Benefits of adjuvant therapy for rectal cancer
National Cancer Institute (NCI)
March 13, 1991
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 the announcement faxed 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.
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 superior to that produced 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 also noted 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 fully recovered 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.
- 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.