patients undergoing resection of rectal or colon cancer. 3,16,55-57These analyses have established the association of pathologic stage and survival and subsequent risk 618

Curr Probl Surg, August 1997

of local failure, distant metastases, or both after surgery. In addition, differences in the natural history after operation of rectal cancer versus colon cancer have been demonstrated by these investigations. Whereas local failure is a significant clinical problem in rectal carcinoma, this failure pattern is less frequent after operation for colonic carcinoma. In colonic cancer, peritoneal dissemination occurs with frequency after operation but is an unusual site of metastases after resection of rectal cancer. Because of these differences in the natural history, adjuvant and neoadjuvant treatment strategies have evolved in separate ways for patients with rectal cancer and those with colon cancer. In rectal cancer, the most important cause of local failure is residual disease left in the perirectal soft tissues after resection. 38'58After either a low anterior resection or abdominoperineal resection, the proximal and distal margins on the bowel may be between 2 and 15 cm or more. Because rectal cancer has a minimal propensity to spread longitudinally along the bowel wall, these margins are usually more than adequate. The circumferential or radial margin is often in the range of millimeters because it is difficult to remove a large amount of perirectal fat along with the primary specimen. Several studies have demonstrated that this failure in the soft tissues is very common after low anterior resection or abdominoperineal resection. 38'58This residual tumor would likely be affected by adjuvant radiation therapy. The reason that the surgeon cannot obtain a wide soft tissue margin in the pelvis is that the true rectum is a retroperitoneal structure that is located below the peritoneal reflection. In tumors that are located above the peritoneal reflection, the sigmoid is covered by a serosa and is attached to a large mesentery. Thus, the sigmoid colon (above the peritoneal reflection) is a mobile structure and the surgeon can easily obtain a very wide circumferential margin on the bowel. Soft tissue failure is unlikely. There has been controversy in the literature as to what distinguishes rectal cancer from colonic cancer? 8 The distance from the anal verge by itself is relatively unimportant, because there is no anatomic significance to this distance. Because local failure stems primarily from tumor extension into the retroperitoneal soft tissues, a good operational definition of a rectal tumor is one that is located at or below the peritoneal reflection. 58Tumors located above the reflection (colonic tumors) are intraperitoneal and are not likely to extend locally into tissues that cannot easily be resected. Thus, such lesions are less likely to lead to local failure. Therefore, the rationale for a local adjuvant treatment such as radiation therapy applies to tumor with invasion through the bowel wall and/or with positive lymph nodes when the primary tumor lies at or below the peritoneal reflection. Not all tumors can be defined as being above or below the peritoneal reflection, and some Curr Probl Surg, August 1997

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tumors do truly straddle the reflection. In addition, the peritoneal reflection is not a straight line but rather is a substantially curved structure extending more distally anteriorly than posteriorly. Therefore one can have a tumor that is located below the peritoneal reflection posteriorly but above it anteriorly. Because the likelihood of a local failure will be determined by the ability to obtain a wide surgical margin in the most surgically confined area, if even a portion of the tumor is located below the peritoneal reflection, it would be appropriate to treat the patient with radiation therapy as for a rectal carcinoma. The terms "rectosigmoid" and "intraperitoneal rectum" should not be used because they provide no meaningful insight into the risk of local failure after operation. Instead, tumors should be defined in relationship to the peritoneal reflection, and the decision regarding radiation therapy should be based on whether the lower edge of the tumor is located above or below the peritoneal reflection. Patterns of Failure after Curative Operations for Colon Cancer. Unlike the rectum, which is a retroperitoneal and immobile structure without serosa or mesentery, the colon (above the peritoneal reflection) has varying degrees of serosal covering, mesentery, and mobility) 9The ascending and descending colon and hepatic and splenic flexures are partially (and variably) retroperitoneal and immobile structures without a true mesentery and a serosal surface often limited to the anterior wall. At the other extreme, the sigmoid and transverse colon are freely mobile and completely intraperitoneal, having a complete mesentery and serosal covering. The cecum and proximal and distal segments of the sigmoid and transverse colon also have a variable mesentery and mobility. Analogous to rectal cancer, lesions of "immobile bowel" (i.e., ascending and descending colon and flexures invading through the bowel wall, particularly the lateral and posterior wall) may have compromised radial or pericolonic operative margins, because often only a small surgical margin is possible. Lesions extending anteriorly to the serosal surface may also be at risk for peritoneal spread. For tumors of mobile bowel (i.e., sigmoid and transverse colon) the surgeon can usually obtain a wide circumferential margin and the risk of a subtotal resection is usually limited to situations in which there is tumor invasion or adherence to adjoining structures. Because of their variable mesentery and retroperitoneal position, tumors arising in the cecum and proximal and distal portions of the transverse and sigmoid colon (partially mobile bowel) with extracolonic extension may have compromised radial resection margins. A number of studies have examined the failure patterns of colonic carcinoma after resection. 16,56,6°In the Massachusetts General Hospital (MGH) series of 533 patients undergoing resection of colonic cancer, both the 5620

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year survival rate and the incidence of local failure were closely correlated to t u m o r s t a g e J 6 The crude incidence of local failure according to stage was as follows: A, 1/29 (3%); B 1, 2/89 (2%); B2, 18/163 (11%); B3, 25/83 (30%); C1, 0/20 (0%); C2, 32/100 (32%); and C3, 24/49 (49%). Local failure occurred predominantly in the tumor bed and adjoining structures and not by nodal failures. Gunderson and colleagues 61 reported on 91 patients with predominantly stage C1 to C3 disease (73 patients) who had reoperation after initial resection and observed a 48% incidence of locoregional failure. For patients with stages C2 and C3 disease, a further analysis was performed to stratify patients according to the anatomic mobility of the primary site: mobile bowel (i.e., transverse colon and cecum) and immobile bowel (i.e., ascending and descending colon and flexures). Local failure increased as a function of anatomic immobility and with progressive extension of disease through the bowel wall. For patients with stage C2 disease with microscopic extension into fat, local failure occurred in 13% of tumors located in mobile bowel and in 29% of tumors located in immobile bowel. For patients with stage C2 disease with gross extension into fat, local failure was seen in 22% of tumors located in mobile bowel and in 72% of those in immobile bowel. Thus, the anatomic location and the tumor stage may be important in estimating the risk for local recurrence and the need for a localized adjuvant treatment such as postoperative irradiation. Although local failure is common after resection of colonic carcinoma, distant metastases also occur frequently in patients with advanced-stage disease. In the MGH series, the incidence of distant metastases was 25% (131/533). Only 21 patients had failure limited to extraabdominal sites, whereas 110 patients failed abdominally (e.g., liver, peritoneal surface, or abdominal lymph nodes). The rate of distant metastases rose from 3% for stage A disease to 45% for stage C3 disease. The highest incidence of abdominal failure occurred in patients with stage B3, C2, and C3 disease, with rates between 24% and 43%, but the rate was only 15% for patients with stage B2 and C1 disease. Within the abdomen, the liver was the most common site of metastasis. The highest failure rates occurred in patients with C2 and C3 disease, with liver failure rates of 29% and 31%, respectively. The incidence of failure in the peritoneal surface was highest in stage C2 and C3 disease (16% and 14%, respectively) but less than 4% for less advanced tumors. Thus, adjuvant systemic approaches are considered routinely for patients with stage B3 and C colon cancer. Patterns of Failure after Curative Operationfor Rectal Cancer. The University of Minnesota "second-look" series and other surgical series have identified patients at risk for local failure and distant metastases after curative resection of rectal cancer.55,62Patients with tumors extending through the bowel wall, with or Curr Probl Surg, August 1997

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without involvement of lymph nodes or extension to adjacent structures, have been found to have local failure rates of 20% to 70%. Generally the incidence of local failure increases as the extent of the disease increases. Patients with positive nodal disease plus extension through the bowel wall have a higher incidence of local failure than patients with only one of these characteristics. In addition, there is information to suggest that patients with tumors located low in the rectum have a higher incidence of local failure than patients with disease located high in the rectum? 8 One likely explanation for local recurrence includes residual disease left in the perirectal soft tissues after surgery. Another potential cause of local failure after operation is recurrence in the regional lymph nodes that have not been excised with the specimen. Lymphatic drainage of the upper rectum is primarily cephalad, paralleling the superior rectal blood vessels. These superior rectal lymphatics follow the inferior mesenteric vessels and empty into the inferior mesenteric nodes. The middle rectal and inferior rectal vessels that drain the mid and low rectum also have lymphatics associated with them, which tend to empty into the internal iliac or hypogastric lymph node chains. It is possible for carcinomas located very low in the rectum, especially those with extensive nodal disease, to metastasize through the anal lymphatics into the superficial inguinal lymph nodes. This, however, is an uncommon mode of spread because relatively few lymphatics cross between the lower rectum and the anus. Thus, for tumors located in the upper portion of the rectum the lymphatic drainage is virtually entirely by the mesenteric system, and this is treated well surgically. Little is to be gained by additional radiation to lymphatics that have already been excised. However, the surgeon usually makes no attempt to excise the internal iliac lymph nodes, which can be involved for tumors located in the mid and low rectum. It is this nodal failure that could be affected by a course of adjuvant radiation therapy, but this would be true only for tumors located in the mid and lower portion of the rectum, not for tumors located in the high rectal segment. Conclusions. Analogous to colonic cancer, the risk of systemic metastases correlates closely with pathologic stage. For patients with stage B2 and C rectal cancer, the risk of distant metastases ranges from 17% to 56%. Patients with rectal cancer and transmural invasion or lymph node metastases are at risk for local recurrence and systemic metastases. Adjuvant therapies of pelvic irradiation and chemotherapy are considered routinely for these subsets of patients. What remains unstudied is whether routine application of precise surgical technique with sharp pelvic dissection and total mesorectal excision can obviate the need for pelvic radiation therapy in a subset or perhaps most patients. Selected single institution local failure rates are summarized in Table 4. 622

Curr Probl Surg, August 1997

TABLE 4. Local failure after operation alone for resectable rectal cancer: selected single institution series

Series Gunderson3 Rich 55

Minsky 269

Definition of failure Cumulative by operation Cumulative by clinical exam and surgery

Total First failure by clinical exam and surgery

Total

No. of paUents 74 39 12 32 15 4 7 27 6 142 11 36 60 9 11 31 10 168

Stage B2/C A/B 1 B2m B2m+g B3 C1

C2m C2m+ g C3 A B~ B2 Bs C1 C2 Cs

Local failure rate (%) 65 (crude) 8 (crude) 17 25 53 50 28 52 67 30 11(5-year actuarial) 3 23 11 14 25 22 15

m, Microscopic penetration; m+g, gross penetration, confirmed microscopically.

Colon CancerAdjuvantTherapy The intended purpose of adjuvant therapy is to cure those patients who are rendered free of disease by operation but who will ultimately have a relapse if monitored without further intervention. Such relapses, if they occur, would be due to undetected microscopic metastases present at the time of operation. Patients without such microscopic metastases are cured by operation alone, and if these patients could be identified accurately, then they would require no further therapy. Appropriate application of adjuvant therapy therefore requires proper identification of those patients at risk for harboring microscopic metastases at the time of resection. Having identified such patients, one must then evaluate the potential effectiveness of available therapies in reducing the risk that these micrometastases will develop into clinical disease and then weigh this effectiveness against the potential risks and complications of such therapies.

5-Fluorouracil (5FU) The earliest adjuvant chemotherapy trials in patients with colorectal cancer studied the chemotherapeutic agents that were available at that time, despite the lack of evidence of specific efficacy of these agents against colorectal cancer. In one early report, nitrogen mustard or other alkylating agents were administered either during or shortly after operation. 63Another Curr Probl Surg, August 1997

623

early trial assigned patients randomly to either operation alone or to a brief course of triethylene-thiophosphoramide (thiotepa) in the immediate postoperative period. 64These trials did not demonstrate any evidence of clinical benefit. When the fluorinated pyrimidines were shown to have activity against metastatic colorectal cancer, efforts were focused on investigation of these agents in the adjuvant setting. Several early trials claimed to demonstrate a survival advantage for patients undergoing postoperative treatment with 5-fluorouracil (5FU) either alone 65,66 or in combination with immunotherapy with bacillus Calmette-Guerin (BCG). 67These were, however, uncontrolled single institution studies that used a historic control group for comparison. The Veteran's Administration Surgical Adjuvant Group reported a controlled trial of operation alone versus postoperative treatment with 5-fluorodeoxyuridine (floxuridine).68,69 The chemotherapy dose was 20 mg/kg/day for the first 3 days after surgery, and then, 6 weeks later, 30 mg/kg/day for 5 consecutive days, followed by four additional 15 mg/kg doses as tolerated. This trial demonstrated no significant difference in the overall survival between the treated and untreated groups after long-term follow-up. A second Veteran's Administration Surgical Adjuvant Group study explored the use of FU as a postoperative adjuvant compared with surgery alone. 7° Patients with both curative and palliative resections were enrolled. Patients receiving chemotherapy were treated beginning on postoperative day 14 with 5FU (12 mg/kg/day) for 5 consecutive days. A second course was repeated approximately 6 weeks later. The 5-year survival rate in the 308 patients who underwent resection with curative intent was 58.5% for those receiving chemotherapy and 49.4% for those treated with operation alone. These differences did not reach statistical significance, although the results did appear to suggest a trend towards improved survival with chemotherapy. However, in a somewhat larger trial, 522 patients underwent operation with curative intent and were randomized to either observation or a more protracted course of 5FU. 69"70This trial resulted in a 5-year survival rate of 48.9% for the group receiving chemotherapy and 44.2% for the group treated with operation alone (differences not significant). Several studies were reported with oral administration of FU for postoperative adjuvant treatment. 71,72In one study from Sweden 421 patients with resected Dukes' B or C colorectal cancer were randomized to receive either FU (5 mg/kg/day) orally for 3 months or placebo for the same time period. 7~ There were no significant differences in either the disease-free survival rate or the overall survival rate between the two groups. Because FU has been recognized to have wide interpatient variability in terms of 624

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oral bioavailability, further trials of oral FU have not been pursued. In 1984 the GITSG 73reported a four-arm trial in patients with Dukes' B2 and C colon cancers. Patients were randomized to receive either no postoperative therapy, postoperative BCG, postoperative FU plus BCG, or postoperative FU plus semustine. Of the 621 patients randomized, 572 were available for evaluation with a median follow-up of 5.5 years. No significant differences were observed in terms of recurrence or survival rates among any of the four arms. In 1988, Buyse and colleagues 74 published a recta-analysis of all randomized controlled trials of adjuvant therapy in patients with colorectal cancer published in English through 1986. Seventeen trials comparing chemotherapy with a no-treatment control group were included. Analysis of 5FU-containing regimens indicated a small benefit of therapy in terms of overall survival, with a mortality odds ratio of 0.83 in favor of therapy (95 % confidence interval, 0.70 to 0.98). Overall, this meta-analysis suggested that a small benefit may be achievable with chemotherapy but that larger studies would be needed to detect such a minimal difference. The first large random assignment trial to demonstrate a statistically significant benefit for patients receiving adjuvant chemotherapy was reported by the NSABE 75 These investigators reported a study of 1166 patients with Dukes' B and C colon carcinoma randomized to receive either (1) 5FU, semustine, and vincristine, (2) BCG, or (3) no further therapy. At 5 years of follow-up, patients treated with operation alone were at 1.29 times the risk of having a treatment failure and 1.31 times the risk of dying compared with patients receiving chemotherapy. Both the disease-free survival and overall survival benefits were statistically significant (p = 0.02 andp = 0.05, respectively). There was no demonstrable benefit for patients receiving BCG compared with the surgery-only control group. Three patients in the chemotherapy group had acute leukemia, and three additional patients in this group had myelodysplastic syndrome, presumably caused by the semustine.

5-Fluorouracil Plus Levamisole Levamisole is an agent with a long-standing use in veterinary medicine as an antihelminthic. Preliminary evidence suggested that levamisole enhanced the immunization of mice against Brucella abortus. These putative immunostimulatory properties led to its investigation as an anticancer agent. 76'77Based on encouraging preliminary data, 77 the NCCTG conducted a three-arm study that randomly assigned patients with Dukes' B2 and C cancer to either operation alone, operation followed by levamisole, or operation followed by 5FU plus levamisole, z6 The results from this adjuvant trial were encouraging, leading to a large confirmatory trial 78-8°conducted through the intergroup mechanism (Table 5). Curr Probl Surg, August 1997

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TABLE 5. Long-term follow-up results of adjuvant 5FU plus levamisole Intergroup Trial (INT0035)8±, 82

Dukes' Dukes' Dukes' Dukes'

C operation + 5FU/levamisole C operation alone B2 operation + 5FU/levamisole B2 operation alone

No. of patients

Percent of patients recurrence-free*

Long-term survival rate*

304 315 159 159

61 44 80 72

60 47 73 72

*Median follow-up for Dukes' C patients is 6.5 years. Median follow-up for Dukes' B2 patients is 7 years.

In this intergroup trial, a total of 929 eligible patients with node-positive (Dukes' C) disease and 318 patients with transmural, node-negative (Dukes' B2) disease were enrolled. The study data have been reported with a median follow-up of 6.5 years for patients with Dukes' C cancer and 7 years for patients with Dukes' B2 cancer. Of the patients with node-positive cancer treated with operation alone, 44% remained alive and free of disease at 5 years compared with 61% of patients who received fluorouracil and levamisole. This difference was not only highly significant (p < 0.0001) but is also highly clinically significant as well. This 17% difference between disease-free survival rates represents a 39% reduction in mortality. When considering the frequency of node-positive colon cancer, with approximately 30,000 cases expected in the United States annually, appropriate administration of this adjuvant regimen would be expected to save approximately 6,000 lives per year. This treatment schedule was recommended by the 1990 National Cancer Institute Consensus Conference on adjuvant therapy for colorectal cancer as standard therapy for node-positive colon c a n c e r . 81

The rationale for adjuvant treatment for patients with stage B2 disease remains unclear. Data from the intergroup levamisole/FU trial 8° failed to demonstrate a statistically significant benefit for treatment of this patient population. At 7 years after operation, 79% of patients receiving chemotherapy and 71% of patients in the observation arm were free of recurrence. This difference was not statistically significant (p = 0.10). The 7-year survival rate for each arm of the study was 72%. On the basis of these data, it would be difficult to recommend the routine use of currently available adjuvant chemotherapy for patients with Dukes' B2 tumors. Certain prognostic factors, however, have been correlated with a higher risk for recurrence in patients with stage B2 tumors. These factors have included obstruction of the bowel lumen or perforation of the bowel wall by tumor. 82Analysis of risk factors for recurrence in the intergroup FU plus 626

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levamisole trial confirmed perforation to be an independent risk factor but did not find obstruction to correlate with higher risk for recurrence. Other potential risk factors that are less well established include an elevated preoperative carcinoembryonic antigen, poorly differentiated histologic characteristics, or a high S-phase fraction. Data have been reported indicating that the presence of an 18q deletion in colorectal tumors may correlate with a poor prognosis. 83Patients with full-thickness tumors and one or more of the previously mentioned risk factors are at higher risk for recurrence. Although the usefulness of adjuvant therapy in these high-risk patients with Dukes' B2 tumors has not been proven conclusively, and the available data in this matter have substantial limitations, it would appear to be reasonable to offer adjuvant chemotherapy to younger patients with Dukes' B2 tumors and high-risk negative prognostic factors. The mechanism by which levamisole functions in the adjuvant treatment of colon cancer is not fully understood. Early data suggesting immunostimulatory properties in animals led to the assumption that levanlisole functions as an immunostimulant in the adjuvant setting. However, it has not been demonstrated consistently that there is a detectable, reproducible effect on the immune system at the concentrations that are achieved clinically in plasma. 84,85It has been suggested that levamisole may simply potentiate 5FU by inhibiting intracellular phosphatases involved in its degradation. 86Once again, however, this effect cannot be demonstrated at the concentrations typically achieved clinically.87A recent report has indicated that levamisole stimulates the expression of major histocompatability class 1 antigens on the surface of colon cancer cells grown in vitro. 88 This finding led to speculation that such antigen expression could make the cells more vulnerable to surveillance and destruction by the immune system. Such speculation is intriguing, but it is premature to accept this as a mechanism of action for levamisole. It is not known whether an increase in major histocompatability class 1 antigen expression with levamisole occurs in vivo and whether this would, in fact, lead to a clinically significant improvement in immune function. 8s At this time we must conclude that the mechanism of action for levamisole remains unknown. In fact, it has been proposed that levamisole might not be an active agent at all. ~9 The large trials performed with 5FU and levamisole may simply have adequate numbers of patients and adequate treatment duration and dose intensity of 5FU to permit detection of a modest clinical benefit.

5-Fluorouracil Plus Leucovorin In the United States, unresectable metastatic colorectal cancer is most commonly treated with a combination of 5FU and leucovorin. 9° Randomized Curr Probl Surg, August 1997

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comparisons have demonstrated equal efficacy for 5FU schedules modulated by either high-dose or low-dose leucovorin. 91.92 It is reasonable to expect that 5FU plus leucovorin, on the basis of activity in metastatic disease, would be active in the adjuvant setting as well. Several investigators have evaluated this possibility. The NSABP CO-3 study compared 5FU and leucovorin with the regimen of semustine, vincristine, and 5FU, which had been found to be superior to observation in the NSABP C-01 trial. These investigators found superior long-term disease-free survival rates for patients treated on the 5FU plus leucovorin arm. 93 Three virtually identical trials of 5FU plus high-dose leucovorin conducted in Italy, Canada, and France were pooled to permit analysis of a large patient population. 94This pooled analysis, referred to as the International Multicenter Pooled Analysis of Colon Cancer Trials, compared the outcome of 757 patients with operation alone with that of 736 patients receiving chemotherapy. Fifty-six percent of patients had Dukes' B and 44% had Dukes' C tumors. Overall, the 3-year event-free survival rates were 62% and 71% for the operation only and chemotherapy groups, respectively (p < 0.0001). The differences were most apparent in the patients with Dukes' C tumors, in whom the 3-year survival rate was 44% versus 62% for operation only versus chemotherapy. The difference in patients with Dukes' B tumors was substantially smaller, with 76% and 79% of patients in the operation only and chemotherapy groups, respectively, remaining free of events at 3 years (p value not given). Several important trials addressing the role of leucovorin in the adjuvant treatment of colon cancer have completed patient accrual, and the data are nearing maturation. The C-04 trial from the NSABP has recently been reported in abstract form. 95This trial randomly assigned patients with Dukes' B and C tumors to receive one of three postoperative treatments: 5FU plus high-dose leucovorin on a weekly schedule for six cycles (each cycle followed by a 2-week break, thus therapy given for almost 1 year), the same 5FU plus leucovorin schedule with the addition of standard dose oral levamisole (50 mg orally three times daily for 3 days, every other week), or 5FU plus levamisole with the current standard dose and schedule for 1 year of therapy. A total of 2151 patients were entered on this trial. The addition of levamisole to 5FU plus leucovorin in this trial appeared to have no substantial effect. The actuarial 5-year disease-free survival rate for each of these two arms was 64%. The overall 5-year survival rate was 74% for the 5FU plus leucovorin and group and 72% for the 5FU plus leucovorin madlevamisole group. The 5FU plus levamisole group appears to have fared slightly worse, with 5-year disease-free and overall survival rates of 60% and 69%, respectively. Both of these values reached statistical significance in comparison with 628

Curt Probl Surg, August 1997

the 5FU plus leucovorin arm (p values <0.05). It should be noted that these data are reported in preliminary abstract form, with only 49% of patients contributing survival information through 5 years. Definitive interpretation of these data must await full publication of the mature data. Another important trial that has recently been reported in abstract form is a collaborative effort of the NCCTG and the National Cancer Institute of Canada. 96This four-arm randomized trial compared 6 months of 5FU plus levamisole versus 12 months of 5FU plus levamisole with or without the addition of low-dose leucovorin. The conclusions of this report were that 12 months of chemotherapy offered no significant advantage over 6 months and that 6 months of 5FU plus leucovorin and levamisole was superior to 6 months of 5FU and levamisole (p < 0.005). It is difficult to know exactly how to interpret these data, because 6 months of 5FU/levamisole/leucovolin was found to be superior to 6 months of 5FU/levamisole, but 12 months of 5FU/levamisole/leucovorin was not superior to 6 months of 5FU/ levamisole. Again, definitive interpretation of the data from this trial must await the complete analysis of the data and publication of the full manuscript. A four-arm intergroup trial, INT-0089, stratified patients for disease stage (Dukes' C vs high-risk B2) and randomized them to receive either standard postoperative 5FU plus levamisole, 5FU plus high-dose leucovorin, 5FU plus low-dose leucovorin, or 5FU plus low-dose leucovorin and levamisole. The three leucovorin-containing arms were continued for 6 months, and the 5FU plus levamisole was continued for the standard 12 months. Preliminary data from this trial, also reported in abstract form, do not demonstrate a significant superiority of one arm over another at this point. 97

Investigational Approaches As the data from the International Multicenter Pooled Analysis of Colon Cancer Trials and intergroup trials mature, 6 months of 5FU plus leucovorin may prove to be an acceptable or even superior alternative to the current standard of 1 year of 5FU and levamisole. Clearly, however, none of the systemic 5FU-based adjuvant regimens will be a completely satisfactory solution to the problem of preventing recurrent disease, and more effective adjuvant treatment techniques will require development. Investigators are exploring a number of different approaches to improve the adjuvant therapy of colon cancer (Table 6). Portal Vein Infusion. Of all potential sites for distant metastases of colorectal cancer, the liver is the most commonly involved, ~6,98,99with approximately one half of all patients who have a relapse presenting with liver involvement as the first site of failure. Tumor cells presumably enter the eurr Probi Surg, August 1997

629

TABLE 6. Novel approaches to adjuvant treatment of

high-risk colon cancer currently under investigation Alternative 5FU biomodulation schemes (leucovorin, levamisole plus leucovorin) Intraportal chemotherapy Early systemic chemotherapy Intraperitoneal chemotherapy Monoclonal antibodies Antitumor vaccines New anticancer agents

liver from the abdominal cavity by way of the intraperitoneal lymphatics and venules that empty into the portal vein. 1°°,1°1 Intraportal delivery of chemotherapy, therefore, would be a logical approach for the administration of adjuvant treatment. In animal models, tumors greater than 1 cm in diameter derive most of their blood supply from the hepatic artery, and tumors from 1 to 5 m m obtain their blood supply from both the hepatic and portal circulations.~°2,1°3Thus, at the early stages of its development, a liver metastasis would be exposed to high concentrations of an anticancer agent delivered intraportally. Initial phase I studies demonstrated that 5FU could be administered safely intraportally and that higher doses could be administered safely by intraportal infusion than by intravenous infusion. This is due to the extraction, or "first pass clearance" of 5FU by the liver. 1°4An early report of a small randomized triaP °5 of systemic versus intraportal 5FU stimulated extensive interest in this approach, although a later report that included a larger number of patients appeared to show a benefit only for patients with Dukes' B tumors. I°6 The Swiss Group for Clinical Cancer Research reported a large controlled trial of intraportal adjuvant chemotherapy. 1°7,~°8Five hundred thirty-three patients received either operation alone or operation followed by a single intraportal 2-hour infusion of mitomycin C (10 mg/m 2) plus a 7-day intraportal infusion of fluorouracil at a dose of 500 mg/m2/day. With a median follow-up of 8 years, the 5-year disease-free and overall survival rates were modestly improved in those patients who received the intraportal treatment (57% vs 48% and 66% vs 55%, respectively). Contrary to expectations, however, there was no statistically significantly different incidence of hepatic metastases between the treatment and control groups. Similar results were obtained in a somewhat larger trial by the NSABP group. Their C-02 trial 1°9randomly assigned 1158 patients with Dukes' A, B, or C colon cancers to either a 7-day intraportal infusion of 600 mg 5FU/ day or no postoperative chemotherapy. Again, a small but statistically significant survival advantage was demonstrated for the treatment group (74% 630

Curr Probl Surg, August 1997

vs 64% disease-free survival rate at 4 years), but there was no difference in the incidences of hepatic metastases between the two groups. The consistent failure of controlled intraportal chemotherapy studies to demonstrate a reduction in hepatic metastases suggests that the modest degree of benefit may be a result of systemic activity of the intraportally administered chemotherapy. However, most controlled trials of adjuvant portal vein chemotherapy have demonstrated a survival advantage over operation only, and it is noteworthy that the benefits obtained with brief intraportal treatments appear to be similar to those derived from a year of adjuvant systemic therapy. A current intergroup trial is exploring the additive benefit of immediate postoperative systemic infusional 5FU followed by standard 5FU and levamisole. Intraperitoneal Chemotherapy. Hematogenous metastases of colorectal cancer enter the liver by way of the portal circulation. Studies on the clinical failure patterns of patients with colorectal cancer after resection~8and on the basis of planned second-look laparotomy 3,11°have demonstrated a high frequency of hepatic and peritoneal metastases. Because the peritoneal cavity is drained by way of lymphatics into the portal vein, intraperitoneal administration of chemotherapy should result in high concentrations of drug in the portal vein. Direct measurements of drug levels in the portal vein after intraperitoneal drug administration has confirmed this expectation.111'112There is therefore a strong rationale for postoperative intraperitoneal chemotherapy, because this approach delivers high concentrations of drug both directly to the peritoneal surfaces and, by way of the portal vein, to any early hepatic metastases that may be present. Before intraperitoneal adjuvant treatment in humans was evaluated, animal studies yielded supportive data for this approach. Injection of colon cancer cells both intraportally and intraperitoneally in a rat model demonstrated that intraperitoneal 5FU prevented macroscopic peritoneal tumor growth in 57% of the animals treated and yielded a 50% decrease in hepatic metastases compared with an untreated control group. When a third cohort of rats was treated with systemic 5FU, they had no reduction in peritoneal metastases compared with the untreated control group.ll2 Floxuridine, and to a lesser extent, fluorouracil, have a high first-pass clearance through the liver. This makes these drugs logical choices for intraperitoneal administration, because the hepatic clearance would be expected to create substantially lower systemic concentrations compared with intraperitoneal levels. This expectation was confirmed by pharmacologic investigations of intraperitoneal 5FU and floxuridine. These clinical trials demonstrated that intraperitoneal concentrations 200- to 400-fold higher than were achievable by systemic administration could be obtained. 1l 1.~13 Curr Probl Surg, August 1997

631

A small randomized trial of adjuvant systemic versus intraperitoneal chemotherapy in patients with resected colon cancer has been reported. H4 This study did show a substantial decrease in the incidence of peritoneal metastases in the group receiving intraperitoneal chemotherapy, but no differences in the overall survival or in the incidence of hepatic metastases were observed. The ability to draw meaningful conclusions from this study is hampered both by its small size and by the fact that this trial permitted the initiation of chemotherapy up to 2 full months after resection. Earlier initiation of intraperitoneal therapy may be necessary to optimize the effectiveness of this approach. Delays in the initiation of treatment would be expected to increase the chance of spread and growth of tumor outside of the peritoneal cavity and might possibly permit hepatic microscopic metastases to establish an hepatic artery-dominant circulation. A more recent trial investigated the combination of immediate postoperative intraperitoneal floxuridine and leucovorin plus systemic levamisole and 5FU. H5In this trial, patients received intraperitoneal therapy twice daily for 3 consecutive days every other week for three cycles. Patients began levamisole orally with the second intraperitoneal cycle, and 5 days of bolus injections of 5FU were administered starting with the beginning of the third intraperitoneal cycle. These systemic doses of 5FU given concurrently with intraperitoneal chemotherapy were escalated to tolerance in a phase I dose escalation schema. On day 29 after the start of 5FU, weekly standard dose 5FU and standard dose every-other-week levamisole were started and continued to complete 1 year of therapy. This combined local-regional and systemic treatment schedule was well tolerated, with no apparent increase in the perioperative morbidity. At a median follow-up of 24 months, 24 of 28 patients were alive and free of disease. Although these preliminary results are encouraging, long-term followup and large-scale randomized controlled trials will be needed to determine whether or not this approach is superior to systemic therapy alone. MonoclonalAntibodies. Results with monoclonal antibodies as antineoplastic agents in clinical trials have been disappointing in general. One possible reason for the relative lack of success thus far in what would appear to be a promising antitumor approach could be that the relatively large molecular size of these agents interferes with efficient transport into solid tumor tissue. 116This problem could be circumvented, however, by targeting monoclonal antibodies against small-volume minimal residual disease. A patient who has had all gross tumor resected but who is at risk for harboring microscopic residual disease presents an optimal minimal residual disease situation. Following this course of logic, several investigators have explored the use of monoclonal antibody therapies in the adjuvant setting in patients with colon cancer. 632

Curr Probl Surg, August •997

Studies have shown that monoclonal antibodies can be used to identify microscopic metastases in bone marrow specimens taken from patients with colorectal cancer 117and that the presence of these bone marrow metastases correlated with a poor outcome. 118 In vitro studies performed with a mufine monoclonal immunoglobulin G2a antibody directed against the 171A antigen have demonstrated the ability of this antibody to induce antibody-dependent cellular cytotoxicity119-121and to inhibit the growth of human colon cancer xenografts in nude mice. 1~2 The first clinical trials of this antibody were undertaken in patients with advanced metastatic disease. These studies reported several instances of minor tumor regression and no major t o x i c i t y . 123 Once tolerable toxicity and evidence of clinical activity had been demonstrated, a randomized trial was undertaken to evaluate this antibody in the adjuvant setting in patients with resected lymph node-positive colon cancer? z4 One hundred sixty-six patients were entered into the trial and were randomized to receive either monoclonal antibody or operation alone. Patients in the adjuvant treatment group received 500 mg of 17-1A antibody 2 weeks after operation by 1hour intravenous infusion followed by four 100 mg infusions administered at 4-week intervals. With a median follow-up of 5 years (range 2.5 to 7.5 years), 64% of the patients who received monoclonal antibodies were alive, whereas the surviving percentage of patients receiving operation alone was 49 %. This 15 % difference represents a 30% reduction in mortality. Caution must be used when interpreting these data because of the relatively small sample size. Nevertheless, these initial results are encouraging, and large-scale phase III testing of this antibody is currently in progress. AntitumorVaccines. The perfect target for immunologic therapy would be a tumor-specific antigen that is unique to, and always expressed by, tumor cells, and which is never expressed by nonmalignant cells. Thus far, no such ideal tumor-specific antigen has been identified. Efforts have been focused either on identification of an antigen with a high frequency of expression on tumor cells or on the use of autologous tumor cells with immunoadjuvants. The blood group-related epitopes Tn and sialylated Tn (sTn), which are expressed on mucins of many epithelial tumors including colorectal carcinomas, have been identified as potential immunologic targets. A vaccine has been developed from partially desialylated ovine submaxillary gland mucin (modified OSM), which contains both Tn and sTn determinants. In a clinical trial, cohorts of patients were selected for treatment with either modified OSM, modified OSM plus the immunologic adjuvant DETOX, or modified OSM plus B C G . 125 The goal of this study was to determine Curr Probl Surg, August 1997

633

whether antibody titers to Tn and sTn could be raised by these vaccinations.Although none of the six patients receiving modified OSM alone had antibodies, four of eight patients receiving modified OSM plus DETOX and five of six patients receiving modified OSM plus BCG demonstrated marked increases in antibody titers. Further investigations into this approach are continuing. Investigators are exploring the use of more potent immune adjuvants and are augmenting Tn and sTn by covalent attachment of immunogenic carder proteins to further increase the immunogenicity of these epitopes. Other investigators have taken a different approach to immunologic stimulation through clinical investigations of a technique termed active specific immunity. In this approach, patients receive immunizations with a combination of BCG and a preparation of their own irradiated tumor cells. Irradiation of tumor cells has been shown to destroy tumorigenicity but not the immunogenicity of the cells.A small randomized trial involving 80 patients with colon and rectal cancer has been reportedJ 26Although this trial demonstrated no overall benefit for the immunized patients compared with those treated with operation alone, a retrospective subset analysis did show a statistically significant improvement in survival for the immunized patients with colon cancer only. The limitations of retrospective subset analyses, the small number of patients with colon cancer (47), and other serious methodologic problems 127in this study, however, make interpretation of these data difficult. Larger, more carefully constructed trials have been performed, and analysis of the data from these trials is pending. Conclusions. Important advances have been made in the area of adjuvant chemotherapy for colon cancer. Currently available drugs have been shown convincingly to reduce the incidence of recurrences and to prolong the overall survival. Still, many patients with resected colon cancer ultimately have a relapse and die of their disease. Thus, there is a strong need for continued development of improved adjuvant treatment strategies. As information becomes available from the trials currently in progress, approaches now regarded as investigational may move into standard practice. Several new drugs including tomudex, irinotecan (CPT- 1 1), and oxaliplatin have shown substantial clinical activity against colorectal cancer in patients with metastatic disease. These drugs, alone or in combination with standard agents, will require evaluation in the adjuvant setting.

Rectal Cancer Adjuvant Therapy Combined modality therapy is an integral component of the management of rectal cancer in the adjuvant setting. There are two components of adjuvant therapy: pelvic radiation and 5FU-based chemotherapy. In patients with 634

Curr Probl Surg, August 1997

clinically resectable disease, the role of radiation therapy is to decrease the risk of local recurrence and to increase the chance for sphincter preservation. In patients with locally advanced/unresectable disease, radiation therapy has the added role of potentially increasing the resectablility rate. The role of chemotherapy, regardless of the resectability status, is to enhance the effectiveness of radiation (radiosensitization) and to improve survival by eradicating microscopic distant metastases.

Postoperative Adjuvant Therapy Nonrandomized, retrospective matched data from the MGH 128and the M.D. Anderson Cancer Center 129"13°reveal a decrease in local recurrence rate in patients with stage T3_4NoM 0 (B2,B3) disease and in patients with stage T3_4Nl_2M0 (C2,C3) disease who received pelvic radiation at a dose of 4500 to 5500 cGy. The primary advantages of the postoperative approach are that the tumor stage is already known (therefore those 10% to 15% of patients with stage TI_2NoM0 or hepatic metastases may be spared treatment) and more accurate definition of the tumor bed for radiation planning can be obtained by the placement of clips at the time of operation. Disadvantages include an increased amount of small bowel in the radiation field] 31 a potentially hypoxic postsurgical radiation field, and, after an abdominoperineal resection, the need to extend the field inferiorly to include the perineal s c a r . 132 Preoperative Versus Postoperative Radiation Therapy. It is difficult to compare, stage for stage, the results of preoperative versus postoperative radiation therapy because (1) preoperative trials usually include a limited number of patients withTl_2N0 disease, (2) full-dose preoperative radiation will downstage both theT and N stage, and (3) patients with pathologically confirmed M1 disease are excluded from adjuvant postoperative trials. The only randomized trial of preoperative versus postoperative radiation therapy for resectable rectal cancer was reported by Pahlman and Glimelius.133 In this multicenter randomized trial from Sweden (Uppsala Trial), 471 patients were randomized to receive either 2550 cGy before surgery (in 1 week) or 6000 cGy (split course) after surgery. Postoperative radiation therapy was limited to patients with stages T3 or N~_2disease. Patients with stage TI_2N0 disease who were randomized to the postoperative radiation arm did not receive radiation and were observed. The treatment results 133 and the long-term toxicity TM have been reported. Patients who received preoperative radiation therapy had a significant decrease in local recurrence (13% vs 22%, p = 0.02), but there was no difference in the 5-year survival rate (42% vs 38%). Although no increase occurred in immediate radiation-related complications or postoperative mortality, a significant increase occurred in the incidence of perineal wound Curr Probl Surg, August 1997

635

sepsis in the preoperative group (33% vs 18%, p < 0.01). Similar to other randomized trials of preoperative abdominoperineat resection radiation therapy, the excessively large fraction size (510 cGy/day) may have contributed to this complication. Despite the increased incidence of acute toxicity, the long-terrn toxicity was lower in patients receiving preoperative radiation therapy. The incidence of small bowel obstruction was 5 % in patients receivingpreoperative radiation therapy and 11% in patients receiving postoperative radiation therapy (p = 0.01). In a historic surgical control group, the incidence was 6%. Likewise, the overall incidence of serious toxicity (gastrointestinal, genitourinary, skin, neurologic) was 20% for the preoperative treatment group and 41% for the postoperative group. By comparison, the incidence of serious toxicity was 23 % for the historic surgical control group. Sphincter Function with PostoperativeRadiation Therapy. Two investigators have reported on the impact of postoperative radiation therapy on long-term sphincter functionJ 35.~36It must be emphasized that both of these trials were nonrandomized, nonblinded, retrospective telephone surveys. Kollmorgen and colleagues ~35from the Mayo Clinic assessed the impact of postoperative combined modality therapy on bowel function in patients who received conventional doses and techniques of pelvic radiation therapy and 5FU-based chemotherapy. The results were compared with a matched group of patients who underwent operation alone.~3~The 41 patients who received combined modality therapy had a significant increase in the number of bowel movements, clustering of bowel movements, nighttime bowel movements, occasional incontinence, and urgency and wore pads more often compared with 59 patients who underwent operation alone. Sphincter function after a coloanal anastomosis was reported by Paty and colleagues a36from Memorial Sloan-Kettering Cancer Center (MSKCC). The 40 patients who received preoperative radiation therapy, postoperative radiation therapy (with or without chemotherapy), or both after a coloanal anastomosis had increased stool frequency and difficulty with evacuation compared with 41 patients who underwent operation alone. These toxicities must be examined in perspective. The benefits of radiation therapy include decreasing local recurrence and, in the preoperative setting, sphincter preservation. The observed side effects highlight the importance of paying careful attention to treatment techniques that decrease the acute and delayed toxicities of pelvic radiation therapy.132 Postoperative Combined Modality Therapy (Chemoradiation). The anatomy and natural history of rectal cancer requires attention to the issues of local and systemic tumor control. Despite many clinical trials, until recently there has been considerable controversy about whether additional 636

Curr Probl Surg, August 1997

therapy improved the survival rate for patients undergoing surgical resection of a primary tumor. Even a meta-analysis of the worldwide published experience, which demonstrated a statistically significant benefit for adjuvant chemotherapy in patients with rectal cancer (38% decrease in the mortality rate), did not completely convince many physicians. 74 However, a Consensus Development Conference sponsored by the National Institutes of Health in 1990 concluded that effective adjuvant therapy exists for stages 2 and 3 (Astler Coller stages B2 and C or TNM stage T3_4 and/or nodepositive) rectal cancer. This conclusion was based on the clinical data derived over the past 20 years. Especially important were five studies recently reported or updated, which are summarized in Table 7. Two of the studies included operation-only groups, and three studies used operation plus postoperative pelvic radiation as the means for achieving definitive local contro1.7.137-139 The GITSG study 7175 was initiated in 1975 and allocated patients with completely resected stage Dukes' B2 or C tumors to one of four treatment groups 7,137: ( 1) operation only (control), (2) methyl-CCNU ( 130 mg/m 2 on day 1) and 5FU (325 mg/m 2 on days 1 through 5; 375 mg/m 2 on days 36 through 40), repeated every 10 weeks for 18 months, (3) radiation therapy to the pelvis with 4000 to 4800 cGy to the pelvis, and (4) radiation therapy to the pelvis with 4000 to 4400 cGy with concomitant 5FU (500 mg/m 2) on the first 3 and last 3 days of radiation plus 5FU and methyl-CCNU (doses as in the second group). Although initially projected to accrue more than 500 patients, this trial was terminated after the entry of only 227 patients because of observed outcome differences between the regimens. At an 80-month median follow-up time patients treated with operation only experienced a 55% recurrence rate compared with 33% for the combined modality therapy group (p < 0.009). Fourteen local recurrences occurred in the 32 patients in the control group, and five local recurrences occurred in the 46 patients treated with combined modality therapy. A subsequent analysis at a median follow-up of 94 months revealed an even larger margin of benefit for combined modality therapy. In addition to a disease-free survival advantage, combined modality therapy was associated with a statistically significant overall survival benefit (p = 0.005). There was an approximate 20% superiority in survival rates at 6 years for the 96 patients at r i s k . 137 Although these data support an aggressive multimodality approach to patients with rectal cancer, the morbidity of combined radiation therapy plus FU and methyl-CCNU must be considered? 4° Severe or life-threatening acute toxic effects occurred in 18% of patients in the combined modality therapy arm. Three late deaths occurred, two from enteritis in the comCurr Probl Surg, August 1997

637

TABLE 7. Rectal cancer: selected completed adjuvant trials

Series

Accruals

GITSG 7 1 7 5 ~,137

227

NCCTG 79-47-51139

204

NSABP R01 T M

555

GITSG 7 1 8 9 T M

210

NCCTG 86-47-51146

453

Treatment

Results

Control MF RT+MF RT MF-~RT +5FU-~ MF RT RT Control Pelvic RT MOF

RT + MF results in 59% 5year survival; 43% in controls (p < 0.01)

RT + 5FU-~ 5FU RT + MF MF MF--~ RT +5FU--~ MF 5FU-~ RT + 5FU-~ 5FU (infusion vs bolus for 5FU)

RT + MF resulted in 63% 7-yr survival; 48% for RT alone (p = 0.04) MOF resulted in 52% 5-yr survival; 42% in controls (and RT); significantly superior DFS 3-yr DFS is 45% for MF and 69% for 5FU With 46-mo median followup MF was not superior to 5FU; 5FU infusion superior to bolus in time to relapse and survival

GITSG, Gastrointestinal Tumor Study Group; RT, pelvic radiagon therapy; MF, Methyl-CCNU+ 5FU; NCCTG, North Central Cancer Treatment Group; NSABP,National Surgical and Adjuvant Breast and Bowel Project; MOF,methyI-CCNU + vincristine (oncovin) + 5FU; DFS,disease-free survival, *All patients underwent complete surgical resections and had stages T3-4 and/or N+.

bined modality therapy group and one from acute nonlymphocytic leukemia in patients treated with chemotherapy alone. Another major trial of adjuvant therapy for rectal cancer was initiated by the NCCTG in 1979) 39A total of 204 eligible patients with Astler Coller stage B2 or C rectal cancer were randomly assigned to postoperative radiation therapy only (4500 cGy with a 540 cGy boost) or to an integrated program of methyl-CCNU (130 mg/m 2 on day 1) plus 5FU (350 mg/mV day on days 1 through 5; 400 mg/mZ/day on days 36 through 40), radiation therapy beginning on day 64 with concomitant 5FU (500 mg/m 2) on the first 3 and last 3 days of radiation followed by one additional cycle of methyl-CCNU plus 5FU (i.e., sandwich therapy). At a median follow-up of more than 7 years, 62 recurrences occurred in the group treated with radiation therapy alone, and only 40 recurrences occurred among those treated with combined modality therapy (p < 0.0025). Even after adjustment was performed for known prognostic factors, the risk of relapse for patients receiving combination treatment was reduced by 47% compared with postoperative radiation therapy alone. The local recurrence rate in the combined modality therapy group was 13.5% but was 25% in those treated with postoperative radiation only. The overall disease-free survival was superior with combined modality therapy (p = 0.0016).An overall survival advantage 638

Curr Probl Surg, August 1997

was also demonstrable for the combined modality therapy. The risk of cancer-related death was reduced by 36% (p = 0.0071) and the overall death rate by 29% (p = 0.025). The largest study was performed by the NSABP (R01) and required almost a decade to complete accrual. 141A total of 555 patients with Astler Coller stage B2 or C rectal cancer were randomized to one of three arms: postoperative observation; postoperative pelvic radiation therapy of 4700 cGy with a boost to 5300 cGy maximum; or MOF chemotherapy (methylCCNU, vincristine, 5FU). After a 64-month mean follow-up time period, a statistically significant disease-free survival advantage was found for MOF chemotherapy (p = 0.05) and an overall survival improvement for selected subsets of patients receiving MOF, particularly men and patients younger than 65 years. Additional studies revealed that overexpression of thymidylate synthase in the primary tumor was associated with a worse prognosis m and that such patients derived the greatest benefit from adjuvant MOF chemotherapy. Patients who received only postoperative radiation had no statistically demonstrable improvement in the overall or relapse-free survival compared with those who underwent operation alone. There was, however, a significant reduction in the local recurrence rate from 25% without radiation therapy to 16% with radiation therapy. Despite 80 weeks of MOF chemotherapy, no leukemias have been observed. Other toxic effects were predictable and tolerated. These three studies permit the conclusion that combined modality therapy is superior to operation alone, but the optimal protocol for chemotherapy is not yet defined. Two studies addressed the relative value of the addition of methyl-CCNU to 5FU as part of a combined modality therapy treatment. The GITSG study 7180 evaluated 210 patients who successfully underwent surgical resection followed by 4140 cGy of pelvic radiation and 5FU (500 mg/m 2 administered intravenously daily for 3 days at the beginning and end of radiation). Patients were then assigned to receive 5-day courses of bolus 5FU (300 to 500 mg/m2) for 6 months or 5FU (300 to 375 mg/m2/day for 5 days each month) plus methyl-CCNU (100 to 130 mg/m2 for 10 weeks) for a total of 12 months of treatment. With 3-year follow-up data no superiority was seen in recurrence or survival rates evident for the addition of methyl-CCNU. 143,144 The NCCTG study 86-47-51 used a 2 x 2 factorial statistical design to quantify the relative benefits of continuous (protracted venous) infusion compared with bolus 5FU during pelvic radiation therapy and to determine the value of including methyl-CCNU in the chemotherapy regimen. All patients received pelvic radiation therapy and concomitant 5FU in the sandwich sequence of chemotherapy-radiation chemotherapy. One half of the Curr Probl Surg, August 1997

639

patients received methyl-CCNU and 5FU chemotherapy as in the previous NCCTG trial (79-47-51), and the other half received only 5FU (500 mg/m 2 on days 1 through 5 and days 36 through 40). During the radiation patients received 5FU (500 mg/m 2 on days 1 through 3 and days 36 through 39 as an intravenous bolus or 225 mg/m 2 as a continuous infusion each day for 5 weeks). The planned pelvic radiation therapy dose was 4500 cGy, with a boost to a total of 5400 to 5900 cGy. Patients received two more 5-day cycles of chemotherapy beginning 1 month after completing radiation. With a median follow-up of 46 months patients who received a continuous infusion of 5FU during radiation had a significantly increased time to relapse and improved survival rate compared with those receiving bolus 5FU during radiation. 145,146The tumor relapse rate was reduced by 27%, and the death rate was reduced by 31%. There was no difference in the local recurrence rate for the two methods of 5FU administration. The incidence of severe diarrhea was significantly higher among patients who received 5FU by continuous infusion, whereas severe leukopenia was significantly more frequent among those who received the drug by bolus injection. The addition of methyl CCNU to 5FU did not result in any improvement in relapse-free or overall survival. In summary, the integrated experience of the five U.S. studies described previously indicate that meaningful survival benefits can be achieved with programs using postoperative combined modality therapy. These data are supported by two earlier trials of adjuvant single-agent 5FU in patients with colorectal cancer. After the results in the patients with rectal cancer were analyzed and reported separately, survival benefits with intensive 5FU regimens were observed by Grage and colleagues ~47for the Central Oncology Group and by Higgins and colleagues 148 for the Veterans Administration group. Several issues remain unresolved: the exact choice of chemotherapy agent(s) that can provide the most benefit with the least toxicity, the duration of chemotherapy, the scheduling of radiation therapy, and the sequence of operation, radiation therapy, and chemotherapy. In an attempt to address some of these therapeutic issues, two large cooperative group randomized efforts were undertaken in the United States (Table 8), The NSABP R-02 study is summarized in Table 9. This protocol compares the standard NSABP MOF chemotherapy regimen with a 5FU plus folinic acid (leucovorin) program and was complementary to NSABP C03 for patients with colon cancer. One half of the patients received radiation therapy in conjunction with chemotherapy. Because of preliminary evidence of qualitative therapy interactions in specific subgroups, women received 5FU plus folinic acid with or without radiation therapy, and men 640

Curr Probl Surg, August 1997

TABLE 8. Ongoing rectal cancer adjuvant randomized trials Series

Stage

Target no.

INT 0 1 4 7

Clinically T3 resectable

770

NSABP R-03

Clinically T3 resectable

900

INT 0 1 4 4

T3-4 a n d / o r N+

2400

Therapy 5 FU+ LV+ RT-~S--~5 FU+ LV S-~5 FU+ LV-~5FU+ LV+RT-~5 FU+LV 5FU +LV-->5FU+LV+RT-->S-->5FU+LV S--~5 FU+ LV-~5 FU+ LV+ RT---~5FU+ LV Bolus 5FU-->RT+PVI 5FU-~Bolus 5FU PVI 5FU-~RT+PVI 5FU-~PVI 5FU Bolus 5 FU+ LV+ LEV-~ RT+5 FU+ LV---~ Bolus 5FU+LV+LEV

INT, Intergroup study; 5FU, 541uorouracil; LV, leucovorin; RT, radiation therapy; S, surgery; NSABP, National Surgical and Adjuvant Breast and Bowel Project; PV/, prolonged venous infusion; LEV, levamisole.

TABLE 9. Recently completed rectal cancer adjuvant trials Series

Stage

Target no.

Comments tNT-0114 ~49

T3-4 a n d / o r N+

1378

NSABP R02*

T3-4 a n d / o r N+

750

Therapy 5FU-~RT+5FU-~5FU 5 FU+LV-~RT+5 FU+LV-~5FU+ LV 5FU+LEV-~RT+5FU-~5FU+LEV 5FU+ LV+LEV--~RT+5FU+ LV--~5FU+ LV+ LEV MOF MOF--~RT+5FU-~MOF 5FU+LV 5 FU+ LV--~RT+5 FU-->5 FU+ LV

INT, Intergroup study; 5FU, 541uorouracil; RT, pelvic radiation therapy of 5040 to 5400 cGy; LV, leucovorin; LEV, levamisole; NSABP, National Surgical and Adjuvant Breast and Bowel Project; MOF, methyl-CCNU+vincristine+5FU. *Women are not randomized to MOF.

were randomly assigned among the four therapy options. The MOF chemotherapy doses were identical to those in NSABP C-03. A large intergroup study (INT-0114) was initiated in 1990 to evaluate more than 1700 patients with rectal cancer. All patients underwent complete resection and then received two cycles of chemotherapy followed by 5000 to 5400 cGy of pelvic radiation with chemotherapy and two additional cycles of therapy (i.e., a treatment strategy similar to NCCTG-7947-51 and 86-47-51). All patients received 5FU alone or with folinic acid and/or levamisole based on persuasive data that 5FU plus leucovorin provided superior responses in patients with metastatic colorectal cancer and levamisole plus 5FU improved the survival of patients with completely resected node-positive colon cancer. Both NSABP R-O2 and INT-0114 have completed accrual and the efficacy results are pending. Preliminary analysis of the toxicity in INT-0114 reveals a significant increase in high-grade diarrhea for the three-drug regimen. 149The ongoing rectal cancer adjuvant studies are summarized in Table Curr Probl Surg, August 1997

641

9. The INT-0147 and NSABP R-03 trials address the important question of whether combined modality therapy is most effective when administered before or after operation, whereas SWOG 9304 seeks to determine the optimal method of 5FU administration in the context of postoperative combined modality therapy. Until a complete analysis of all the previously cited studies becomes available, some form of adjuvant combined modality therapy should be recommended for patients with T3_ 4 o r node-positive rectal cancer. Participation in a formal clinical trial should be encouraged. For those patients not entering a clinical study, the choice of adjuvant therapy depends on many medical, psychologic, and financial factors. An acceptable program for most patients would be 6 cycles of 5FU-based chemotherapy with concurrent pelvic radiation therapy during cycles 3 and 4 of chemotherapy.

