Phase I/II trial evaluating combined radiotherapy and in-situ gene therapy with or without hormonal therapy in the treatment of prostate cancer-an interim report on PSA response and biopsy data

Purpose/Objective: The preliminary results addressing the safety of this Phase I/II study combining radiotherapy and gene therapy with or without hormonal therapy in the treatment of prostate cancer have been previously reported. (Int J Radiat Oncol Biol Phys 2001; 51:605-613). We now report the PSA response and biopsy data. Materials/Methods: Arm A: low risk patients (T1-T2a, