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Benefits of adjuvant therapy for rectal cancer Benefits of adjuvant therapy for rectal cancer National Cancer Institute (NCI) March 13,1991 Abstract: On March 13,1991, the National Cancer Institute released a clinical announcement concerning the benefits of adjuvant therapy for rectal cancer. The data, which are_described in the clinical announcement, state that a sequential regimen of 5-fluorouracil-based chemotherapy and radiation_therapy can reduce overall tumor recurrence rates, substantially reduce local recurrence, and prolong survival in patients with resected, TNM stage II (Dukes'B) and III (Dukes'C) rectal cancer. The full text of this clinical announcement can be_obtained by selecting the NEWS option in the PDQ database. Those with access to a fax machine can have_faxed the announcement to them by calling on their fax machines the NCI's new service CANCERFAX, at 1-301-402-5874 and entering ID#400004. Patients and the public may obtain information on rectal cancer by calling NCI's Cancer Information Service at 1-800-4-CANCER. Full Text: The National Cancer Institute wants to bring_to the attention of clinicians the benefits that may_be_achieved with adjuvant therapy of rectal cancer. The data, presented here for your review, suggest that a sequential regimen of 5-fluorouracil (5-FU) based chemotherapy and radiation_therapy can reduce overall tumor recurrence rates, substantially reduce local recurrence, and prolong patient survival. Such a regimen may_be_recommended as therapy for individuals with resected, TNM stage II (Dukes'B2, 3) and III (Dukes'C) rectal cancer. While previous clinical trials have_utilized a combination of postoperative radiation_therapy to the pelvis plus 5-FU and the investigational drug methyl-CCNU (semustine), current preliminary information suggests that substantial treatment benefits may_be_achieved using irradiation and standard doses of 5-fluorouracil. This combination avoids the potential risks of leukemia and chronic renal_insufficiency associated with protracted administration of methyl-CCNU. The intent of this announcement is to supplement the recent NIH Consensus Development Conference statement on adjuvant therapy of rectal cancer and to provide data to assist you in treatment planning for your patients. Carcinoma of the rectum is one of the more common malignant diseases in the United_states, afflicting an estimated 45,000 individuals a year. The clinical course of patients treated with surgery alone has_been_characterized by a_high death_rate (55%of patients die within five years) and also by the pain and disability associated with pelvic recurrence of tumor. Therapy that simply reduces local relapse would be a meaningful advance for many patients. Radiation alone, given in doses of 45 to 50 Gy has_produced a modest reduction in local recurrence but has not been_shown to have an influence on survival (1). In April 1990, the NIH Consensus Development Conference on Adjuvant Therapy for Patients with Colon and Rectal Cancer stated that: Combined postoperative chemotherapy and radiation_therapy improves local control and survival in stage II and III patients (with rectal cancer) and is_recommended; At the present_time, the most effective combined modality regimen appears to be fluorouracil plus methyl-CCNU and high dose pelvic irradiation (45 to 55 Gy), but chronic toxicity considerations of methyl-CCNU militate against using this regimen outside ongoing clinical trials (2). Newly available information, presented here, reinforces the observation that adjuvant therapy benefits patients with rectal cancer and suggests that a regimen of 5-fluorouracil plus pelvic irradiation without methyl-CCNU may well be the optimal combination. Appearing in the March 14 issue of the New_england Journal of Medicine is the final report of one major study that served as the basis for the Consensus Conference recommendations (3 4). The NEJM-reported trial was_conducted by the North Central Cancer Treatment Group (NCCTG 794751) from 1980 to 1986 and involved the participation of about 200 patients. Beginning four to ten weeks after curative intent surgery for stage II or III rectal cancer, patients were_randomized to receive either combined modality radiation plus chemotherapy or radiation_therapy alone. In both treatment regimens, radiation_therapy consisted of 45 Gy to the pelvis delivered over four and one-half weeks followed by a 5. 4-Gy boost to the tumor bed. In the combined modality treatment, patients received an initial nine-week cycle of 5-FU and methyl-CCNU. This chemotherapy was_followed by radiation plus concurrent 5-FU. Patients then received another nine-week cycle of 5-FU and methyl-CCNU. With further follow-up, the results of this study show a clear advantage for the combined modality treatment in all parameters of evaluation, including reduced overall recurrences (p=0. 