PreoperativeAdjuvant Therapy Preoperative therapy has been used for patients with resectable and locally advanced/unresectable disease. Predictors of Response to Preoperative Radiation. In general, rapidly dividing cells are more sensitive to radiation. Willett and colleagues from the MGH analyzed the proliferative index in patients who underwent preoperative radiation therapy with or without 5FU.15oTumors with a higher proliferation index had a higher likelihood of response to preoperative radiation therapy. After preoperative radiation therapy was performed, a reduction in the proliferative index occurred. 151This index may be useful for predicting the response to preoperative radiation therapy. By multivariate analysis, however, Neoptolemos and colleagues 15~-showed that it did not add to the prognostic value of the Dukes' staging system. Preoperative Radiation Therapy. There are several potential advantages to preoperative radiation therapy for resectable rectal cancers including biologic (decreased tumor seeding at the time of operation and increased radiosensitivity resulting from more oxygenated cells), physical (no postsurgical small bowel fixation in the pelvis), and functional (ability to change the operation from an abdominoperineal resection to a sphincter-sparing low anterior resection/coloanal anastomosis)? 53 An additional benefit in patients with locally advanced/unresectable disease is the ability to increase the resectability rate. The major potential disadvantage of preoperative combined modality therapy in patients with clinically resectable disease is the possibility of overtreating patients (i.e., those patients with stages TI.zNoM0or metastatic disease). With the use of modern imaging modalities such as computed tomography and endorectal magnetic resonance imaging, ~54-~s6which in642

Curr Probl Surg, August 1997

TABLE 10. Local recurrence after local excision and postoperative radiation + 5FU by T Series

New England 2°~ Deaconess Hospital M.D. Anderson Hospital 21° Memorial Sloan-Kettering212 Massachusetts General Hospital 2°s (initial Report) (Update) 213 Total (Crude only)

T1

Stage T2

T3

0% (0/12) 0% ( 0 / 1 6 ) 0% (0/4) 10% (1/10)

7% (1/15) 17% (2/12) 18% (2/11)

20% (3/15) 33% (2/6) 33% (1/3)

17%* 3% (1/30)

20%* 10% (5/50)

24% (6/25)

*5-year actuarial survival.

crease the detection of unsuspected liver metastases, transrectal ultrasonography,157 which increases the detection of transmural tumor penetration, and positron emission tomography, 158the true incidence of patients overtreated may be reduced. In addition, there are a variety of other factors such as pathologic features, 159molecular markers, 16° and 31 N M R spectroscopy 161 that can help to predict the presence of positive pelvic nodes. Randomized Trials of Preoperative Radiation. There are 1 1 contemporary randomized trials of preoperative radiation therapy for resectable rectal cancer. 162-171All used low to moderate doses of radiation. Some show a decrease in the local recurrence rate, and in five studies (Stockholm 1,162 Stockholm 11,169 Swedish Rectal Cancer Trial, 17° European Organization for the Research and Treatment of Cancer (EORTC), and the Imperial Cancer Research Fund 171) this difference reached statistical significance. The Stockholm I trial (Stockholm-Malmo) ~6zshowed a significant advantage in disease-free survival, and the EORTC combined radiation therapy/5FU trial 166 revealed a borderline advantage in survival (p = 0.06). The Stockholm II trial revealed an advantage in survival in some subsets of patients. 169The most impressive results were reported from San Paulo Catholic University, but a statistical analysis of the results was not performed. 168Although in some trials a subset analysis has revealed a significant improvement in local control or survival, none of the trials report an advantage for the total treatment group. Design flaws are present in all of these randomized trials. First, none use standard radiation doses (>4500 cGy). Second, the interval between the completion of radiation and operation is inadequate. An interval of 4 to 6 weeks is recommended for maximum tumor downstaging and the recovery of normal tissues in the radiation field. Third, the radiation techniques used Curr Probl Surg, August 1997

643

were suboptimal and are known to be associated with an increased incidence of complications. For example, simple anterior/posterior rather than multiple field techniques were used, and no attempt was made to limit the dose to the small bowel. The superior border in most series was extended to L2 (rather than the more standard L5/S 1), thereby further increasing the volume of small bowel in the radiation field. The fraction sizes were unconventional and were as high as 510 cGy/day. These inferior radiation techniques contributed to the significant increase in complications, most notably in the EORTC and the Stockholm 1162series. The Swedish Rectal Cancer Trial reported a significant increase in postoperative mortality in patients who received radiation with an anterior/posterior compared with a 3- or 4-field technique (15% vs 3%, p < 0.001). 17° The postoperative mortality with surgery alone was 12% (p = NS). The postoperative morbidity for the total group of patients receiving radiation therapy (regardless of the technique) was still significantly higher when compared with the surgery control arm (44% vs 34%, p = 0.001). In summary, even with suboptimal radiation techniques, the more recent randomized trials reveal a significant decrease in local recurrence rates with preoperative radiation therapy. Although the 1-week course of preoperative radiation therapy is commonly used in Europe, it is not favored in North America because (1) it is unlikely that it can be combined with adequate doses of systemic chemotherapy, (2) it is not designed to enhance sphincter preservation, and (3) regardless of the radiation techniques, it is still associated with a significant increase in postoperative morbidity. Nonrandomized Trials of Preoperative Radiation. In patients with clinically resectable disease, the primary rationale for preoperative radiation has been to enhance sphincter preservation. Only two series have reported results in patients who were examined prospectively by their surgeon before preoperative radiation therapy was administered and were declared to require an abdominoperineal resection. There is a large experience with preoperative radiation alone from Mohiuddin and colleagues, 172but the data have not been reported in that fashion. In the series from Minsky and colleagues, 17630 patients with resectable primary adenocarcinoma of the rectum received preoperative radiation therapy (5040 cGy). Of the 29 patients who underwent operation, 10% had a pathologic complete response and 83% were able to undergo successfully a low anterior resectiordcoloanal anastomosis. Sphincter function in the 22 patients eligible for analysis was good or excellent in 77%. A similar approach was reported by Rouanet and colleaguesJ 53A total of 37 patients (T2: 15, and T3: 12) received 4000 cGy before operation. Additional treatment was based on the response of the primary tumor. If at 644

Curr Probl Surg, August 1997

3 weeks after the completion of radiation there was at least a 30% response, an additional 2000 cGy was delivered and a low anterior resection with coloanal anastomosis was performed 2 to 4 weeks later. If there was less than a 30% response, patients then underwent operation. Of the 27 patients who underwent operation, 17 (63%) underwent a low anterior resection with coloanal anastomosis, and 4 (15%) underwent a transanal local excision; 78% of the patients who underwent operation were able to undergo a sphincter-preserving procedure. Of the 14 patients available for sphincter function analysis, 71% had "perfect continence" 86% had no more than two bowel movements per day, and 14% had urgency. One series has reported that the detrimental effect on sphincter function encountered after postoperative radiation 135,136may not be as problematic with preoperative radiation. Bimbaum and colleagues 173,174have prospectively examined the short-term and long-term impact of preoperative radiation therapy on sphincter function. Conventional doses and techniques of radiation were used, and patients were assessed objectively by anal manometry with or without transrectal ultrasonography. In the 20 patients assessed for short-term and 10 patients assessed for long-term results, radiation therapy had a minimal effect on sphincter function. In summary, the limited data suggest that preoperative radiation therapy allows sphincter preservation in approximately 80% of patients who were examined prospectively and declared to require an abdominoperineal resection. Of those 80%, approximately 75% to 80% have good to excellent sphincter function. Additional experience is required to assess the longterm efficacy and functional results of this approach. Preoperative Combined Modality Therapy (Chemoradiation). Preoperative combined modality therapy is being used increasingly for clinically resectable T3 cancers and for locally advanced/unresectable disease. A common approach for patients with locally advanced/unresectable disease includes preoperative radiation therapy and 5FU-based chemotherapy followed by operation with or without intraoperative radiation therapy, and additional postoperative chemotherapy. Although the most common adjuvant approach for patients with clinically resectable, T 3, or node-positive disease is postoperative combined modality t h e r a p y , 7,137,139 a n increasing number of patients are receiving preoperative combined modality therapy. There are several potential advantages of preoperative combined modality therapy. First, nonrandomized data from MSKCC suggest that patients are able to tolerate higher chemotherapy doses and experience lower acute toxicity. ~75Furthermore in patients with unresectable disease, the addition of chemotherapy to preoperative radiation therapy increases the downstaging and resectability rates. 176 Second, there is no delay in starting systemic Curr Probl Surg, August 1997

645

therapy. A third advantage is the potential for sphincter preservation. To date, most of the experience with sphincter preservation has been limited to patients with resectable rectal cancer who receive preoperative radiation therapy without chemotherapy. ~s3Finally, a theoretic reason for adding systemic chemotherapy at the time of diagnosis is to deliver therapy when the metastatic burden is the smallest. Several trials have used preoperative combined modality therapy. Some of these have included patients with both resectable and locally advanced/ unresectable d i s e a s e , 177-19lwhereas others have been limited to patients with u n r e s e c t a b l e d i s e a s e . 192-196Three trials have been limited to patients with clinically resectable disease. 166'197-199The only phase III trial is reported from the EORTC. 166With the exception of the phase I dose escalation trials from Minsky and colleagues 177-179,193and the dose attenuation trials from Bosset and colleagues, 183 all were phase II trials. The EORTC reported the results of a randomized trial comparing preoperative radiation therapy with preoperative combined modality therapy. 166 A total of 247 patients with clinically resectable rectal cancer were randomized to receive preoperative radiation plus 5FU (375 mg/m 2bolus days 1 through 4) or radiation therapy alone. Similar to the other preoperative randomized trials in patients with resectable rectal cancer, the total dose (3450 cGy), fraction size (230 cGy/fraction), field size (extended to the superior border of L2), and technique of radiation (anterior/posterior) and the short radiation-surgery interval (2 weeks) were not conventional. Although no difference was seen in local control, patients who received combined modality therapy had a decrease in liver metastases (8% vs 18%,p = 0.07). Overall, combined modality therapy had a negative impact on survival (46% vs 59%, p = 0.06). The EORTC has designed a four-arm replacement trial in which more conventional doses and techniques of radiation and chemotherapy are used. The results are pending at this time. Three nonrandomized trials have been reported that are limited to patients with clinically resectable disease (Table 10). Chaff and colleagues 197 from Duke University reported the results of treatment in 43 patients with transrectal ultrasound staged T2 or T 3 rectal cancer. Patients received 4500 cGy and, within a week of starting radiation, 5FU (500 mg/m 2) and cisplatin (20 mg/m 2) bolus daily × 5 for 2 cycles. No postoperative chemotherapy was administered. The incidence of overall grade III+ acute toxicity was 21%. Of the 41 patients who underwent operation, 27% had a pathologic complete response. With a median follow-up of 25 months, the local recurrence rate was 5%, and the 5-year actuarial survival rate was 93%. In the series from the M.D. Anderson Hospital reported by Rich and colleagues, 198patients received 4500 cGy and concurrent continuous infusion 646

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5FU (300 mg/m2). All had T 3 disease based on clinical examination. Transrectal ultrasonography was performed in 63 of the 77 patients. Of the 63 patients, 58 hadT3 and the remaining 5 hadT1 orT2 disease. Postoperative chemotherapy was delivered in 43%. The overall incidence of toxicity was not presented, but individual serious acute toxcities during the preoperative segment included diarrhea, 1%; nausea, 6%; vomiting, 1%; skin, 5%; mucositis, 6%; hand/foot, 1%; and hematologic, 4%. All patients underwent operation, and the pathologic complete response rate was 29%. Sphincter-preserving surgery was possible in 68%. With a median followup of 27 months the local recurrence rate was 4% and the 3-year actuarial survival rate was 83%. Grann and colleagues 199from MSKCC reported the results of 32 patients with T 3 t u m o r s staged by transrectal ultrasonography who received 5040 cGy and 2 monthly cycles (bolus daily × 5) of concurrent leucovorin (20 mg/m2) and 5FU (325 mg/m2). They underwent operation 4 to 5 weeks later and received a median of 2 monthly cycles of postoperative LV/5FU. The overall incidence of toxicity during the preoperative segment was 25% (8 of 32) and individual grade III+ acute toxicities included 16% diarrhea and 12% leukopenia. The complete response rate was 9% pathologic and 13% clinical, for a total of 22%. Of the 25 patients thought initially to require an abdominoperineal resection, 17 (68%) were able to undergo sphincter-preserving operations. Of the 25 patients, 5 had involvement of the anal sphincter at initial presentation, and preoperative therapy was not performed with the goal of sphincter preservation because an abdominoperineal resection was planned regardless of the degree of downstaging. Excluding those 5 patients, the incidence of sphincter preservation would have been 17 (85%) of 20. The outcome analysis was limited to the 15 patients with a minimum follow-up of 1 year or who had failure before 1 year. With a median follow-up of 24 months there were no local recurrences, the 2-year actuarial disease-free survival rate was 86%, and the overall 2-year survival rate was 100%. The preoperative concurrent low-dose leucovorin regimen from M S K C C 179~t99is the basis of the combined modality segments of two separate randomized trials of preoperative versus postoperative combined modality therapy for clinically resectable T 3 rectal cancer. Both of these trials use bolus 5FU/leucovorin, and the end points are patterns of failure, survival, sphincter preservation and function, and quality of life (Table 9). The first trial (RTOG 94-01, INT 0147) is an Intergroup trial comparing this preoperative regimen with arm 2 of the postoperative adjuvant Intergroup rectal trial 0114. In this trial the design of the treatment arms are identical with the exception of the sequencing of the therapy, The second trial is NSABP R-03. This trial has a similar design to INT 648

Curr Probl Surg, August 1997

0147, but patients receive 6 cycles of weekly 5FU/high dose leucovorin followed by a 3-week rest before the combined modality therapy. The combined modality segment is identical to the schedule in INT 0147. It should also be noted that R-03 allows patients to undergo a local excision, whereas INT 0147 requires conventional operation.

Postoperative Adjuvant TherapyAfter Local Excision Conservative management has been used in two types of rectal cancers. The first are favorable tumors such as small, exophytic, mobile tumors without adverse pathologic features (i.e., high grade, blood or lymphatic vessel invasion, colloid histology, or the penetration of tumor into or through the bowel wall). 159'2°°~2°1These selected tumors comprise 3% to 5% of all rectal cancers and are treated adequately with a variety of local therapies such as local excision alone, cryosurgery, e l e c t r o c o a g u l a t i o n , or endocavitary (contact) radiation therapy. 2°2,2°3 The second type of rectal cancers are those tumors that otherwise would be suitable for one of the previously described local therapies except for (1) invasion of tumor into or through the muscularis propria, (2) positive regional lymph nodes, or (3) the presence of one or more adverse clinical or pathologic factors. In the context of conservative management, these tumors are considered unfavorable because local therapy alone is not adequate treatment. Given the morbidity of standard operations and the frequent need for adjuvant therapy for many rectal cancers, there is an increasing use of local excision and postoperative radiation therapy as primary therapy. Local excision has been performed both before and after radiation therapy. 2°4-213The advantage of performing a local excision before radiation therapy is that the pathologic features such as margins, depth of bowel wall penetration, and histologic features can be identified. Knowledge of these pathologic features is useful to help determine which patients require postoperative adjuvant therapy. The pathologic details can be obscured by preoperative radiation therapy. 214Therefore, the preferred approach is initial local excision and, if needed, postoperative adjuvant therapy. Selection Criteria. To determine which tumors have a high incidence of local recurrence or positive mesorectal or pelvic lymph nodes and therefore require adjuvant therapy, it first must be determined which tumors are treated adequately with local therapy alone. The selection of tumors for local therapy is based on both clinical and pathologic factors. Clinical information such as tumor size, mobility, location, and circumference can be obtained at the time of physical examination. Accurate pathologic information is more difficult to obtain from a biopsy. Of the available local therapies, only a full-thickness local excision provides accurate pathologic information. Curr Probl Surg, August 1997

649

A major limitation of the series that examine local excision alone is that the analyses are often univariate rather than multivariate. As a result, clinical and pathologic features are not examined as independent variables. Furthermore, there is variation in patient selection, the definition of clinical and pathologic features, and the duration of follow-up among the series. One reason for the variation in patient selection is individual surgeon preference. Because of this subjective difference, it is difficult to make firm recommendations for the selection of patients for conservative management based solely on clinical criteria. It is reasonable to proceed with local excision if the clinical criteria for an adequate local excision have been met (i.e., full thickness, nonfragmented, and with negative margins). Pathologic criteria are more objective. Patients with T1 tumors without adverse pathologic features have a low incidence of local recurrence and positive nodes and do not require adjuvant therapy. However, if adverse pathologic features are present (i.e., high histologic grade, blood or lymphatic vessel invasion, colloid histology, signet-ring cell) 159'2°5or the tumor invades into or through the muscularis propria, 2~5-217the local recurrence rate is at least 17% and the incidence of positive mesorectal or pelvic nodes is at least 1 5 % J 59 Therefore, local therapy alone is inadequate for tumors with these adverse pathologic factors. Results with Local Excision. Depending on the series, the overall survival rates vary from 70% to 100%. Because the pelvic lymph nodes do not undergo pathologic examination at the time of a local excision, it is not possible to compare, stage for stage, the results of local excision and postoperative radiation therapy with standard surgery. In the recent data from the M G H , 213 56 patients were compared with a retrospective group of 69 patients with stage TI_2NoM0disease who underwent an abdominoperineal resection. For patients with favorable pathologic features, the 5-year actuarial local recurrence rates (local excision: 4% vs abdominoperineal resection: 9%) and the disease-free survival (local excision: 87% vs abdominoperineal resection: 91%) were similar. However, the results were not equivalent in the subset of patients with unfavorable pathologic features. The 5-year actuarial local recurrence rate was higher (local excision: 33% vs abdominoperineal resection: 11%) and the disease-free survival was lower (local excision: 57% vs abdominoperineal resection: 79%). Although there are data to help predict the incidence of positive nodes based on the clinical and pathological features of the primary tumor, 159'2~8-223 only a randomized trial can adequately address this issue. Because the accrual to a randomized trial may be difficult, there is an Intergroup phase II trial examining the approach of local excision and postoperative radiation 650

Curt Probl Surg, August 1997

therapy (CALGB 8984 / RTOG 9109).Accrual to this study has been completed, but the results are pending at this time. Most series in which patients are treated with local excision alone exclude tumors with unfavorable clinical and pathologic features. For example, in the series of 12 patients from the New England Deaconess Hospital, all tumors were exophytic, well- to moderately differentiated without colloid features, less than 4 cm, and occupied less than 30% of the circumference of the bowel wall. 2°7'2°8 Historically, clinically unfavorable features have included tumors that are greater than 3 x 5 cm, annular, fixed, or have perforated the bowel wall. Unfavorable pathologic features have included blood vessel invasion, lymphatic vessel invasion, colloid histology, or transmural disease. The M G H update 213revealed a significant increase in local recurrence in patients with poorly differentiated versus well- to moderately differentiated tumors (36% vs 12%) and in the presence of blood or lymphatic vessel invasion (positive: 53% vs negative: 15%). There is an increase in the local recurrence rate with extension of tumor through the bowel wall in patients who undergo local excision and postoperative radiation therapy (Table 11). Combining the series, the incidence of local recurrence by stage is T1:3%, T2:10%, and T3:24%. Because of the high local recurrence rate, when there are positive margins, most authors recommend either a reexcision or an abdominoperineal resection. In the setting of positive margins, is local excision and postoperative radiation therapy a reasonable option? In the original New England Deaconess series] °4 the local recurrence rate was 56%. In contrast, none of the six patients in the M G H series who had positive margins had local recurrence. 2°5 Because the boost doses were routinely increased to 6000 to 6500 cGy in this group of patients, the local control rate may have been a function of the high radiation doses delivered. Of the four patients who had local recurrence in the M G H series, all had negative margins, but two of four had fragmented resections. In the M.D. Anderson series, all patients had negative margins and none had fragmented resections. 2~°At MSKCC, one patient (who was locally controlled) had unassessable margins, but otherwise all of the patients had a full-thickness local excision and negative margins. 212Although it cannot be determined with certainty from the available data, most investigators would recommend that negative margins be obtained, if possible. If not, radiation doses of more than 5040 cGy may be necessary to minimize the risk of local recurrence. In the M G H series, there was a suggestion that tumor size greater than 3 cm was associated with an increased local recurrence rate. 2°5The MSKCC series reported a similar increase in the risk of local recurrence (>3 cm: 25% Curr Probl Surg, August 1997

651

vs <3 c m : 14%). 212 In the M.D. Anderson 2~°and the recent New England Deaconess series, 2°7 all tumors were less than or equal to 4 cm, and in the University of Florida 2°9series all were less than 3 cm. The MGH reported an increase in the local recurrence rate in patients whose tumors had blood or lymphatic vessel invasionY In the MSKCC series, patients with tumors showing vascular invasion had a slight increase in the local recurrence rate compared with those without vascular invasion (21% vs 13%).212This increase may have been due to the increased number o f T 3 tumors in the group (25% vs 5%) without vascular invasion. The only factors associated with an increase in local recurrence that could not be explained by the presence of other features were tumor size greater than 3 cm and ulceration. However, because none of the series have adequate numbers to perform a multivariate analysis, the influence of these features on one another cannot be determined. Conclusions. The standard adjuvant therapy for resectable T 3 or nodepositive rectal cancer is pelvic radiation therapy plus 5FU-based chemotherapy. Local excision followed by postoperative radiation therapy ± chemotherapy is an alternative treatment for selected patients. The Intergroup randomized trials INT 0114 and INT 0144 will help to determine the ideal chemotherapeutic agents and their routes of administration in the postoperative setting. The Intergroup 0147 and N S A B P R-03 randomized trials will compare the efficacy and functional results of the preoperative and postoperative combined modality therapy approaches. For patients with clinically resectable T 3 disease treated in the adjuvant setting, either the preoperative or postoperative approach is acceptable at this time.

Adjuvant Therapy of LocallyAdvanced Rectal Cancer Locally advanced primary cancer of the rectum poses a major problem to the patient, surgeon, medical oncologist, and radiation oncologist. That outcomes are dismal for locally advanced unresectable tumors is best illustrated by Moertel and Reitemeyer's 224 report on the natural history, in which the mean survival for patients undergoing palliative bypass procedures was only 7.8 months. Palliative resections only marginally improved the survival to a mean of 10.9 months. Perhaps more disheartening than the fact that these patients have a foreshortened life expectancy is the fact that they often face severe and disabling pelvic symptoms including unrelenting pain. With at best a chance for cure and at worst an opportunity for palliation, these patients should be treated aggressively. As the descriptive term "unresectable" implies, locally advanced tumors are rarely amenable to complete or curative resection, and for this reason other cytoreductive therapies should be incorporated in a combined mo652

Curr Probl Surg, August 1997

dality strategy. Because both local and systemic failures occur in the setting of unresectable disease, both radiation therapy and chemotherapy may be indicated. In contrast to the adjuvant setting where the relative merits of preoperative versus postoperative radiation therapy continue to be debated, the inability to achieve clear resection surgical margins with locally advanced lesions makes it more important that downstaging be accomplished with the use of preoperative radiation therapy. In addition, because external beam radiation therapy (EBRT) alone in tolerable doses may not be adequate to maintain local control in these advanced cases, additional measures such as the use of intraoperative radiation therapy or sensitizing agents may be required. It must be recognized at the outset that there are many limitations to the clinical study of patients with locally advanced rectal cancer. First, unresectable lesions account for only a small fraction of rectal cancer cases and so most clinical series are small and uncontrolled. Second, the definition of unresectable is typically variable and vague. Although some authors restrict the use of this term to lesions that are fixed, others apply it to cases considered inoperable for nonsurgical indications. Furthermore, the aggressiveness of the surgeon is likely to be critical in the determination of "resectability," because radical en bloc exenterations are described by some 2~-5-23° but not practiced by all surgeons. Third, the ability to determine the preoperative stage, even with modem endoluminal imaging techniques, remains an inexact science.

External Beam Radiation Therapy (EBRT) The two goals of treatment for locally advanced rectal cancer are to accomplish local control, thereby preventing disabling symptoms such as pain, and to provide cure. The rationale for the use of radiation as a component of treatment for patients with unresectable rectal cancer is based on the risk of local recurrence after incomplete resection and the strength of evidence in support of the radio-responsiveness of rectal c a n c e r Y 1 Radical EBRTAlone. For a variety of reasons, including the fact that some patients refuse or are unfit for surgery, the delivery of EBRT alone for the treatment of advanced rectal carcinoma has previously been evaluated. 232-235For radiation of inoperable, residual, or recurrent colorectal cancers, doses of 4500 to 5000 cGy can achieve short-term palliation. UrdanettaLafee and colleagues 232reported 102 patients who received 3000 to 5000 cGy for primary rectosigmoid and recurrent rectal cancer. Short-term symptomatic relief was achieved in 80% and a colostomy was avoided in 71% of patients, but the overall survival rate was only 5% at 5 years. In a similar report, Cummings and colleagues 235at the Princess Margaret Hospital noted Curr Probl Surg, August 1997

653

that in 67 patients with unresectable rectal cancer, local control was achieved in only 9% and 5-year survival was achieved in only 2% of patients. Although the effect of radical EBRT on rectal carcinoma remains a feasible option for patients who refuse or are unfit to undergo operation, its role in locally advanced rectal cancer remains palliative rather than curative when used as a single modality. That EBRT alone is palliative without surgery is further emphasized by the updated analysis of Princess Margaret Hospital by the findings of Brierly and colleagues,233who reported that for patients receiving 4500 to 5000 Gy of EBRT, the 5-year actuarial survival rate was 48% for patients with mobile tumors, 27% for those with partially fixed tumors, and only 4% for those with fixed tumors. 233 It is interesting that for those 50 patients who underwent salvage surgery after radical EBRT, the overall 5-year actuarial survival rate was better at 42%, with a rate of 59% in patients with mobile tumors, 30% in those with partially fixed tumors, and 23% for those with fixed lesions. Because salvage surgery has been associated with improved outcomes,23z233it is logically anticipated that optimal results can be accomplished with a combined modality strategy. Having established a role for combined surgical and radiation therapies, pertinent questions remain regarding optimal radiation doses, routes of delivery (external alone or combined with intraoperative), timing (preoperative vs intraoperative vs postoperative), and the use of sensitizing agents. Surgery Plus Postoperative EBRT. Historically, radiation therapy for advanced rectal cancer was delivered postoperatively. The primary advantage of this approach was that the need for additional therapy was based on histologically confirmed positive resection margins. Schild and colleagues236 from the Mayo Clinic reported on 17 patients with locally advanced rectal cancer who were treated with subtotal resection followed by EBRT at doses of between 4000 and 5000 cGy in 180 to 200 cGy fractions. Ten patients had microscopic and seven had macroscopic residual disease. Thirteen (76%) of 17 patients had a local recurrence and 10 (59%) of 17 patients had systemic metastases. Local control was achieved in 3 of the 10 patients with microscopic residual disease and in only 1 of the 7 patients with macroscopic residual disease. The overall disease-free 5-year survival rate was 24%. Results from this study highlighted the need to improve both local and systemic components of therapy. Allee and colleagues237reported a similar series of 56 patients who received postoperative radiation doses of between 4500 and 7000 cGy. In patients with residual disease, local failure rates for microscopic and macroscopic residual disease were 30% and 57%, respectively. This translated into 5-year disease-free survival rates of 45% and 10.6% for the respective 654

Curr Probl Surg, August 1997

groups. The most significant finding from this study was that radiationrelated benefits in the setting of microscopic residual disease were dosedependent, with doses less than 6000 cGy associated with a local failure rate of 40% and doses of or exceeding 6000 cGy associated with a local failure rate of only 11%. Toxicifies, especially involving the small bowel, are unfortunately also dose-dependent, 238and EBRT doses exceeding 5400 cGy in 180 cGy fractions are rarely recommended if the small bowel is within the radiation field. The possibility that small bowel toxicities could be reduced together with the concern that tumor transection during operation may predispose to tumor dissemination led to the recommendation of preoperative EBRT for fixed rectal cancers. It was expected that preoperative EBRT would achieve tumor downstaging, thereby increasing the opportunity for clear surgical margins. In all, dismal past results coupled with theory-based optimism resulted in a movement away from postoperative toward preoperative EBRT for locally unresectable rectal cancers. Preoperative EBRTPIus Surgery. Experimental evidence supporting the value of preoperative EBRT as an effective modality for the treatment of advanced rectal cancer comes from studies performed by Willett and colleagues. 239After examining preoperative and postoperative tumor samples from 122 patients who had received preoperative EBRT (4500 to 5000 cGy), these investigators reported several important findings including: (1) 31% of tumors were significantly downstaged, (2) preirradiation proliferative scores were predictive of the degree of tumor regression, (3) the postirradiation stage was highly predictive of survival, and (4) downstaged tumors were smaller and were associated with less proliferative activity and better survival. The fact that moderate to high doses of preoperative EBRT decreased both tumor size and proliferative activity and that postirradiation stage and proliferative activity were independent factors associated with survival after operation bolsters theoretic arguments favoring preoperative EBRT. The clinical efficacy of preoperative EBRT for locally advanced rectal cancers has also been investigated in several studies (Table 12). First, in support of the concept of preoperative EBRT for downstaging, several studies demonstrate that clinically unresectable lesions can be converted to resectable lesions, with rates of"resectability" ranging from a low of 40% 240 to a high of 88%.241 Even though most cases become resectable after radiation therapy, it should be kept in mind that not all tumors will be amenable to complete resection. For example, in a series of 44 "unresectable" rectal cancers reported by Emami and colleagues] 4~-33 (75%) were downstaged to "resectable" lesions and these patients underwent operation. It is noteCurr Probl Surg, August 1997

655

TABLE 12. Preoperative EBRT and surgery for locally advanced primary rectal cancer Institution (yr)

No. of patients

EBRT dose

Resectability rate

Survival*

University of Oregon

40

50-60 Gy

55%

62%

(1976) 270 Tufts (1982) 242

44

45-50 Gy

75%

25 Massachusetts General Hospital (1983) T M Bergen, Norway (1984) 240 55 42 University of Florida

40-52 Gy

80%

45-47 Gy 35-60 Gy

40% 88%

19%- CR 36% - AR 28% 38% - CR 7% - CR 14% 67% -IR 48% - CR 52% t 80% - IR 25% - CR 33%

(1992) T M

Memorial SloanKettering (1991) 2T1

22

50-61 Gy

58%

M.D. Anderson (1995) 272

55

45 Gy

75%

Local control

69%*-CR

43%-CR

29%-CR

62%*

IR, Incomplete resection; CR, complete resection; AR, any resection. *5-year survival for overall group unless otherwise specified. tAt 3 years

worthy that of the 33 "resectable" cases, only 26 were considered completely resected at the time of operation. That the adequacy of resection matters is illustrated by the fact that 18 (69%) of the 26 patients in the completely resected group were alive at a minimum of 36 months, whereas the mean survival in the incompletely resected group was only 17 months. Other series corroborate the necessity for complete surgical resection. In a series of initially unresectable patients reported by Mendenhall and colleagues, 241doses of 3500 to 6000 cGy in 180 cGy fractions converted 88% of the tumors to resectable lesions, with 21 complete and 20 incomplete resections. Although the overall survival in this series was 14%, it was 0% when the resection was incomplete and 29% when complete. Local control was also better with complete resection (52%)compared with incomplete resection (33%). Although the benefit of preoperative EBRT in this clinical situation is not debated, the risk of complications deserves attention. Stevens and coll e a g u e s 243 treated 40 patients with 5000 to 6000 cGy in 200 cGy fractions and reported no difference in complications when this group was compared with a historical control group undergoing operation alone. Other authors report treatment-related mortality rates as high as 4.5% to 12%. 235,244 Mendenhall and colleagues, ~4l who applied doses of 3500 to 6000 cGy, reported that complications occurred in 9 (21%) of 42 patients with EBRT alone and in only 12% of patients after operation. In contrast, Emami and 656

Curr Probl Surg, August 1997

colleagues 242reported a complication rate of 76% with EBRT doses of 4500

to 5000 cGy. The reasons for these reported differences are not apparent. Although it has been demonstrated in the adjuvant setting that preoperative EBRT increases the risk of postoperative complications, ~33the magnitude of risk appears to be reasonable and far overshadowed by the magnitude of benefit. Finally, in an attempt to expedite care and perhaps decrease complications, at least one group has reported an experience with high dose per fraction, short duration, preoperative EBRT. Marsh and colleagues 245 reported a randomized trial of 284 patients with tethered or fixed rectal cancers treated with either operation alone or with preoperative EBRT as four daily fractions of 500 cGy each for a total of 2000 cGy. Because operation followed EBRT within 1 week, no downstaging was anticipated or noted. It is interesting that local recurrence rates were reduced from 36.5% for patients undergoing operation alone to 12.8% for patients undergoing EBRT plus operation. Unfortunately, no survival advantage was evident for the combined modality group. 245This is an interesting and in some respects appealing approach to preoperative EBRT, and perhaps combined with chemotherapy it would provide a survival advantage. In summary, the fact that overall survival rates remain low at 14% to 28% when operation is combined with postoperative radiation therapy alone, together with the fact that survival rates can be extended to 29% and 43% with complete resection, supports the use of preoperative EBRT and operation but encourages the addition of other therapies. In theory, additional modalities should enhance the local effects of EBRT, provide for better systemic control, or both.

Chemotherapy Plus EBRT Improvements in both local control and survival have been observed in two postoperative adjuvant trials of rectal carcinoma in patients at risk who are resected for cure. In both studies, bolus 5FU was administered with EBRT, and patients received 5FU with methyl CCNU before and after EBRT. 137,139 Randomized trials have also been conducted in patients who have undergone resection for high-risk colon cancer with 5FU plus levamisole regimens .26.78These studies have demonstrated improvements in tumor response rates and survival rates in patients with node-positive tumors with the addition of chemotherapy. Favorable results from the adjuvant trials suggest that combined radiation and chemotherapy strategies may be effective in locally advanced disease, both with respect to local downstaging and control of systemic disease. Indeed, this has been examined in a number of Curr Probl Surg, August 1997

657

studies of advanced and metastatic disease, most of which are smaller and less rigorously controlled trials. Moertel and colleagues 246 reported on 40 patients who received 5FU, leucovorin, and EBRT (4500 to 5400 cGy) for locally recurrent or unresectable gastrointestinal carcinoma. The median survival with this regimen was 31 months for 10 patients with primary sigmoid or rectal tumors. Two patients with rectal cancer had a disease-free survival period of between 38 and 50 months. Petrelli and colleagues 247reported results for 74 patients with previously untreated metastatic colorectal cancer. Although these patients had systemic rather than locally advanced disease, when three 5FU-based chemotherapy regimens were tested, 48% of the patients receiving 5FU and leucovorin exhibited partial or complete responses. Similarly, Poon and colleagues 248 reported on 429 patients with advanced colorectal cancer and found that high- and low-dose leucovorin plus 5FU regimens improved tumor response rates and improved interval-to-tumor progression rates when compared with 5FU alone. Finally, Erlichman and colleagues '249 data from a report of a series of 130 patients support the use of 5FU-based therapy in advanced rectal cancer, with an emphasis on 5FU plus leucovorin. Based on these findings, the use of 5FU-based regimens appears to be appropriate as a component of combined modality treatment in patients with locally advanced primary rectal cancer. One attractive aspect of the rationale for preoperative combined modality treatment remains the proposition of starting the systemic component of treatment before resection, with the theoretic benefit of eradicating established or circulating tumor cells. This approach may enhance tumor downstaging, thereby affecting both resectability and intraoperative tumor dissemination. Furthermore, the unavoidable fact of postoperative morbidity, which may detain or disrupt the standard delivery of postoperative therapy in some patients, may be avoided with preoperative treatments. Whether these theoretic considerations translate into real clinical advantages remains to be addressed by future trials such as the current Intergroup phase III adjuvant rectal trial.

EBRT and Chemotherapy Plus Surgery (+_Intraoperative Electron Radiation Therapy [IOERT]). The effects of combined radiation and chemotherapy have been investigated in a group of 52 patients at Memorial SloanKettering, all receiving identical preoperative doses of EBRT (5040 cGy). These patients received either EBRT alone (11 patients with unresectable and 21 patients with resectable disease) or EBRT plus bolus 5FU and leucovorin (20 patients with unresectable disease). 176Most impressive was the fact that patients with unresectable disease who received 5FU and leucovorin plus EBRT had a higher complete response rate (20% vs 6%) and a 658

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TABLE 13. Preoperative radiation + chemotherapy and surgery for locally advanced primary or recurrent eolorectal cancer Institution (yr)

No. of patients

Stockholm (1989) T M

21

Massachusetts General Hospital (1991) 2~3 Memorial Sloan-Kettering (1993) 178 M.D. Anderson (1995) 2T2

Chemotherapy

EBRT dose

Local failure

40 Gy

Survival rate

21

5FU/LV 5FU/MTX 5FU

60% t (20 mo)

45-50 Gy

29%(5 yr)

60% (5 yr)

20

5FU/LV

50 Gy

26% (3 yr)

69% (3 yr)

37

5FU/cisplatin

45 Gy

3% (3 yr)*

82% (3 yr)

LV, Leucovorin; MTX, methotrexate; MeCCNU, methyl CCNU. *includes any resection, and 11 patients with adherent tumor receiving IOERT. tCancer-specific, derived from figure.

lower incidence of positive nodes (30% vs 53%) compared with those who had resectable disease but did not receive chemotherapy. Similar advantages in clinical responses were observed when patients with unresectable disease receiving EBRT plus chemotherapy were compared with the patients who had unresectable disease but received only EBRT. Furthermore, of those patients with initially unresectable disease, the resectability rate was higher in those patients who received 5FU and leucovorin compared with those who did not receive chemotherapy (90% vs 64%, respectively). In addition to these measurable local effects, the chemotherapy component, analogous to adjuvant therapy, has the potential to reduce the risk of distant spread. Nonetheless, additional cycles of chemotherapy would need to be administered after operation for a systemic effect. A summary of reported series using this form of multimodality therapy is presented in Table 13. Minsky and colleagues 176,178'25°reported on the use of preoperative 5FU and leucovorin combined with radiation therapy for the treatment of unresectable rectal cancer. Patient numbers were small and the population consisted of a mixed group of advanced primary and recurrent unresectable tumors. Despite these limitations, the resection rates varied between 89% and 91%, with clinical complete response rates of between 9% and 20%. Frykholm and colleaguesTM reported that for patients with advanced rectal cancer, the curative resectability rate was greater for patients who received combined radiation and chemotherapy (71%) than it was for patients who received radiation therapy alone (34%). A small price must be paid, by way of complications, however, for the benefits of combined modality therapy. In several reports, combined modality treatment has been associated with higher morbidity rates when compared with radiation therapy alone. 176,252,253Fortunately, rates of acute and chronic toxicity appear to be reduced with the preoperaCurr Probl Surg, August 1997

659

tive approach for patients with rectal cancer when compared with postoperative delivery. 254

Intraoperative Radiation Therapy (IORT) Despite improvements that have been accomplished with multimodality chemoradiotherapy in terms of tumor downstaging and resectability, local failure rates as high as 33% are still reported. 178'196When there is microscopic or macroscopic residual disease after surgical resection, the incidence of local failure is higher. 236'237"255Although it is evident that preoperative or postoperative EBRT combined with operation diminishes the rate of local failure in both prospective nonrandomized and randomized trials for patients with locally advanced primary rectal cancer, it is also evident that high doses (6000 to 7000 cGy) of radiation are desirable but toxic. One strategy for maximizing tumor-specific radiation effects is to perform intraoperative radiation therapy (IORT) as a supplement to tolerable doses of EBRT (4500 to 5000 cGy in 180 to 200 cGy fractions). IORT in its broadest sense refers to the delivery of radiation at the time of operation. This allows for the tumor-directed delivery of an intense irradiation dose while at the same time limiting the dose delivered to radiation-sensitive structures by surgical mobilization and displacement (e.g., stomach, small bowel). Single-dose IORT boosts are biologically equivalent to 2 to 3 times that amount of fractionated EBRT (i.e., 1000 cGy of IORT is equivalent to 2000 to 3000 Gy of fractionated EBRT). Dose delivery is typically tailored to the individual based on the extent of tumor residual after maximal resection. Intraoperative radiation therapy may be delivered with an electron beam or high-voltage brachytherapy. Intraoperative Electron Radiation Therapy (IOERT). Intraoperative electron radiation therapy (IOERT) is accomplished with a linear accelerator to generate an electron beam of variable energy (6 to 18 MeV) depending on the maximum depth of disease. Lower energies (6, 9, or 12 MeV) are used after gross total resection or with minimal residual disease. Energies of 15 to 18 MeV are used more typically in patients with recurrent disease in whom gross residual or unresectable disease remains after attempted surgical resection. 256-258At the Mayo Clinic, an electron beam boost of 1000 to 1250 cGy is administered for microscopic residual disease or narrow margins, 1500 to 1750 cGy is administered for gross residual disease less than 2 cm, and 2000 cGy is administered for unresected or gross residual greater than 2 cm. The size and shape of the IOERT lucite cylinder or cone used to direct the electron beam depends on the extent and location of the tumor. For pelvic tumors, circular cones with 15- or 30-degree bevels are typically required to conform to the anatomy of the presacrum, pelvic sidewall, or anterior pelvis. 660

Curr Probl Surg, August 1997

TABLE 14. Results of intraoperative and external irradiation 5: resection in primary and recurrent adenocarcinoma of the rectum (Massachusetts General Hospital, MGH) or colorectum (Mayo)

MGH 5-year actuarial survival (%) Extent of resection

Mayo 5-year actuarial survival (%)t

No. of patients

LC

SR

No. of patients

LC

SR

42 20

77 89

43 53

56 ¢ 20

84 94

46 68

16 6

69 50

47 17

19 16

86 73

55 21

Primary tumor* Complete resection Partial resection Microscopic residual Gross residual

LC, Local control; SR, survival. *Modified from Willet CG, Shellito PC, Tepper JE, Eliseo R, Convery K, Wood WC. Intraoperative electron beam radiation therapy for primary locally advanced rectal and rectosigmoid carcinoma. J Clin Oncol 1991;9:843-9. tModified from Gunderson LL, Helson H, Martenson J, Haddock M. Locally advanced primary and recurrent colorectal cancer: disease control and survival with IOERTcontaining regimens. Int J Radiat Oncol Biol Phys 1995;32:267, and personal communication.

