Purpose: Amifostine has been shown to be able to reduce acute radiation toxicity if administered daily prior to radiation during a course of a conventionally fractionated radiotherapy. A disadvantage is the necessity of daily intravenous injection. We have used amifostin in patients undergoing adjuvant radiochemotherapy for rectal cancer. Amifostine was administered only in the first and fifth week of radiotherapy together with 5-FU chemotherapy. The objective was to determine whether the intermittent use of amifostine may be effective in reducing acute radiation toxicity.
Patients and methods: From September 1997 through October 1998, 30 patients with stage II/III rectal cancer underwent postoperative radiochemotherapy at our department. All patients had undergone curative (R0) resection and received 50.4 Gy to the pelvis with a 3-field technique using a belly board followed by a boost of 5.4 Gy to the presacral space in conventional fractionation with 1.8 Gy per fraction. 5-FU chemotherapy was administered as 120-hours continuous infusion in the first and fifth radiation week via a central venous catheter in a daily dosage of 1,000 mg/m2. All patients were offered to participate in a phase-II study using additional amifostine. Fifteen patients participated and received 500 mg amifostine daily on chemotherapy days (days 1 to 5 and 29 to 33) immediately prior to the daily radiation fraction. Fifteen patients did not participate and served as non-randomized control. The study was approved by the ethical committee of the Martin-Luther-University and informed consent was obtained from all patients.
Results: The distribution of patients' characteristics and prognostic parameters was comparable in both groups. Side effects of amifostine were mild and included hypotension (53% grade I, 7% grade II) and nausea (47% grade I, 13% grade II). Antiemetics were not routinely used. All patients completed radiochemotherapy plus amifostine without unplanned breaks or dose reductions. One patient developed a cerebral infarction which was considered to be not related to the use of amifostine. As compared to the non-randomized control group, patients with additional amifostine had less acute skin and bowel toxicity (maximum erythema score 1.47 +/- 0.64 without vs 0.87 +/- 0.52 with amifostine, p = 0.009 and maximum diarrhea score 1.07 +/- 1.03 vs 0.40 +/- 0.63, p = 0.044). Oral 5-FU-related mucositis and hematological toxicity were not significantly different.
Conclusions: In this phase-II study, amifostine significantly reduced acute skin and bowel toxicity of adjuvant chemoradiation in patients with rectal cancer even if the drug was administered only intermittently and not during the whole course of radiotherapy. This finding might be important with regard to intense combined regimes and should be further investigated.