DETROIT-Intrarectal topical application of amifostine (Ethyol), given as a "mini-enema," is extremely tolerable, produces no systemic toxicity, and may be an alternative to systemic administration for preventing rectal damage in patients undergoing radiotherapy for prostate cancer. Results of a phase I study were reported by Edgar Ben-Josef, MD. He is associate professor in the Department of Radiation Oncology at Wayne State University’s Karmanos Cancer Institute in Detroit.
DETROITIntrarectal topical application of amifostine (Ethyol), given as a "mini-enema," is extremely tolerable, produces no systemic toxicity, and may be an alternative to systemic administration for preventing rectal damage in patients undergoing radiotherapy for prostate cancer. Results of a phase I study were reported by Edgar Ben-Josef, MD. He is associate professor in the Department of Radiation Oncology at Wayne State University’s Karmanos Cancer Institute in Detroit.
"With 3D conformal treatment planning, it is possible to substantially reduce grade 3 toxicity, but at doses in the vicinity of 75 Gy, 15% to 25% of patients will still develop grade 2 or higher rectal toxicity," Dr. Ben-Josef explained. "With conventional, nonconformal radiotherapy, the rate of grade 3 or 4 late rectal complications is up to 10%."
Adding shielding can keep the dose to the anterior rectal wall less than 75.6 Gy and reduce grade 2 or higher rectal toxicity to 7%, according to Dr. Ben-Josef. The problem is that also risks shielding tumor tissue from therapeutic dosages.
"With that problem in mind, in 1998 we started a phase I study using a topical, intrarectal application to attempt to protect the rectum from radiation effects. The major objective was to evaluate the feasibility of an intrarectal application of amifostine. We were not sure if patients could tolerate and hold the mini-enema," Dr. Ben-Josef said.
The trial was also intended to determine the maximum tolerated dose (MTD) of intrarectal amifostine, to characterize the pharmacokinetics of intrarectal application, and to gather some data regarding efficacy.
Amifostine was given as an aqueous solution 30 minutes before treatment during the first 15 days of radiotherapy. Dose escalation was from 500 mg to 2,500 mg in 500-mg cohorts. Pharmacokinetics assessments were done on days 1 and 10 of radiotherapy to see if changes in systemic absorption were induced by changes in the rectum wall secondary to radiotherapy, such as inflammation.
Patients had sigmoidoscopy with rectal wall biopsies of all quadrants, then definitive radiotherapy with intrarectal application of amifostine, and finally follow-up and assessment of late morbidity. The study endpoints were the Radiation Therapy Oncology Group (RTOG) symptom score, a proctoscopy score, and a pathology score.
The seminal vesicles and immediate periprostatic lymph nodes received 46.8 Gy. The prostate received 70.2 Gy in the first 20 patients and 73.8 Gy in the last 9. The dose per fraction was 1.8, and the method was 4-field axial (box) technique. All treatment was done with 3D conformal methodology. The margin was 1.7 cm. on the gross tumor volume," Dr. Ben-Josef said.
Feasible, Well Tolerated
Symptoms developed in 9 of 29 (31%) patients. Grade 1 bleeding occurred in 8 of the 9 patients. There was no grade 3 bleeding toxicity. "One patient had grade 2 bleeding, which is about 3%, vs the 15% to 25% incidence of grade 2 bleeding reported in previous 3D conformal series," Dr. Ben-Josef said.
There was a suggestion of a dose-response effect of amifostine protection against rectal bleeding. Patients who received 1,500 to 2,500 mg of amifostine were significantly less likely to develop rectal bleeding than those at lower dose levels (P = .0325).
The symptom score is not an accurate method of evaluating rectum wall damage, according to Dr. Ben-Josef. Four patients (14% of all patients, 39% of symptomatic patients) developed symptoms suggestive of radiation damage that proved to be secondary to other problems.
Pathology analysis of some of these patients has been completed. Normal mucosa shows regular crypts, little submucosal edema, and few oddly placed vessels. Postradiation tissue from a patient who took 500 mg of amifostine showed submucosal edema two to three times normal and vascular changes including prominence, ectasia, congestion, and intimal thickening. Mild architectural changes included budding and irregularities of the crypts, mucosal atrophy, and erosion. Vascular changes included ectasia and ectopic formation in the mucosa.
The researchers concluded that intrarectal application of amifostine is feasible and well tolerated. There is no systemic absorption or systemic toxicity. Rectal changes are mature by 9 months.
"We would like to see a phase II study of intrarectal amifostine in about 60 prostate cancer patients treated with 74 to 78 Gy of radiation. We recommend a beginning amifostine dose of 1,500 mg, with endpoints of symptom scores and sigmoidoscopy scores," Dr. Ben-Josef said.