Controlled IOERT trial results are not available. However, differences between historical (non-IOERT) and current (IOERT) results provide convincing evidence of the efficacy of this therapy (Table 14). In an early report, Schild and colleagues 236described 17 patients with locally advanced primary colorectal cancer treated at the Mayo Clinic with subtotal resection followed by postoperative EBRT. A more recent Mayo analysis describes 55 patients with locally advanced primary colorectal cancer who received an IOERT boost in addition to resection and EBRT? 59When the two series were compared, local progression of disease was observed in 76% of the 17 patients treated by surgery and EBRT versus 13% of the 55 who received an IOERT boost. The improvement in local control appeared to translate into improved 3- and 5-year survival rates for IOERT versus non-IOERT groups (53% vs 24% and 42% vs 24%, respectively). In a similar analysis, Willett and colleagues 253 reported improved local control in 42 patients who received preoperative EBRT followed by operation and IOERT compared with a group of 18 historical controls. In this study, a 5-year actuarial survival rate of 53% and a local control rate of 88% at 5 years was reported for 20 patients who had undergone a complete surgical resection and received IOERT. In 16 patients with microscopic residual disease who received IOERT, 5-year local control was 69% and the 5-year disease-free survival rate was 47%. In six patients in whom gross residual disease was present, the 5-year local control was still acceptable at 50%, but the 5-year survival was only 17%. Despite the merits of IOERT, it is clearly not a substitute for aggressive surgical resection, because disease persistence or relapse within the IOERT and Curr Probl Surg, August 1997

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EBRT fields remains high when gross total resection is not accomplished. 260262 This fact plus the risk of systemic failure, which is approximately 50%,259 suggests that chemotherapy should be combined with EBRT, IOERT, and operation for the treatment of these patients--not just for radiosensitization, but for systemic effects. It is only with combined local and systemic cytoreductive strategies that survival can be influenced favorably. Intraoperative High Dose Rate Brachytherapy (IOHDR). Brachytherapy with a nigh dose rate after-loading machine with a cable-mounted Iridium192 source has been used as an alternative method for delivering intraoperative radiation therapy with a plastic"flab" delivery system.A flexible device 1 cm thick and made of vinyl plastic on a synthetic oil base has been designed that allows direct apposition of radiation from a multichannel after-loader that traverses the mid-plane of the pad. 263,264Because of its flexibility, the flab can conform to the shape of the surface to which it is applied. In particular, it is ideal for curved or complex surfaces such as the pelvic sidewall, presacral area, pubic region, or other irregular abdominal surfaces. The material is translucent, allowing placement of the device onto the desired surface under direct visualization.Although IOHDR may be technically more feasible than IOERT in certain pelvic locations, its depth of penetration is limited to 1 cm. Anterior tumors with a maximum thickness of 5 mm of residual disease are therefore most suitable for this method. The dose that can be delivered with this system (1000 to 2000 cGy) is comparable to that of IOERT. Huber and colleagues265reported their preliminary experience with this technique in 56 patients withT3 orT4 primary rectal cancers. Patients were treated with either preoperative (T 4 patients) or postoperative (T 3 patients) chemoradiotherapy. Eighteen patients did not complete the protocol, either because they had been overstaged and did not require postoperative chemoradiotherapy (n = 15), did not receive adjuvant therapy because of postoperative morbidity (n = 1), or they were understaged before operation and found to have diffuse metastatic disease at operation (n = 2). There were 5 local recurrences: 3 (16%) in the 19 patients with T 3 lesions and 2 (11%) in the 19 patients with T4 lesions. Only one local recurrence was identified within the EBRT field and none was identified within the IORT field. The Memorial Sloan-Kettering experience with IOHDR in 30 patients corroborates the Munich experience. Ten of these 30 patients underwent IOHDR supplements to EBRT for primary unresectable rectal cancer with a median follow-up of 8 months. Actuarial local control at 1-year was achieved in 86% of patients with a disease-free survival rate of 57%. 264

Combined Modality Treatment with Chemotherapy, EBRT, and IORT. In view of the fact that most failures in patients who receive EBRT and operation plus IORT occur in patients in whom there is residual disease, 662

Curr Probl Surg, August 1997

and that the risk of subsequent systemic metastases remains high, 5FUbased chemotherapy should be considered not only as a radio-sensitizing agent but perhaps also as adjuvant to control systemic disease. Again in support of the use of chemotherapy, an early randomized Mayo series of 65 patients with locally unresectable or recurrent disease demonstrated that patients treated with 4000 cGy EBRT plus placebo did poorly, with a 10month median survival compared with those treated with EBRT plus 5FU who experienced a 16-month median survival (p < 0.05). 266 Furthermore, the fact that the addition of IORT and chemotherapy improves patient outcome is illustrated by the comparison between the Mayo primary rectal s e r i e s 236 and the Mayo locally recurrent colorectal cancer series involving EBRT, IOERT, plus chemotherapy reported by G u n d e r s o n and colleagues. 257 In the most recent analysis of 116 patients with local or regional recurrence and no previous EBRT, the use of EBRT, 5FU, maximal surgical resection, and IORT achieved 2-year survival rates of 6 0 % , 259 which compares favorably to the 35% 2-year survival rate for patients with primary cancer and positive margins who underwent operation and received postoperative EBRT + 5FU with n o I O E R T . 236 The Munich experience with preoperative chemoradiotherapy followed by operation and intraoperative brachytherapy observed a T-stage (depth) downstaging effect in 17 of the 19 patients with an initial T4 lesion. Remarkably, after chemoradiation therapy only 4 of the 19 T 4 patients had node-positive disease identified at operation. In contrast, of the 19 patients who had initial T 3 tumors and received chemoradiation therapy after operation, 10 patients were found to have metastatic nodal disease. 265 Tolerance oflORT Regimens. Although it is somewhat difficult to differentiate surgical, EBRT, and IORT-related complications, at least two complications, peripheral neuropathy and ureteral stricture, appear at least in part related to the IORT component. Peripheral nerve damage is the principal dose-limiting complication for IOERT in the pelvis. In a previous analysis of 37 patients available for evaluation who received IOERT as a component of treatment for locally advanced colorectal cancer, the incidence of peripheral neuropathy of any degree was 32% (12 p a t i e n t s ) Y 6 All 12 patients with neuropathy had pain (3 severe), 8 patients had sensory changes (none severe), and 7 had motor disturbances (one severe). Based on recent analyses, there appears to be a relationship between IOERT dose levels and the incidence of grade II or III neuropathy. Of 13 patients with neuropathy in a total series of 52 patients receiving IOERT, 12 had received a dose greater than or equal to 2000 cGy, 267 The second IOERT dose-limiting structure in the pelvis is the ureter. In a previous Mayo analysis of 51 patients receiving pelvic IOERT for primary or recurrent malignancies, 44% of previously unobstructed ureters became Curr Probl Surg, August 1997

663

partially or totally obstructed when included in the IOERT field. 256'268Stent insertion, when indicated, most often manages this problem adequately. Conclusion. There are encouraging trends in the delivery of aggressive multi-modality treatment including preoperative chemoradiation therapy followed by operation and IORT for the treatment of locally advanced primary rectal cancer. Complete surgical resection is associated with the best local control and disease-free survival. Because the incidence of distant metastases is excessive in patients with locally advanced disease, postoperative maintenance and concomitant chemotherapy with EBRT should be evaluated as a component of treatment. Radiation dose modifiers, which use sensitizers or hyperthermia, represent another potential means of improving the therapeutic response to IORT and deserve further evaluation.

References 1. Dukes CE. The classification of cancer of the rectum. J Pathol 1932;35:323-32. 2. Turnbull RB Jr, Kyle K, Watson FR, Spratt J. Cancer of the colon: the influence of the no-touch isolation technique on survival rates. Ann Surg 1967;166:420-7. 3. Gunderson LL, Sosin H. Areas of failure found at reoperation (second or symptomatic look) following "curative surgery" for adenocarcinoma of the rectum: clinicopathologic correlation and implications for adjuvant therapy. Cancer 1974;34:127892. 4. AnonymousAmerican Joint Committee on Cancer: manual for staging of cancer. 3rd ed. Philadelphia: JB Lippincott, 1987. 5. Harmer MH. TMN classification of malignant tumors. 3rd ed. Geneva: 1978, 1978. 6. Wolmark N, Fisher B, Wieand HS. The prognostic value of the modifications of the Dukes' C class of colorectal cancer. Ann Surg 1986;203:115-22. 7. GastrointestinalTumor Study Group. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 1985;312:1465-72. 8. Michelassi F, Ayala JJ, Balestracci T, Goldberg R, Chappell R, Block GE. Verification of a new clinicopathologic staging system for colorectal adenocarcinoma. Ann Surg 1991;214:11-8. 9. Michelassi F, Block GE, Vannucci L, Montag A, Chappell R. A 5- to 21-year followup and analysis of 250 patients with rectal adenocarcinoma.Ann Surg 1988;208:37989. 10. Grinnell RS. Distal intramural spread of carcinoma of the rectum and rectosigmoid. Surg Gynecol Obstet 1954;99:421-30. 11. Grinnell RS. Results of ligation of inferior mesenteric artery at the aorta in resections of carcinoma of the descending and sigmoid colon and rectum. Surg Gynecol Obstet 1965;120:1031-6. 12. Pezim ME, Nicholls RJ. Survival after high or low ligation of the inferior mesenteric artery during curative surgery for rectal cancer. Ann Surg 1984;200:729-33. 13. Surtees P, Ritchie JK, Phillips RKS. High versus low ligation of the inferior mesenteric artery in rectal cancer. Br J Surg 1990;77:618-21. 14. Galandiuk S, Wieand H, Moertel Ch, et al. Patterns of recurrence after curative resection of carcinoma of the colon and rectum. Surg Gynecol Obstet 1992;174:27-32. 15. Cass AW, Million RR, PfaffWW. Patterns of recurrence following surgery alone for adenocarcinoma of the colon and rectum. Cancer 1976;37:2861-5. 16. Willett CG, Tepper JE, Cohen AM, Orlow E, Welch C. Failure patterns following curative resection of colonic carcinoma. Ann Surg 1984;200:685-90. 664

Curr Probl Surg, August 1997

17. Chung CK, Stryker JA, DeMuth WEJ. Patterns of failure following surgery alone for colorectal carcinoma. J Surg Oncol 1983;22:65-70. 18. Griffin MR, Bergstralh EJ, Coffey RJ, Beart RW, Milton LJ. Predictors of survival after curative resection of carcinoma of the colon and rectum. Cancer 1987;60:2318-24. 19. Devereux DE Deckers PJ. Contributions of pathologic margins and Dukes' stage to local recurrence in colorectal carcinoma. Am J Surg 1985;149:323-6. 20. Garcia-Valdecasas JC, Llovera JM, deLacy AM, et al. Obstructing colorectal carcinoma: prospective study. Dis Colon Rectum 1991 ;34:759-62. 21. Stulc JP, Petrelei NJ. Anastomotic recurrence of adenocarcinoma of the colon. Arch Surg 1986;121:1077-80. 22. Keighley MRB, Hall C. Anastomotic recurrence of colorectal cancer: a biological phenomon or an avoidable calamity. Gut 1987;28:786-91. 23. Eisenberg B, DeCosse JJ, Harford F, Michalek J. Carcinoma of the colon and rectum: the natural history reviewed in 1704 patients. Cancer 1982;49:1131-4. 24. Gastrointestinal Tumor Study Group. Adjuvant therapy of colon cancer: results of a prospectively randomized trial. N Engl J Med 1984;310:737-43. 25. Cohen AM, Tremittera S, Candela E Thaler JT, Sigurdson ER. Prognosis of nodepositive colon cancer. Cancer 1991 ;67:1859-61. 26. Laurie JA, Moertel CG, Fleming TR, et al. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. J Clin Oncol 1989;7:1447-56. 27. Rifkin MD, Ehrlich SM, Marks G. Staging of rectal carcinoma: prospective comparison of endorectal US and CT 1. Radiology 1989;170:319-22. 28. Waizer A, Zitron S, Ben-Baruch D, Baniel J, Wolloch Y, Dintsman M. Comparative study for preoperative staging of rectal cancer. Dis Colon Rectum 1989;32:53-6. 29. Baker JW, Margetts LH, Schutt RP. The distal and proximal margin of resection in carcinoma of the pelvic colon and rectum. Ann Surg 1955; 141:693-706. 30. Wolmark N, Fisher B. An analysis of survival and treatment failure following abdominoperineal and sphincter-saving resection in Dukes' B and C rectal carcinoma. Ann Surg 1986;204:480-9. 31. Williams NS, Dixon MF, Johnston D. Reappraisal of the 5 centimetre rule of distal excision for carcinoma of the rectum: a study of distal intramural spread and of patient's survival. Br J Surg 1983;70:150-4. 32. Williams NS, Durdey P, Johnston D. The outcome following sphincter-saving resection and abdominoperineal resection for low rectal cancer. Br J Sur 1985;72:595-8. 33. Quer EA, Dahlin AC, Mayo CW. Retrograde intramural spread of carcinoma of the recutm and rectosigmoid. Surg Gynecol Obstet 1953;96:24-30. 34. EnkerWE, Heilweil ML, Hertz REL, et al. En bloc pelvic lymphadenopathy and sphincter preservation in the surgical managment of rectal cancer. Ann Surg 1986;203:426-33. 35. Enker WE, Laffer UT, Block GE. Enhanced survival of patients with colon and rectal cancer is based upon wide anatomic resection. Ann Surg 1979;190:350-60. 36. Moriya Y, Hojo K, Sawada T, Koyama Y. Significance of lateral node dissection for advanced rectal carcinoma at or below the peritoneal reflection. Dis Colon Rectum 1989;32:307-15. 37. Glass RE, Ritchie JK, Thompson HR, Mann CV. The results of surgical treatment of cancer of the rectum by radical resection and extended abdomino-iliaclymphadenectomy. Br J Surg 1985;72:599-601. 38. Quirke P, Durdey P, Dixon ME Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: histopathological study of lateral tumor spread and surgical excision. Lancet 1986; 1:996-9. 39. Cawthorne SJ, Parmus DV, Gibbs NM, et al. Extent of mesorectal spread and involvement of lateral resection margin as prognostic factors after surgery for rectal cancer. Lancet 1990;335:1055-9. Curr Probl Surg, August 1997

665

40. Heald RJ, Ryall RDH. Recurrence and survival after total meso-rectal excision for rectal cancer. Lancet 1986; 1:1479-82. 41. Murray D, Hreno A, Dutton J, Hampson LG. Prognosis in colon cancer: a pathologic reassessment. Arch Surg 1975; 110:908-13. 42. Athlin L, Bengtsson NO, Stenling R. Local recurrence and survival after radical resection of rectal carcinoma. Acta Chir Scand 1988;154:225-9. 43. Herrera L, Villarreal JR. Incidence of metastases from rectal adenocarcinoma in small lymph nodes detected by a cleating technique. Dis Colon Rectum 1992;35:783-8. 44. Billingham RP. Conservative treatment of rectal cancer: extending the indications. Cancer 1992;70:1355-63. 45. Habib NA, Peck MA, Sawyer CN, Blaxland JW, Luck RJ. Does fixity affect prognosis in colorectl tumours? Br J Surg 1983;70:423-4. 46. Durdey P, Williams NS. The effect of malignant and inflammatory fixation of rectal carcinoma on prognosis after rectal excision. Br J Surg 1984;71:787-90. 47. Bonfanti G, Bozzetti F, Doci R, et al. Results of extended surgery for cancer of the rectum and sigmoid. Br J Surg 1982;69:305-7. 48. Spratt JS Jr, Spjut HJ. Prevalence and prognosis of individual clinical and pathologic variables associated with colorectal carcinoma. Cancer 1967 ;20:1976-85. 49. Eisenberg SB, Kraybill WG, Lopez MJ. Long-term results of surgical resection of locally advanced colorectal carcinoma. Surgery 1990;108:779-86. 50. Eldar S, Kemeny MM, Terz JJ. Extended resections for carcinoma of the colon and rectum. Sttrg Gynecol Obstet 1985; 161:319-22. 51. Hafner GH, Herrera L, Petrelli NJ. Patterns of recurrence after pelvic exenteration for colorectal adenocarcinoma. Arch Surg 1991; 126:1510-3. 52. Hunter JA, Ryan JA Jr, Schultz E En bloc resection of colon cancer adherent to other organs. Am J Surg 1987;154:67-71. 53. Deckers PJ, Olssom C, Williams LA, et al. Pelvic exenteration as palliation of malignant disease. Am J Surg 1976;131:509-15. 54. Brophy PF, Hoffman JR Eisenberg BL. The role of palliative pelvic exenteration. Am J Surg 1994;167:386-90. 55. Rich T, Gunderson LL, Lew R, Galdibini JJ, Cohen AM, Donaldson G. Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer 1983;52:1317-29. 56. Gunderson LL, Sosin H, Levitt S. Extrapelvic colon: areas of failure in a reoperation series: implications for adjuvant therapy. Int J Radiat Oncot Biol Phys 1985;11:731-41. 57. Gunderson LL, Tepper JE, Dosoretz DE, et al. Patterns of failure after treatment of gastrointestinal cancer. Cancer Treat Reports 1983 ;2:181-97. 58. Tepper J. Reflections in rectosigmoid: retro-pefitoneal vs. intra-peritoneal. Int J Radiat Oncol Biol Phys 1988;14:1043-6. 59. Willett CG, Tepper JE, Shellito PC, WoodWC. Indications for adjuvant radiotherapy in extrapelvic colonic carcinoma. Oncology 1989;3:25-33. 60. Thomas WH, Larson RA, Wright HK, Cleveland JC. An analysis of patients with carcinoma of the fight colon. Surg Gynecol Obstet 1968; 127:313-8. 61. Reddy BS, Sharma C, Simi B. Metabolic epidermiology of colon cancer: effect of dietary fiber on fecal mutagens and bile acids in healthy subjects. Cancer Res 1987;47:644-8. 62. Welch CE, Burke JF. Carcinoma of the colon and rectum. N Engl J Med 1962;266:2119. 63. Mrazek R, Economou S, McDonald GO, Slaughter DE Prophylactic and adjuvant use of nitrogen mustard in the surgical treatment of cancer. Ann Surg 1959;150:745-55. 64. Holden GA, Dixon WJ, Kuzma JW. The use of triethylene thiophosphoramide as an adjuvant to the surgical treatment of colorectal carcinoma. Ann Surg 1967; 165:481-9. 65. Grossi CE, Nealon TF Jr, Rousselot LM. Adjuvant chemotherapy in resectable cancer of the colon and rectum. Surg Clin North Am 1972;52:925-33. 666

