In his excellent, thorough review of the current status of multidisciplinary treatment for rectal cancer, Dr. Minsky appropriately emphasizes the role that data from prospective clinical trials have played in providing the foundation for adjuvant therapy for patients with this disease. The principal therapeutic options discussed by Dr. Minsky are preoperative therapy and postoperative therapy.
Results from clinical trials discussed in the Minsky article indicate that postoperative radiation therapy and chemotherapy should represent the current standard of care for these patients because this is the only adjuvant treatment approach demonstrated by randomized trials to have a favorable impact on survival. Randomized clinical trials have shown that preoperative radiation therapy results in improved local control. A clear improvement in overall survival has not been demonstrated, however.
Dr. Minsky questions the adequacy of the dose utilized in the preoperative studies. The consistent improvement in local control seen in these studies, however, suggests that inadequate dose is not the reason for the lack of a demonstrable impact on survival. It is likely that systemic therapy is a necessary component of adjuvant treatment if it is to have a favorable impact on survival. Future trials of preoperative adjuvant therapy should include systemic therapy.
Clinical trials of postoperative irradiation and fluorouracil (5-FU)-based chemotherapy in patients with resected high-risk rectal cancer, in contrast, have consistently demonstrated improved survival.[1-3] The most recent publication of results from the intergroup trial coordinated by the North Central Cancer Treatment Group showed improved survival when 5-FU was given by prolonged infusion during radiation therapy rather than by bolus. Based on these results, postoperative 5-FU and radiation therapy, as given in this study, should be considered the standard of care for patients with resected high-risk rectal cancer.
The value of preoperative irradiation, with or without chemotherapy, in improving survival remains unproven. Accordingly, preoperative radiation therapy, with or without chemotherapy, should not be used in patients with technically resectable rectal cancer outside of a clinical trial.
Dr. Minsky has taken a leadership role in advancing our scientific understanding of therapy for rectal cancer by assuming responsibility as the principle investigator for intergroup protocol 0147, which is designed to evaluate whether a preoperative or a postoperative approach to the adjuvant treatment of rectal cancer is superior. This study, which is widely available in the United States through the intergroup mechanism, should be actively supported by oncologists through entry of eligible patients.
Long-Term Morbidity Significant
The cost of therapy to patients in long-term morbidity is significant. Using a telephone survey, Kollmorgen and colleagues assessed bowel function in patients treated by surgery and postoperative chemoradiotherapy or by surgery alone. This study clearly demonstrated that adjuvant radiation and chemotherapy adversely affect multiple measures of bowel function.
Although Dr. Minsky correctly points out that Kollmorgen's data resulted from a nonrandomized, nonblinded telephone survey, it is very unlikely that these unavoidable limitations in the study led to an incorrect conclusion. Of the 11 major items in the survey, 10 were straightforward questions with yes or no answers and the other question addressed the number of bowel movements the patient had each day. It is therefore very unlikely that the collection of data was biased. Although the study was not randomized, a comparison of factors with a potential effect on bowel function showed that the male-female ratio, level of the anastomosis, and the type of anastomosis were all similar. Patient age was the only factor in which there was a borderline significant difference between the two groups (P = .054), and this difference actually favored the irradiated patients (median age, 66.6 years for nonirradiated patients vs 62.6 years for the irradiated patients). For all 11 major categories of bowel function assessed, a worse result was seen in the irradiated patients, and the P value in each case was extreme, ranging from .009 to less than .001. For example, 56% of the irradiated patients described at least occasional incontinence, as compared with only 7% of nonirradiated patients (P less than .001).
A recent evaluation of the Stockholm trials suggests that preoperative radiation therapy may also be associated with significant long-term morbidity. Future clinical trials should prospectively assess the impact of adjuvant treatment on long-term bowel function. Methods for reducing treatment-related morbidity should also be evaluated. Prior studies using doses of 4,000 to 4,400 cGy together with chemotherapy have resulted in approximately the same level of local control as more recent studies using 5,000 cGy.[1,2] Accordingly, it may be possible to reduce the radiation dose without adversely affecting outcome. Investigation of pharmacologic agents designed to reduce radiation morbidity is also warranted.[6,7]
Prospective clinical trials have clearly demonstrated that adjuvant postoperative chemoradiotherapy improves survival. Despite this, approximately 30% of patients treated adjuvantly die within 4 years. Entry of patients into prospective clinical trials designed to assess potential methods for improving adjuvant treatment remains our best hope for improving outcome for patients with this disease.
1. O'Connell MJ, Martenson JA, Weiand HS, et al: Improving adjuvant therapy for rectal cancer by combining protracted infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331:502-507, 1994.
2. Krook JE, Moertel CG, Gunderson LL, et al: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324:709-715, 1991.
3. Gastrointestinal Tumor Study Group: Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 312:1465-1472, 1985.
4. Kollmorgen CF, Meagher AP, Pemberton JH, et al: The long term effect of adjuvant postoperative chemoradiotherapy for rectal cancer on bowel function. Ann Surg 220:676-682, 1994.
5. Holm T, Singnomklao T, Rutqvist L, et al: Adjuvant preoperative radiotherapy in patients with rectal carcinoma: Adverse effects during long term follow-up of two randomized trials. Cancer 78:968-976, 1996
6. Martenson, JA, Hyland G, Moertel C, et al: Olsalazine is contraindicated during pelvic radiation therapy: Results of a randomized trial. Int J Radiat Oncol Biol Phys 35(2):299-303, 1996.
7. Henriksson R, Franzen L, Litlbrand B: Effects of sucralfate on acute and late bowel discomfort following radiotherapy of pelvic cancer. J Clin Oncol 10:969-975, 1992.