Safety and Efficacy of Pre-Operative, Short Course Radiation Therapy for Prostate Cancer: Results From a Phase I Trial

Up to 60% of patients (pts) with prostate cancer that extends beyond the prostatic capsule will have positive resection margins following radical prostatectomy. Post-operative radiation therapy (PostOp) is routinely offered to those pts. Although this improves local control and overall survival, it results in significantly more late toxicity than surgery alone. Pre-operative radiation therapy (PreOp) has become the standard for soft tissue sarcoma and rectal cancer, improving local control and reducing toxicity compared to PostOp. We report the results of a Phase I trial, investigating the use of PreOp for prostate pts at high risk of extra-capsular extension. Following REB approval, prostate cancer pts at high risk of extra-capsular extension were prospectively identified for inclusion based on T-stage, N-stage, PSA and Gleason score. Since this was a Phase I study of safety and efficacy for a novel treatment regimen, a small sample size was used (15 pts). Patients received 25 Gy in 5 daily fractions to the prostate-only, followed by a radical prostatectomy 1-2 weeks after RT completion. Study endpoints were descriptive in nature due to the small sample size, and included intra-operative morbidity, early, late and ultra-late urinary (U) and gastrointestinal (GI) toxicity (using RTOG and CTCAE grading (G) systems). Between 2001 and 2004, 15 pts enrolled in the trial and all received 25 Gy over 5 consecutive fractions. Fourteen pts were irradiated with a 6-field conformal plan, and one with IMRT. Planning constraints were used to limit the dose to the femoral heads, bladder and rectal walls. Patients were treated with a full bladder / empty rectum protocol, employing daily portal image guidance based on intra-prostatic markers. G2 diarrhea (1 pt) and G2 cystitis (1 pt) were reported during RT. Fourteen pts went on to receive a non-nerve sparing radical retropubic prostatectomy, which included bilateral lymph node dissection for 13 pts. Four pts required a blood transfusion, and 3 pts had adhesions surrounding the prostate. Surgical margins were positive in 7 pts, PSA was detectable immediately after surgery in 5 pts. By 45 months, one patient had reported one episode of rectal bleeding that resolved with corticosteroids. Eleven pts reported urinary incontinence (73%), 3 had a urethral stricture (20%), and 1 reported G2 intermittent haematuria. To date, the median follow-up is 147 months. Two pts (14%) report G2 U toxicity, and 6 pts (43%) G3 U toxicity. One patient experienced transient G2 proctitis. At last follow-up, 8 (57%) and 6 (43%) pts have biochemical and metastatic progression, respectively. There were two prostate cancer related deaths. Delivery of short-course radiation therapy followed by an immediate prostatectomy is feasible. However, the incidence of late U toxicity is approximately 3-fold higher in this study than in Phase III trials of PostOp, with no appreciable benefit in biochemical or metastases free survival compared to those PostOp studies. Future studies of this regimen must be cautiously considered, and should include radiotherapy and surgical advances that might reduce toxicity, and multiparametric and/or molecular imaging to more precisely identify pts who may benefit from such an approach. This study emphasizes the need for long term follow-up data to fully appreciate the toxicity of such novel approaches.