0016), reduced local recurrences (p=0. 036), reduced distant metastases (p=0. 011), and improved survival (p=0. 026). There_is a 46%reduction in pelvic recurrence, a 37%reduction in distant tumor spread, and a 29%reduction in patient deaths. Acute, severe toxicity was infrequent. Delayed, severe reactions, usually bowel obstruction requiring surgical intervention, occurred in about 6. 5%of all patients and were comparable in incidence whether patients received radiation_therapy alone or radiation plus chemotherapy. This study confirms for_the_first_time that the benefit achieved with chemotherapy when combined with irradiation is_produced superior to_that by radiation_therapy alone, which many clinicians regard_as a standard adjuvant therapy for rectal cancer. The NCCTG trial design evolved from earlier work such_as the Gastrointestinal Tumor Study Group study (GITSG 7175)( 5, 6) that used a combined modality regimen in which radiation (40 to 44 Gy) plus 5-FU was_given initially, followed by cycles of 5-FU and methyl-CCNU given for_one and one-half years. That study demonstrated the superiority of chemo-radiation_therapy when compared to surgery alone. A reduction in local recurrence was_noted also when compared to radiation_therapy alone. The NCCTG trial now convincingly confirms that post-surgical, combined modality therapy can improve control of tumor relapse and patient survival not_only when compared to surgery alone but_also when compared to full dose postoperative radiation_therapy. The new and confirmatory evidence of effective surgical adjuvant therapy for rectal cancer has_stimulated a search for safer and still more effective approaches. Important questions remain. 1. Is methyl-CCNU a necessary component of the chemotherapy or is 5-FU as a single agent sufficient? Methyl-CCNU is an investigational agent that currently can be_obtained only from the NCI. No long-term bone_marrow or renal toxicities were_observed after limited methyl-CCNU treatment on the NCCTG trial. However, after chronic administration, this drug has_been_associated with a 12-fold increased risk for secondary leukemia or preleukemia (7) as_well_as with chronic renal toxicity. One clinical study of adjuvant therapy in rectal cancer (GITSG 7180) showed no superiority for combined modality therapy that included methyl-CCNU when compared to treatment with radiation and 5-FU (8). An intergroup trial, led_by the North Central Cancer Treatment Group (NCCTG 864751), with 453 rectal cancer patients entered between 1987 and 1990, tested combined modality therapy with or without methyl-CCNU administered in a manner identical to the treatment in the superior regimen of the trial reported in the New_england Journal of Medicine (NCCTG 794751). The protocol specified an interim analysis after 50%of the predicted tumor recurrences had_occurred. That preliminary analysis of the study, which will_be_presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in May 1991 (9), reveals a rate of recurrence 1. 2 times higher for patients receiving methyl-CCNU, statistically ruling out the likelihood that the addition of methyl-CCNU actually confers a 25%or greater advantage in disease control. Severe thrombocytopenia was_seen only in patients receiving methyl-CCNU, affecting 12.4%of these individuals. To_date, there_are not sufficient data to compare survival rates. But based_on increased toxicity and lack of evidence for improved effectiveness the NCI agrees with the study's investigators that methyl-CCNU, delivered in_this manner, is probably not a necessary component of multimodality adjuvant therapy for rectal carcinoma. This conclusion is provisional while we await further maturation of the intergroup study (NCCTG 864751). However, the data have_been found to be sufficiently convincing that the currently active, NCI-supported, Intergroup study (INT 0114) utilizes 5-FU alone and radiation as the control treatment. 2. Do 5-FU/levamisole, 5-FU/leucovorin or other promising therapies have a role in adjuvant therapy of rectal cancer? The demonstration that 5-FU/levamisole can be effective adjuvant therapy of colon_cancer (10) and the acceptance that 5-FU/leucovorin combinations are superior to 5-FU alone for metastatic colorectal tumors have_produced hope for further improvement in the systemic component of adjuvant treatment of rectal cancer. Both of these combinations are currently being_evaluated in protocols sponsored by the National Cancer Institute and are available to eligible, rectal cancer patients throughout North_america. In these trials, all patients receive active, postoperative, systemic therapy. Continued accrual of patients to these trials is essential to define further advances in Care_for patients with resected rectal cancer with transmural extension (TNM stage II or Dukes'B2 3) or with positive regional lymph_nodes (TNM stage III or Dukes'C) who would be appropriate candidates for adjuvant care but who lack access to or who decline participation in clinical trials, it would be reasonable to consider the following treatment regimen based_on available evidence. This regimen is the control arm for the currently active Intergroup study (INT 0114) mentioned above. Treatment should be_initiated from one to two months after surgery if the patient is_recovered fully from the operative procedure, maintaining a reasonable state of nutrition, and has normal hematologic parameters.