Curr Probl Surg, August 1997

66. Li MC, Ross ST. Chemoprophylaxis for patients with colorectal cancer: prospective study with five-year follow-up. JAMA 1976;235:2825-8. 67. Mavligit GM, Burgess MA, Seibert GB, Jubert AV. Prolongation of postoperative disease-free interval and survival in human colorectal cancer by B.C.G. or B.C.G. plus 5-fluorouracil. Lancet 1976;1:871-6. 68. Dwight RW, Humphrey EW, Higgins GA, Keehn RJ. FUDR as an adjuvant to surgery in cancer of the large bowel. J Surg Oncol 1973;5:243-9. 69. Higgins GA, Humphrey E, Juler GL, et al. Adjuvant chemotherapy and the surgical treatment of large bowel cancer. Cancer 1976;38:1461-7. 70. Higgins GA, Dwight RW, Smith JV, et al. Fluorouracil as an adjuvant to surgery in carcinoma of the colon. Arch Surg 1971;102:339-43. 71. Lawrence WJ, Terz JJ, Horsley SI, Donaldson M. Chemotherapy as an adjuvant to surgery for colorectal cancer. Ann Surg 1975;113:616-23. 72. Hafstrom L, Rudenstam CM, Domellof L. A randomized trial of oral 5-fluorouracil versus placebo as adjuvant therapy in colorectal cancer Dukes B and C: results after 5 years observation time. Br J Surg 1985 ;72:138-41. 73. Anonymous. GastrointestinalTumorStudy Group: Adjuvant therapy ofcoloncancer: results of a prospectively randomized trial. N Engl J Med 1984;310:737-42. 74. Buyse M, Zeleniunch-Jacquotte A, Chalmers T. Adjuvant therapy of colorectal cancer: why we still don't know. JAMA 1988;259:3571-8. 75. Wolmark N, Fisher B, Rockette H, et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP Protocol C-01. J Natl Cancer Inst 1988;80:30-6. 76. Chirigos MA, Amery WK. Combined levamisole therapy: an overview of its protective effects. In: Anonymous Immunotherapy of human cancer. New York: Raven, 1978:181-95. 77. Renoux G. The general immunopharmacology of levamisole. Drugs 1980;20:89-99. 78. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352-8. 79. Moertel CG, Fleming TR, Macdonald JS, Haller DG. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage HI colon carcinoma: a final report. Ann Intern Med 1995;122:321-6. 80. Moertel CG, FlemingTR, Macdonald JS, Hailer DG. Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage IIDukes'B2 colon cancer. J Clin Oncol 1995;13:2936-43. 81. NIH Consensus Conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990;264:1444-50. 82. Willett C, Tepper JE, Cohen A, Orlow E, Welch C. Obstructive and perforative coIonic carcinoma: patterns of failure. J Clin Oncol 1985;3:379-84. 83. Jen J, Kim H, Piantadosi S, Liu Z, et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 1994;331:213-21. 84. Stevenson HC, Green I, Hamilton JM, Calabro BA, Parkinson DR. Levamisole: known effects on the immune system, clinical results and future applications to the treatment of cancer. J Clin Oncoi 1991;9:2052-66. 85. Takimoto CH. Enigman of fluorouracil and levamisole. J Natl Cancer Inst 1995;87:471-3. 86. Kovach JS, Svingen PA, Schaid DJ. Levamisole potentiation of fluorouracil antiproliferative activity mimicked by orthovanadate, an inhibitor of tyrosine phosphatase. J Natl Cancer Inst 1992;84:515-9. 87. Grem JL, Allegra CJ. Toxicity of levamisole and 5-fluorouracil in human colon carcinoma cells. J Natl Cancer Inst 1989;81:1413-7. 88. AbdAlla EE, Blair GE, Jones RA, Sue-Ling HM. Mechanism of synergy of levamisole and fluorouracih induction of human leucocyte antigen class I in a colorectal cancer cell line. J Natl Cancer Inst 1995;87:489-96. Curr Probl Surg, August 1997

667

89. Mayer RJ. Does adjuvant therapy work in colon cancer? N Engl J Med 1990;322:399401. 90. Moertel CG. Chemotherapy for colorectal cancer. N Engl J Med 1994;330:1136-42. 91. Poon MA, O'ConneU MJ, Wieand HS, et al. Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 1991;9:1967-72. 92. BurokerTR, O'Connell MJ. Randomized comparison of two schedules of fluorourcil and leucovorin in treatment of advanced colorectal cancer. J Clin Oncol 1994; 12:1420. 93. Wolmark N, Rockette H, Fisher B, Wickerman DL. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from national surgical adjuvant breast and bowel project protocol CO-3. J Clin Oncol 1993;t1:1879-87. 94. Anonymous. InternationalMulticenter pooled analysis of colon cancer trials investigators: efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 1995;345:939-44. 95. Wolmark N, Rockette H, Mamounas EE The relative efficacy of 5FU + leucovorin, 5FU + levarnisole, and 5FU + leucovorin + levamisole in patients with Dukes'B and C carcinoma of the colon: first report of NSABP C-04. Proc Am Soc Clin Oncol 1996; 15:205. 96. O'Connell MJ, Laurie JA, Shepard L. A prospective evaluation of chemotherapy duration and regimen as surgical adjuvant treatment for high-risk colon cancer: a collaborative trial of the north central cancer treatment group and the national cancer institute of Canada clinical trials group. Proc Am Soc Clin Oncol 1996; 15:209. 97. Hailer DG, Catalano PJ, Macdonald JS. Fluorouracil (FU), leucovorin (LV), and levamisole (LEV) adjuvant therapy for colon cancer: preliminary results of INT-0089. Proc Am Soc Clin Oncol 1996;15:211. 98. Minsky BD, Mies C, Rich TA, Recht A, Chaffey JT. Potentially curative surgery of colon cancer: 1. Patterns of failure and survival. J Clin Oncol 1988;6:106-18. 99. Weiss L, Grnndmann E, Torhorst J, et al. Haematogenous metastatic patterns in coionic carcinoma: an analysis of 1541 necropsies. J Pathol 1986;150:195-203. 100. Dukes CE. Discussion on major surgery in carcinoma of the rectum, with and without colostomy, excluding the anal canal and including the rectosigmoid. Proc R Soc Med 1957;50:1031-43. 101. Fisher ER, Turnbull RB Jr. The cytologic demonstration and significance of tumor cells in the mesenteric venous blood in patients with colorectal carcinoma. Surg Gynecol Obstet 1955; 100:102-8. 102. Ackerman NB. The blood supply of experimental liver metastases. IV. Changes in vascularity with increasing tumor growth. Surgery 1974;2:589-97. 103. Basserman R. Changes of vascular pattern of tumors and surrounding tissue during different phases of metastatic growth. Cancer Res 1986;100:256-64. 104. Almersj0 O, Brandberg, Gustavsson B. Concentration of biologically active 5-fluorouracil in general circulation during continuous portal infusion in man, a preliminary report. Cancer Lett 1975; 1:113-8. 105. Taylor I, Rowling J, West C. Adjuvant cytotoxic liver perfusion for colorectal cancer. Br J Surg 1979;66:833-7. 106. Taylor I, Machin D, Mullee M, Trotter G, Cooke T, West C. A randomized controlled trial of adjuvant portal vein cytotoxic perfusion in colorectal cancer. Br J Surg 1985;72:359-62. 107. Weber W, Laffer U, Metzger U. Adjuvant portal liver infusion with 5-fluorouracil and mitomycin in colorectal cancer. Anticancer Res 1993;13:1839-40. 108. Anonymous. Long term results of a single course of adjuvant intraportal chemotherapy of colorectal cancer. Swiss Group for Clinical Cancer Research. Lancet 1995 ;345:34952. 668

Curr Probl Surg, August 1997

109. Wolmark N, Rockette H, Wickerham DL, et al. Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of national surgical adjuvant breast and bowel project protocol C-02. J Clin Oncol 1990;8:1466-75. 110. Tong D, RusselAH, Dawson LE, Wisbeck W. Second laparotomy for proximal colon cancer: sites of recurrence and implications for adjuvant therapy. Am J Surg 1983;145:382-6. 111. Speyer JL, Sugarbaker PH, Collins JM, Dedrick RL, Klecker RW Jr, Myers CE. Portal levels and hepatic clearance of 5-fluorouracil after intraperitoneal administration in humans. Cancer Res 1981;41:1916-22. 112. Archer SG, McCulloch RK, Gray BN. A comparative study of pharmacokinefics of continuous portal vein infusion versus intraperitoneal infusion of 5-fluorouracil. Regional Cancer Treatment 1989;2:105-11. 113. Speyer JL, Collins JM, Dedrick RL, Brennan ME Phase I and pharmacological studies of 5-fluorouracil administered intraperitoneally. Cancer Res 1980;40:567-72. 114. Sugarbaker PH, Gianola FJ, Speyer JC, Wesley R, Barofsky I, Meyers CE. Prospective randomized trial of intravenous versus intraperitoneal 5-fluorouracil in patients with advanced primary colon or rectal cancer. Surgery 1985;98:414-21. 115. Kelsen DP, Saltz L, Cohen AM, et al. A phase I trial of immediate postoperative intrapertioneal floxuridine and leucovorin plus systemic 5-fluorouracil and levamisole after resection of high risk colon cancer. Cancer 1994;74:2224-33. 116. Jain RK. Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumours. Cancer Res 1990;50(Suppl):814s-9s. 117. Riethmuller G, Johnson GP. Monoclonal antibodies in the detection and therapy of micrometastatic epithelial cancers. Curr Opin Immunol 1992;4:647-55. 118. Lindemann F, Schlimok G, Dirschedl P, Witte J, Riethmuller G. Prognostic significance of micrometastatic turnout cells in bone marrow of colorectal cancer patients. Lancet 1992;340:685-9. 119. Herlyn M, Steplewski Z, Herlyn D, Koprowski H. Colorectal carcinoma-specific antigen: detection by means of monoclonal antibodies. Proc Natl Acad Sci U S A 1979;76:1438-42. 120. Heflyn D, Koprowsky H. IgG2a monoclonal antibodies inhibit human tumor growth through interaction with effector cells. Proc Nat Acad Sci U S A 1982;79:4761-5. 121. Gottlinger HG, Funke I, Johnson JP, Gokel JM. The epithelial cell surface antigen 171A, a target for antibody-mediated tumor therapy: its biochemical nature, tissue distribution and recognition by different monoclonal antibodies. Int J Cancer 1986;38:27-53. 122. Hedyn DM, Steplewski Z, Herlyn ME Koprowski H. Inhibition of growth of colorectal carcinoma in nude mice by monoclonal antibody. Cancer Res 1980;40:717-21. 123. Mellstedt H, Fr6din J-E, Masucci G, et al. The therapeutic use of monoclonal antibodies in colorectal carcinoma. Semin Oncol 1991;18:462-77. 124. RiethmuUer G, Schneider-Gadicke E, Schlimok G, et al. Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal carcinoma. Lancet 1994;343:1177-83. 125. O'Boyle KP, Zamore R, Adluri S, et al. Immunization of colorectal cancer patients with modified ovine submaxillary gland mucin and adjuvants induces IgM and IgG antibodies to sialylated Tn. Cancer Res 1992;52:5663-7. 126. Hoover HC Jr, Brandhorst JS, Peters LC, et al. Adjuvant active specific immunotherapy for human colorectal cancer: 6.5-year median follow-up of a phase III prospectively randomized trial. J Clin Oncol 1993; 11:390-9. 127. Moertel CG. Vaccine adjuvant therapy for colorectal cancer: "very traumatic" or hohunl? J Clin Oncol 1993; 11:385-6. 128. Willett CG, Tepper JE, Kaufman DS, et al. Adjuvant postoperative radiation therapy for rectal adenocarcinoma. Am J Clin Oncol 1992;15:371-5. Curr Probl Surg, August 1997

669

129. Romsdahl MM, Withers HR. Radiotherapy combined with curative surgery: its use as therapy for carcinomas of the sigmoid colon and rectum, Arch Surg 1978;113:44653. 130. Vigliotti A, Rich TA, Romsdahl MM, Withers HR, Oswald MJ. Postoperative adjuvant radiotherapy for adenocarcinoma of the rectum and rectosigmoid. Int J Radiat Oncol Biol Phys 1987;13:999-1006. 131. Minsky BD, Conti JA, HuantY. Relationship of acute gastrointestinal toxicity and the volume of small bowel in patients receiving combined modality therapy for rectal cancer. J Clin Oncol 1995;13:1409-16. 132. Minsky BD. Pelvic radiation therapy in rectal cancer: technical considerations. Seminars Rad Oncol 1993;3:42-7. 133. Pahlman L, Glimelius B. Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma: report from a randomized multicenter trial. Ann Surg 1990;211:187-95. 134. Fairweather DS, BradwellAR, Dykes PW, et al. Improved tumour localization using indium- 111 labeled antibodies. Br Med J 1983;287:167-70. 135. Kollmorgen CF, Meagher AP. The long-term effect of adjuvant post-operative chemoradiotherapy for rectal carcinoma on bowel function. Ann Surg 1994;220:676-82. 136. Paty PB, Enker WE, Cohen AM, Minsky BD, Friedlander-Klar H. Long-term functional results of coloanal anastomosis for rectal cancer. Am J Surg 1994;167:90-5. 137. Douglass HO, Moertel CG, Mayer RJ, et al. Survival after postoperative combination treatment of rectal cancer. N Engl J Med 1986;315:1294-5. 138. Fisher B, Wolmark N, Rockette HE, et al. Adjuvant chemotherapy or postoperative radiation for rectal cancer: five year results of NSABP R01. In: Salmon SE, editor. Adjuvant therapy of cancer V. New York: Grune & Stratton, 1987:547-54. 139. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991 ;324:709-15. 140. Thomas PRM, Lindblad AS, Stablein DM, et al. Toxicity associated with adjuvant postoperative therapy for adenocarcinoma of the rectum. Cancer 1986;57:1130-4. 141. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. Natl Cancer lnst 1988;80:21-9. 142. Shank B. Anal cancer: primary radiation therapy. Cancer Res 1990; 116(Suppl):852. 143. Weaver D, LindbladA, for the Gastrointestinal Tumor Study Group (GITSG). Radiation therapy and 5-fluorouracil (5-FU) with or without MeCCNU for the treatment of patients with surgically adjuvant adenocarcinoma of the rectum (abstract). Proceedings of ASCO 1990;9:106. 144, GastrointestinalTumor Study Group. Radiation therapy and fluorouracil with or without semustine for the treatment of patients with surgical adjuvant adenocracinoma of the rectum. J Clin Oncol 1992;10:549-57. 145. O'Connell M, Wieand H, Krook J, et al. Lack of value for Methyl-CCNU (MeCCNU) as a component of effective rectal cancer surgical adjuvant therapyl Interim analysis of Intergroup Protocol 86-47-51 (abstract). Proceedings of ASCO 1991; 10:134. 146. O'Connell M, Martenson JA. Improving adjuvant therapy for rectal cancer by combining protracted infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502-7. 147, Grage TB, Moss SE.Adjuvant chemotherapy in cancer of the colon and rectum: demonstration of effectiveness of prolonged 5-FU chemotherapy in a prospectively controlled randomized trial. Surg Clin North Am 1981 ;61:1321-9. 148. Higgins GA, Lee LE, Dwight RW, et al. The case for adjuvant 5-fluorouracil in colorectal cancer. Cancer Clin Trials 1978; 1:35-41. 149. Tepper J, O'Connell M, Petroni G, Benson A. Toxicity in the adjuvant therapy of rectal cancer: a preliminary report of intergroup 0114. Proceedings of the American Society of Clinical Oncology 1996; 15:210, 670

Curr Probl Surg, August 1997

150. Willett CG, Warland G, Coen J, Shellito PC, Compton CC. Rectal cancer: the influence of tumor proliferation on response to preoperative irradiation. Int J Radiat Oncol Biol Phys 1995;32:57-61. 151. Willett CG, Warland G, Hagan MP, Daly WJ. Tumor proliferation in rectal cancer following preoperative irradiation. J Clin Oncol 1995;13:1417-24. 152. Neoptolemos JP, Oates GD, Newbold KM, Robson AM. Cyclin/proliferation cell nuclear antigen immunohistochemistry does not improve the prognostic power of Dukes' or Jass' classifications for colorectal cancer. Br J Surg 1995;82:184-7. 153. Rouanet P, Fabre JM, Dubois JB, et al. Conservative surgery for low rectal carcinoma after high-dose radiation: functional and oncologic results. Ann Surg 1995;221:6773. 154. Koehler PR, Feldberg MAM, van Waes PFGM. Preoperative staging of rectal cancer with computerized tomography Accuracy, efficacy, and effect on patient management. Cancer 1984;54:512-6. 155. McNicholas MM, Joyce WP, Dolan J, Gibney RG, MacErlaine DP, Hyland J. Magnetic resonance imaging of rectal carcinoma: a prospective study. Br J Surg 1994;81:911-4. 156. Merchant TE, Ballon D, Koutcher JA, Miodownik S, Schwartz L, Minsky BD. A birdcage resonator for intracavitary MR imaging. Magn Reson Imaging 1993; 11:1119-27. 157. Sentovich SM, Blatchford GJ, Falk PM, Thorson AG, Christensen MA. Transrectal ultrasound of rectal tumors. Am J Surg 1994; 166:638-42. 158. Falk PM, Gupta. Positron emission tomography for preoperative staging of colorectal cancer. Dis Colon Rectum 1994;37:153-6. 159. Minsky BD, Rich T, Recth A, Harvey W, Mies C. Selection criteria for local excision with or without adjuvant radiation therapy for rectal cancer. Cancer 1989;63:1421-9. 160. Jen J KH, Piantadosi S. Allelic loss of chromosome 18Q and prognosis in colorectal cancer. N Engl J Med 1994;33l:213-21. 161. Merchant TE, Diamantis PM. Characterization of malignant colon tumors with 31P NMR phospholipid and phosphatic metabolite profiles. Cancer 1995;76:715-23. 162. Cedermark B, Johansson. The Stockholm I trial of preoperative short term radiotherapy in operable rectal cancer: a prospective randomized trial. Cancer 1995;75:2269-75. 163. Higgins GA, Humphrey EW, Dwight RW, Roswit B, Lu LE Jr, Keehn RJ. Preoperative radiation and surgery for cancer of the rectum: Veterans Administration Surgical Oncology Group trial II. Cancer 1986;58:352-9. 164. Rider WD, Palmer JA, Mahoney LJ, Robertson CT. Preoperative irradiation in operable cancer of the rectum: report of the Toronto Trial. Can J Surg 1977;20:335-8. 165. Roswit B, Higgins GA Jr, Keehn R. Preoperative irradiation for carcinoma of the rectum and rectosigmoid colon: report of a nationalVeteransAdministrationrandomized study. Cancer 1975;35:1597-602. 166. Boulis-Wassif S, Gerard A, Loygue J, Camelot D, Buyse M, Duez N. Final results of a randomized trial on the treatment of rectal cancer with preoperative radiotherapy alone or in combination with 5-fluorouracil, followed by radical surgery. Cancer 1984;53:1811-8. 167. Duncan W. Adjuvant radiotherapy in rectal cancer: the MRC trials. Br J Surg 1985;72:$59-$62. 168. Reis Neto JA, Quilici FA, Reis JA Jr. A comparison of nonoperative vs preoperative radiotherapy in rectal carcinoma: a 10 year randomized trial. Dis Colon Rectum 1989;32:702-10. 169. Cedermark B. The Stockholm II trial on preoperative short term radiotherapy in operable rectal carcinoma: a prospective randomized trial. Proc American Society of Clinical Oncology 1994; 13:198. 170. Swedish Rectal Cancer Trial. Local recurrence rate in a randomized multicentre trial of preoperative radiotherapy compared to surgery alone in resectable rectal carcinoma. European Journal of Surgery 1996; 162:397-402. Curr Probl Surg, August 1997

