A pilot study of topical intrarectal application of XXXX for prevention of late radiation rectal injury.

@entity1 @entity3329 @entity137 @entity263 @entity8721 @entity548 @entity1127 @entity8503 @entity4 @entity1066 @entity4272 @entity31 @entity20167 @entity420
PURPOSE: Clinical symptomatic late injury to the rectal wall occurs in about one-third of @entity1 with @entity263 treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of the prostate to the anterior rectal wall. On the basis of our previous observations in an animal model that intrarectal application of @entity8503 resulted in very high concentrations of @entity8503 and its active metabolite @entity20167 in the rectal wall, a Phase I dose-escalation clinical trial was undertaken. METHODS AND MATERIALS: Twenty-nine @entity1 with @entity263 were accrued. Eligibility criteria included histologically confirmed @entity420 , Karnofsky performance status >or=70, and no pelvic @entity3329 or distant metastases. The total dose to the prostate was 70.2 Gy in 20 @entity1 and 73.8 Gy in 9 @entity1 . Therapy was delivered using a 4-field technique with three-dimensional conformal planning. @entity8503 was administered intrarectally as an aqueous solution 30 min before irradiation on the first 15 days of therapy. @entity8503 was escalated in cohorts from 500 to 2500 mg. Proctoscopy was performed before therapy and at 9 months after completion. Most @entity1 underwent repeat proctoscopy at 18 months. On Days 1 and 10 of radiotherapy, serum samples were collected for pharmacokinetic studies. The clinical symptoms (Radiation Therapy Oncology Group scale) and a proctoscopy score were assessed during follow-up. RESULTS: All @entity1 completed therapy with no @entity8503 -related @entity137 at any dose level. The application was feasible and well tolerated. No substantial systemic absorption occurred. With a median follow-up of 26 months, 9 @entity1 (33%) developed @entity548 (8 Grade 1, 1 Grade 2). At 9 months, 16 and 3 @entity1 developed Grade 1 and Grade 2 @entity8721 , respectively. This was mostly confined to the anterior rectal wall. No visible @entity4 , @entity1066 , or strictures were noted. No significant differences were found between the proctoscopy findings at 9 and 18 months. Four @entity1 (14%) developed symptoms suggestive of radiation damage that, on sigmoidoscopy, proved to be secondary to unrelated processes. These included preexisting nonspecific @entity4272 (n = 1), diverticular disease of the sigmoid colon (n = 1), @entity1127 (n = 1), and @entity31 (n = 1). Symptoms developed significantly more often in @entity1 receiving 500-1000 mg than in @entity1 receiving 1500-2500 mg @entity8503 (7 [50%] of 14 vs. 2 [15%] of 13, p = 0.0325, one-sided chi-square test). CONCLUSION: Intrarectal application of @entity8503 is feasible and well tolerated. Systemic absorption of @entity8503 and its metabolites is negligible, and close monitoring of @entity1 is not required with rectal administration. Proctoscopy is superior to symptom score as a method of assessing radiation damage of the rectal wall. The preliminary efficacy data are encouraging, and further clinical studies are warranted.