-----Week 1 and 5: 5-FU 500 mg/M2/day X 5 days Week 9: Radiation_therapy to tumor area and regional node distribution, 45 Gy over 4-6 weeks, followed by 5. 4-Gy boost in 3 fractions to the tumor bed. Give 5-FU 500 mg/M2/day X 3 days during the first_and_last week of irradiation. 4 8 weeks 5-FU 450 mg/M2/day X 5 days after irradiation:-----5-FU should be_given by rapid IV injection for all courses. Appropriate adjustments in 5-FU dosage should be_made based_on toxicity to previous courses. Careful and experienced radiation_therapy treatment planning is_required with special attention to avoid small bowel injury (11. With_regard_to averting these toxicities, the critical role of the surgeon must be_recognized. At the time of surgery, consideration must be_given to the possibility that radiation_therapy may_be a part_of postoperative treatment planning. Delineation of the limits of resection with radio-opaque clips and incorporation of one of the surgical techniques for excluding small bowel from the pelvis may minimize some of the treatment related sequelae. Other doses and schedules of radiation and/or chemotherapy may_be of equal efficacy. It is the responsibility of the individual physician, in_concert with the individual patient to develop the most appropriate plan of therapy. Additional information about the studies cited in_this Announcement and about other clinical trials is available from the NCI's Physician Data Query (PDQ) database. PDQ can be_accessed through a medical library or by calling NCI's Cancer Information Service at 1-800-4-CANCER. The NIH Consensus Development Conference Statement from the April 1990 Conference on Adjuvant Therapy in Colon and Rectum Cancer is available by writing to: Consensus Development Statement: Colon/Rectum Adjuvant Therapy Office of Medical Applications of Research Building 1, Room 260 National_institutes_of_health Bethesda, MD 20892 Some physicians may conclude that the currently available data support a contributory role for methyl-CCNU in an adjuvant regimen. Further information about methyl-CCNU or other NCI sponsored investigational agents may_be_obtained by calling NCI's Drug Management and Authorization Section of the Investigational Drug Branch at 301-496-5725. References: FISHER B, WOLMARK N, et_al. Postoperative adjuvant chemotherapy or radiation_therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst 80: 21-29,1988 NIH Consensus Conference on Adjuvant Therapy for Patients with Colon and Rectal Cancer. JAMA 264: 1444-1450,1990 KROOK JE, MOERTEL CG, et_al. Effective surgical adjuvant therapy for high risk rectal carcinoma. N Engl J Med 324: 709-715, March 14,1991 KROOK J, MOERTEL C, et_al. Radiation vs sequential chemotherapy-radiation -chemotherapy, a study of the North Central Cancer Treatment Group, Duke_university, Mayo Clinic Proc ASCO 6: 92,1987 GASTROINTESTINAL TUMOR STUDY GROUP. Prolongation of disease free interval in surgically treated rectal carcinoma. N Engl J Med 312: 1465-1472 1985 DOUGLASS HO, MOERTEL CG, et_al. Survival after postoperative combination treatment of rectal cancer (letter) N Engl J Med 315: 1294,1986 BOICE JD, GREEN MH, et_al. Leukemia and preleukemia after adjuvant treatment of gastrointestinal cancer with semustine (methyl-CCNU. N Engl J Med 309: 1079-1085,1983 WEAVER D, LINDBLAD AS, et_al. Radiation_therapy and 5-fluorouracil (5-FU) with or without Meccnu for the treatment of patients with surgically adjuvant adenocarcinoma of the rectum. Proc ASCO 9: 106,1990 O'CONNELL M, WIEAND H, et_al. Lack of_value for methyl-CCNU (Meccnu) as a component of effective rectal cancer surgical adjuvant therapy: interim analysis of intergroup protocol 86-47-51. Proc ASCO 1991, in press MOERTEL CG, FLEMING TR, et_al. Levamisole and fluorouracil for adjuvant therapy of resected colon_cancer. N Engl J Med 322: 352-358,1990 GUNDERSON LL, RUSSELL AH, et_al. Treatment planning for colorectal cancer. Int J Radiat Oncol Biol Phys 11: 1379-1393,1985 The full article describing the final results appears in N Engl J Med 1991 Mar 14; 324 (11): 709-15. U_s. National Library of Medicine, 8600 Rockville Pike, Bethesda, MD 20894 National_institutes_of_health, Department_of_health & Human Services Copyright, Privacy, Accessibility Last updated: 25 March 1997