671

171. Goldberg PA, Nicholls RJ, Porter NH, Love S, Grimsey JE. Long-term results of a randomized trial of short-course low-dose adjuvant pre-operative radiotherapy for rectal cancer: reduction in local treatment failure. Eur J Cancer 1994;30A: 1602-6. 172. Motfiuddin M, Ahmad N, Marks G. A selective approach to adjunctive therapy for cancer of the rectum. Int J Radiat Oncol Biol Phys 1993 ;27:765-72. 173. Birnbaum EH, Dreznik Z, Myerson RJ. Early effect of external beam radiation therapy on anal sphincter: a study using anal manometry and transrectal ultrasound. Dis Colon Rectum 1992;35:757-61. 174. Birnbaum EH, Myerson RJ, Fry RD. Chronic effects of pelvic radiation therapy on anorectal function. Dis Colon Rectum 1994;37:909-15. 175. Minsky BD, Cohen AM, Enker WE. Combined modality therapy of rectal cancer: decreased acute toxicity with the pre-operative approach. J Clin Oncol 1992; 10:1218-24. 176. Minsky BD, Cohen AM, Kemeny N, et al. Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy. J Clin Oncol 1992;10:79-84. 177. Minsky BD, Kemeny N, Cohen AM, et al. Preoperative high-dose leucovorin/5fluorouracil and radiation therapy for unresectable rectal cancer. Cancer 199 l ;67:2859-66. 178. Minsky BD, Cohen AM, Kemeny N, et al. The efficacy of preoperative 5-Fluorouracil, high-dose leucovorin, and sequential radiation therapy for unresectable rectal cancer. Cancer 1993;71:3486-92. 179. Minsky B, Cohen A, Enker W, et al. Preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for rectal cancer. Cancer 1994;73:273-8. 180. Minsky BD, Cohen AM, Enker WE. Phase I trial of postoperative 5-FU, radiation therapy and high-dose leucovorin for resectable cancer. Int J Radiat Oncol Biol Phys 1993;22:139-45. 181. Weinstein GD, Rich TA, Shumate CR, et al. Preoperative infusional chemoradiation and surgery with or without an electron beam intraoperative boost for advanced primary rectal cancer. Int J Radiat Oncol Biol Phys 1995;32:197-204. 182. Shumate CR, Rich TA, Skibber JM, Ajani JA, Ota DM. Preoperative chemotherapy and radiation therapy for locally advanced primary and recurrent rectal cancer. Cancer 1993;71:3690-6. 183. Bosset JF, Pavy JJ, Hamers HE Determination of the optimal dose of 5-fluorouracil when combined with low dose d, 1-1eucovorin and irradiation in rectal cancer: results of three consecutive phase II studies. Eur J Cancer 1993;29:476-86. 184. Meterissian S, Skibber J, Rich T. Patterns of residual disease after preoperative chemoradiation in ultrasound T3 rectal carcinoma. Ann Surg Oncol 1994; 1:111-6. 185. Chen ET, Mohiuddin M, Brodovsky H. Downstaging of advanced rectal cancer following combined preoperative chemotherapy and high dose radiation. Int J Radiat Oncol Biol Phys 1994;30:169-75. 186. Meade PG, Blatchford GJ, Thorson AG, Christensen MA. Preoperative chemoradiation downstages locally advanced ultrasound-staged rectal cancer.Am J Surg 1995;170:609-13. 187. Picciocchi A, Cocco C, Magistrelli P, Roncolini G. Concomitant preoperative radiochemotherapy in operable locally advanced rectal cancer. Dis Colon Rectum 1994;37:69-72. 188. Landry JC, Koretz MJ, Wood WC, Bahri S. Preoperative irradiation and fluorouracil chemotherapy for locally advanced rectosigmoid carcinoma: Phase 1-11 study. Radiology 1993;188:423-6. 189. Minsk3' BD, CohenA, Enker W, Kelsen D. Pre-operative 5-FU, low dose leucovorin, and radiation therapy for locally advanced/unresectable rectal cancer. Int J Radiat Oncol Biol Phys 1997;37:289-95. 190. Preston DM, Lennard-Jones JE, Thomas BM. The Balloon proctogram. Br J Surg 1984;71:29-32. 672

Curr Probl Surg, August 1997

191. Smith LE. Anastomosis with EEA stapler after anterior colonic resection. Dis Colon Rectum 1981;24:236-42. 192. Chen ET, Mohiuddin M, Brodovsky H, Fishbein G, Marks G. Downstaging of advanced rectal cancer following combined preoperative chemotherapy and high dose radiation. Int J Radiat Oncol Biol Phys 1994;30:169-75. 193. Minsky BD, Cohen AM, Kemeny N, et al. Pre-operative 5-FU, and low dose leucovorin and sequential radiation therapy for unresectable rectal cancer. Int J Radiat Oncol Biol Phys 1993;25:821-7. 194. Chan A, Wong A, Langevin J, Khoo R. Preoperative concurrent 5-fluorouracil infusion, mitomycin c and pelvic radiaton therapy in tethered and fixed rectal carcinoma. Int J Radiat Oncol Biol Phys 1993;25:791-9. 195. Frykolm G, Glimelius B, Pahlman L. Preoperative irradiation with and without chemotherapy (MFL) in the treatment of primarily non-resectable adenocarcinoma of the rectum: results from two consecutive studies. Eur J Cancer Clin Oncol 1989;25:1535-41. 196. Cooper SG, BonaventuraA, Ackland SP, Joseph DJ. Pelvic radiotherapy with concurrent 5-fluorouracil modulated by leucovorin for rectal cancer. Clin Oncol 1993;5:16973. 197. Chari RS, Tyler DS, Anscher MS. Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg 1995;221:778-87. 198. Rich TA, Skibber JM, Ajani JA, Buchholz DJ. Preoperative infusional chemoradiation therapy for stage T3 rectal cancer. Int J Radiat Oncol Biol Phys 1995;32:1025-9. 199. Grann A, Minsky BD, Cohen AM, Saltz L. Preliminary results of preoperative 5fluorourocil, low-dose leucovorin, and concument rad therapy for clinically resectable T3 rectal cancer. Dis Colon Rectum 1997;40:515 -22. 200. Minsky BD, CohenAM. Conservative management ofinvasive rectal cancer: altemative to abdominoperineal resection. Oncology 1989;3:137-47. 201. Baker AR. Local procedures in the management of rectal cancer. Semin Oncol 1980;7:385-91. 202. Gerard JP, Ayzac L, Coquard R, Romestaing E Endocavitary irradiation for early rectal carcinomas T1 (T2). A series of 101 patients treated with the Papillon's technique. Int J Radiat Oncol Biol Phys 1996;34:775-83. 203. Schild SE, Martenson JA, Gunderson LL. Endocavitary radiotherapy of rectal cancer. Int J Radiat Oncol Biol Phys 1996;3:677-82. 204. Rich TA, Weiss DR, Mies C, Fitzgerald TJ, Chaffey JT. Sphincter preservation in patients with low rectal cancer treated with radiation therapy with or without local excision or fulguration. Radiology 1985;156:527-31. 205. Willet CG, Tepper JE, Donnely S, et al. Patterns of failure following local excision and local excision and postoperative radiation therapy for invasive rectal adenocarcinoma. J Clin Oncol 1989;7:1003-8. 206. Minsky BD, Cohen AM, Enker WE, Mies C. Sphincter preservation in rectal cancer by local excision and postoperative radiation therapy. Cancer 1991 ;67:908-14. 207. Jessup JM, Bothe A, Stone MD, et al. Preservation of sphincter function in rectal carcinoma by a multimodality treatment approach. Surg Oncol Clin North Am 1992;1:137-145. 208. Steele G, Busse P, Huberman M, et al. A pilot study of sphincter-sparing management of adenocarcinoma of the rectum. Arch Surg 1991;126:696-702. 209. Summers GE, MendenhallWM, Copeland EM, III. Update on the University of Florida experience with local excision and postoperative radiation therapy for the treatment of early rectal carcinoma. Surg Oncol Clin N Am 1992;1:25-130. 210. Ota DM, Skibber J, Rich TA. M.D. Anderson Cancer Center experience with local exicision and multimodality therapy for rectal cancer. Surg Oncol Clin N Am 1992;1:147-52. 211. Rosenthal SA, Yeung RS, Weese JL, et al. Conservative management of extensive lowCurr Probl Surg, August 1997

673

212. 213. 214.

215. 216. 217. 218.

219. 220. 221. 222. 223. 224. 225. 226. 227.

228. 229. 230.

231.

232. 233. 234. 235. 674

lying rectal carcinomas with transanal local excision and combined preoperative and postoperative radiation therapy: a report of a phase I-II trial. Cancer 1992;69:335-41. Minsky BD, Enker WE, Cohen AM, Lauwers G. Local excision and postoperative radiation therapy for rectal cancer. Am J Clin Oncol 1994; 17:411-6. Willett CG, Compton CC, Shellito PC, Efird JT. Selection factors for local excision or abdominoperineal resection of early stage rectal cancer. Cancer 1994;73:2716-20. Marks G, Mohiuddin MM, Masoni L, Pecchioli L. High-dose preoperative radiation and full-thickness local excision: a new option for patients with select cancers of the rectum. Dis Colon Rectum 1990;33:735-40. Biggers OR, Beart RW Jr, Ilstrup DM. Local excision of rectal cancer. Dis Colon Rectum 1986;29:374-7. Hager T, Gall FP, Hermanek P. Local excision of rectal cancer. Dis Colon Rectum 1983;26:149-51. Horn A, Halvorsen JF, Morild I. Transanal extirpation for early rectal cancer. Dis Colon Rectum 1989;32:769-72. Greaney MG, lrvin TT. Criteria for the selection of rectal cancer for local treatment: a clinicopathologic study of low rectal tumors. Dis Colon Rectum 1977;20:463-6. Morson BC, Bussey HJR, Samoorian S. Policy of local excision for early cancer of the colorectum. Gut 1997; 18:1045-50. Abrams JS. Clinical staging of colorectal cancer. Am J Surg 1980;139:539-43. Cohen AM, Wood WC, Gunderson LL, Shinnar M. Pathological studies in rectal cancer. Cancer 1980;45:2965-8. Grigg M, McDermott FT, Pihl EA, Hughes ES. Curative local excision in the treatment of carcinoma of the rectum. Dis Colon Rectum 1984;27: 81- 3. Nelson JC, Nimr AF, Thomford NR. Criteria for the selection of "early" carcinomas of the rectum. Are they valid? Arch Surg 1987; 122:533-6. Moertel CG, Reitemeyer RJ. Advanced gastrointestinal cancer: clinical management and chemotherapy. New York: Harper & Row, 1969. Wanebo HJ, Marcove RC. Abdominal sacral resection of locally recurrent rectal cancer. Ann Surg 1981;194:458-71. Wanebo HJ, Gaker DL, Whitehill R, Morgan RF, Constable WC. Pelvic recurrence of rectal cancer. Ann Surg 1987;205:482-95. Pearlman NW, Donohue RE, Stiegmann GV, Ahnen DJ, Sedlacek SM, Braun TJ. Pelvic and sacropelvic exenteration for locally advanced or recurrent anorectal cancer. Arch Surg 1987;122:537-41. Wanebo HJ, Koness RJ, Turk PS, Cohen SI. Composite resection of posterior pelvic malignancy. Ann Surg 1992;215:685-95. Wanebo HJ, Koness RJ, Vezeridis ME Cohen SI, Wrobleski DE. Pelvic resection of recurrent rectal cancer. Ann Surg 1994;220:586-97. Magrini S, Nelson H, Gunderson LL, Sim FH. Sacropelvic resection and intraoperative electron irradiation in the management of recurrent anorectal cancer. Dis Colon Rectum 1996;39:1-9. Overgaard M, Overgaard J, SellA. Dose-response relationship for radiation therapy of recurrent, residual, and primarily inoperable colorectal cancer. Radiother Oncol 1984;1:217-25. Urdaneta-Lafee N, Kligerman MM, Knowlton AH. Evaluation of palliative irradiation in rectal carcinoma. Radiology 1972;104:673-7. Brierley JD, Cummings BJ, Wong CS, KeaneTJ. Adenocarcinomaof the rectum treated by radical external radiation therapy. Int J Radiat Oncol Biol Phys 1995;31:255-9. Wassif SB. Ten years' experience with a multimodality treatment of advanced stages of rectal cancer. Cancer 1983;52:2017-24. Cummings BJ Jr, Rider WD, HarwoodAR, Keane TJ, Thomas GM. Radical external Curr Probl Surg, August 1997

236.

237.

238.

239. 240. 241.

242.

243. 244. 245.

246.

247.

248.

249. 250.

251.

252.

253.

254.

beam radiation therapy for adenocarcinoma of the rectum. Dis Colon Rectum 1983;26:30-6. Schild SE, Martenson JA, Gunderson LL, Dozois RR. Long-term survival and patterns of failure after postoperative radiation therapy for subtotally resected rectal adenocarcinoma. Int J Radiat Oncol Biol Phys 1989;16:459-63. Allee PE, Tepper JE, Gunderson LL, MunzenriderJE. Postoperative radiation therapy for incompletely resected colorectal carcinoma. Int J Radiat Oncol Biol Phys 1989; 17:1171-6. Gunderson LL, Russell AH, Llewellyn HJ, Doppke KP, Tepper JE. Treatment planning for colorectal cancer: radiation and surgical techniques and value of small-bowel films. Int J Radiat Oncol Biol Phys 1985; 11:1379-93. Willet CG, Wafland G, Hagan MP, Daly WJ. Tumor proliferation in rectal cancer following preoperative irradiation. J Clin Oncol 1995; 13:1417-24. Mella O, Dahl O, Horn A, Morild I. Radiotherapy and resection for apparently inoperable rectal adenocarcinoma. Dis Colon Rectum 1984;10:663-8. Mendenhall WM, Souba WW, Blandk KI, Million RR. Preoperative irradiation and surgery for initiallyunresectable adenocarcinoma of the rectum.Am Surg 1992;58:4239. Emami B, Pilepich M, Willett C, Munzenrider JE, Miller HH. Effect of preoperative irradiation on resectability of colorectal carcinomas. Int J Radiat Oncol Biol Phys 1982;8:1295-9. Stevens KR Jr, Allen CV, Fletcher WS. Preoperative radiotherapy for adenocarcinoma of the rectosigmoid. Cancer 1976;37:2866-74. Dosoretz DE, Gunderson LL, Hedberg S, et al. Preoperative irradiation for unresectable rectal and rectosigmoid carcinomas. Cancer 1983;52:814-8. Marsh PJ, James RD, Schofield PF. Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma: results of a prospective, randomized trial. Dis Colon Rectum 1994;37:1205-14. Moertel CG, Gunderson LL, Mailliard JA, McKenna PJ. Early evaluation of combined fluorouracil and leucovorin as a radiation enhancer for locally unresectable, residual, or recurrent gastrointestinal carcinoma. J Clin Oncol 1994; 12:21-7. Petrelli N, Herrera L, Rustum Y, et al. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 1987;5:1559-65. Poon MA, O'Connell MJ, Moertel CG, et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 1989;7:1407-18. Erlichman C, Fine S, WongA, Elhakim T. A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 1988;6:469-75. Minsky BD, Cohen AM, Kemeny N, et al. Pre-operative combined 5-FU, low dose leucovorin, and sequential radiation therapy for unresectable rectal cancer. Int J Radiat Oncol Biol Phys 1993;25:821-7. Frykholm G, Glimelius B, Pahlman L. Preoperative irradiation with and without chemotherapy (MFL) in the treatment of primary non-resectable adenocarcinoma of the rectum: results from two consecutive studies. Eur J Clin Oncol 1989; 11:1535-41. Willett CG, Shellito PC, Tepper JE, Eliseo R, Convery K, Wood WC. Intraoperative electron beam radiation therapy for recurrent locally advanced rectal or rectosigmoid carcinoma. Cancer 1991;67:1504-8. Willet CG, Shellito PC, Tepper JE, Eliseo R, Convery K, Wood WC. Intraoperative electron beam radiation therapy for primary locally advanced rectal and rectosigmoid carcinoma. J Clin Oncol 1991;9:843-9. Frykholm G, Glimelius B, Pahlman L. Preoperative or postoperative irradiation in

Curr Probl Surg, August 1997

675

255. 256. 257.

258. 259.

260. 261.

262. 263. 264. 265. 266.

267. 268. 269.

270. 271. 272.

676

adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 1993;36:564-72. Ghossein NA, Samala EC, Alpert S, et al. Elective postoperative radiotherapy after incomplete resection of colorectal cancer. Dis Colon Rectum 1981 ;24:252-6. Gunderson LL, Martin JK, Beart RW. Intraoperative and external beam irradiation for locally advanced colorectal cancer. Ann Surg 1988;207:52-60. Gunderson LL, Dozois RR. Intraoperative irradiation for locally advanced colorectal carcinomas. Perspectives in colon and rectal surgery. Perspectives in Colon Rectal Surgery 1992;1-23. Gunderson LL. Rationale for and results of intraoperative radiation therapy. Cancer 1994;74:537-41. Gunderson L, Helson H, Martenson J, Haddock M. Locally advanced primary and recurrent colorectal cancer: disease control and survival with IOERT containing regimens. Int J Radiat Oncol Biol Phys 1995;32:267. Pollett WG, Nicholls RJ. The relationship between the extent of distal clearance and survival and local recurrence rates after curative anterior resection for carcinoma of the rectum. Ann Surg 1984;198:159-63. Rominger CJ, Gelber RD, Gunderson LL, Conner N. Radiation therapy alone or in combination with chemotherapy in the treatment of residual or inoperable carcinoma of the rectum and rectosigmoid or pelvic recurrence following colorectal surgery. Radiation Therapy Oncology Group study (76-16). Am J Clin Oncol 1985;8:118-27. Suzuki K, Gunderson LL, Devine RM, et al. Intraoperative irradiaton after palliative surgery for locally recurrent rectal cancer. Cancer 1995;75:939-52. Stepan R, Zimmermann FB, Huber FT, Feldmann HJ. Clinical and experimental evaluation of the HDR-after-loading-IORT-flab-method. Fifth International Meeting on Progress in Radio-Oncology. Progress in Radio-Oncology 1995;613-7. HarrisonLB, EnkerWE, AndersonLL. High-dose-rateintraoperativeradiation therapy for colorectal cancer. Oncology 1995;9:737-55. Huber FT, Stepan R, Zimmermann F, Fink U. Locally advanced rectal cancer: resection and intraoperative radiotherapy (IORT) using the flab method combined with pre-or postoperative radiochemotherapy. Dis Colon Rectum 1996;39:774-87. Moertel CG, Childs DS Jr, Reitemeier RJ, Colby MY Jr, Holbrook M. Combined 5fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 1969;2:865-7. Haddock MG, Gunderson LL, Nelson H, Cha S. Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients. Int J Radiat Oncol Biol Phys 1995;32:268. Shaw EG, Gunderson LL, Martin JK0 Beart RW, Nagorney DM. Peripheral nerve and ureteral tolerance to intraoperative radiation therapy: clinical and dose-response analysis. Radiother Oncol 1990;18:247-55. Minsky BD, Mies C, Recht A, Rich TA, Chaffey JT. Resectable adenocarcinoma of the rectosigmoid and rectum: 1. Patterns of failure and survival. Cancer 1988;61:140816. Sears H, Herlyn D, Steplewski Z, Koprowski H. Effects of monoclonal antibody immunotherapy on patients with gastrointestinal adenocarcinoma. J Biol Res Mod 1984;3:138-50. Minsky BD, CohenAM, EnkerWE, Harrison LB, Sigurdson E. Radiation therapy for unresectable rectal cancer. Int J Radiat Oncol Biol Phys 1991 ;21:1283-9. Weinstein GD, Rich TA, Shumate CR, Skibber JM. Preoperative infusional chemoradiation and surgery with or without an electron beam intraoperative boost for advanced primary rectal cancer. Int J Rad Oncol Biol Phys 1995;32:197-204.

Curr Probl Surg, August 1997