Preliminary toxicity and prostate-specific antigen response of a Phase I/ II trial of neoadjuvant hormonal therapy, ¹⁰³Pd brachytherapy, and three-dimensional conformal external beam irradiation in the treatment of locally advanced prostate cancer^•

Purpose: Standard therapies for locally advanced prostate cancer have resulted in suboptimal disease control rates. A Phase I/II trial was designed for patients with positive seminal vesicle biopsies, prostate-specific antigen (PSA) >15 ng/ml, Gleason score ≥8, or clinical classification T2c-T3 to improve local control and to test the tolerance of the prostate to high-dose radiation by using neoadjuvant hormonal therapy, ¹⁰³Pd brachytherapy, and conformal three-dimensional external beam radiation therapy (EBRT). This article outlines treatment-related morbidity and PSA response to this regimen and analyzes the effect of escalating doses of brachytherapy. Methods and Materials: Forth-three patients with T1c-T3 prostate cancer were enrolled in a Phase I/II trial from March 1994 through September 1997. Follow-up ranged from 12 to 64 months (median, 32 months). Pretreatment PSA ranged from 2.1 to 202 ng/ml (median, 16 ng/ml). Seventy-seven percent (33 of 43) of patients had high-grade tumors (score ≥7). Seventy-four percent (32 of 43) had stage ≥T2c. A total of 21 (49%) patients had positive seminal vesicle biopsies. Treatment consisted of hormonal therapy for 3 months with leuprolide and flutamide followed by a ¹⁰³Pd implant and, 2 months later, 59.4 Gy of three-dimensional EBRT. Hormonal therapy was continued for 9 months. The planned ¹⁰³Pd dose was escalated from 57 Gy (13 patients) to 77 Gy (13 patients) to 86 Gy (17 patients). Results: The actuarial freedom from PSA failure (PSA > 0.5 ng/ml) at 4 years was 74%. There were no significant differences found when analyzing patients by presenting PSA or seminal vesicle status. There was a trend toward improved outcome with higher doses delivered to the prostate via the implant. Patients receiving doses ≥65 Gy (31 patients) had a freedom from PSA failure rate at 4 years of 89.5%, compared with 52.5% for those receiving doses <65 Gy (10 patients; p = 0.08). The last PSA values for those patients free from PSA failure were ≤0.1 ng/ml in 25 (69%), >0.1-0.2 ng/ml in 5 (14%), and >0.2-0.5 ng/ml in 6 (17%). The actuarial freedom from developing Grade 2 proctitis was 75% at 4 years. There was a trend toward increased proctitis with increasing prostate implant doses. Patients with doses ≤70 Gy (n = 12) had a 92% freedom from Grade 2 proctitis compared with 67.5% for those with doses delivered to 90% of the gland from a dose-volume histogram of >70 Gy (n = 29) (p = 0.15). There were no cases of Grade 3 or 4 proctitis. The 3-year actuarial preservation of sexual potency rate was 43%. Conclusions: The preliminary results from this regimen show an improvement in PSA control for this group of locally advanced prostate cancer patients over more standard therapies. To maximize control while minimizing toxicity, doses of 65-70 Gy of ¹⁰³Pd should be used when 59.4 Gy of three-dimensional EBRT is delivered. Longer follow-up will be needed to further substantiate these findings.