In 1994, the results of a randomized intergroup trial coordinated by the North Central Cancer Treatment Group (NCCTG 86-47-51) indicated that protracted fluorouracil(Drug information on fluorouracil) (5-FU) infusion during postoperative adjuvant radiation therapy results in better survival than concurrent bolus 5-FU and pelvic radiation therapy in patients with resected high-risk rectal cancer. The important prior work of Dr. Tyvin Rich had laid much of the groundwork for NCCTG 86-47-51, and Dr. Rich was a coauthor of the paper that described the results of that study. In his review article, "Infusional chemotherapy for operable rectal cancer: Post-, pre-, or nonoperative management?" Dr. Rich places this work within the context of results from other related clinical trials.
Postoperative or Preoperative Chemoradiation?
In the postoperative adjuvant setting, the prolonged infusion chemotherapy regimen used in NCCTG 86-47-51 is the only one demonstrated in a randomized clinical trial to improve survival in resected high-risk rectal cancer patients when compared to a more conventional bolus regimen. Although the other adjuvant prolonged infusion regimens mentioned by Dr. Rich may be theoretically appealing, none has been scientifically demonstrated to be effective. Because of this, the regimen used in NCCTG 86-47-51 should be considered the standard adjuvant treatment of rectal cancer. The use of other infusion regimens in patients receiving adjuvant therapy for rectal cancer should be confined to peer-reviewed, institutionally approved clinical trials.
The possible use of "neoadjuvant," or preoperative, treatment is also discussed by Dr. Rich. A Swedish trial that compared short-course preoperative radiation therapy with conventional postoperative radiation is mentioned as an example of a study that demonstrated reduced local recurrence with the preoperative approach. It is important to point out, however, that this study did not demonstrate improved survival for preoperative radiation therapy. Indeed, no phase III study has documented a statistically significant improvement in survival with preoperative adjuvant treatment, when all randomized patients are considered for analysis. Because postoperative chemoradiation is the only adjuvant approach demonstrated to improve survival in randomized studies, the use of other adjuvant treatment approaches, including preoperative radiation therapy (with or without chemotherapy), should be confined to clinical trials.
Minimizing Radiation Related Toxicity
In oncology, significant short- or long-term morbidity is sometimes the price of success. This is definitely true of adjuvant therapy for rectal cancer. Dr. Rich appropriately emphasizes the value of radiation therapy techniques to minimize toxicity. At the Mayo Clinic, methods for reducing radiation therapy-related toxicity similar to those mentioned by Dr. Rich are routinely used. Despite these efforts, significant long-term treatment-related morbidity occurs in a significant number of patients. Kollmorgen and colleagues used a simple telephone survey to assess bowel function in patients treated by surgery plus postoperative chemoradiotherapy or by surgery alone. Results of this study strongly suggest that long-term bowel function is adversely affected by adjuvant radiation therapy and chemotherapy. For each of the 11 categories of bowel function evaluated, worse function was seen in the irradiated patients. For example, 56% of the patients treated by chemotherapy and irradiation described at least occasional incontinence, in contrast to only 7% of the nonirradiated patients (P <.001).
Recent evaluations of Swedish trials suggest that preoperative radiation therapy may also be associated with significant long-term morbidity.[3,5] Future clinical trials should prospectively evaluate the impact of adjuvant treatment on long-term bowel function. Methods for decreasing treatment-related morbidity should also be evaluated.
Further Improvement Needed
Further improvement is needed in the adjuvant treatment of rectal cancer. Approximately 30% of patients with high-risk rectal cancer die within 4 years despite delivery of the best currently available adjuvant therapy. It is certainly possible that alternative treatment chemoradiation schedules, such as those discussed in Dr. Rich's thoughtful review, will result in improved outcomes. An ongoing clinical trial (INT 0147) will provide valuable information about whether preoperative or postoperative treatment is better in this group of patients. Methods for decreasing treatment-related morbidity are needed. Prospective clinical trials remain the best method for increasing our scientific understanding of these issues and for improving survival of patients with rectal cancer.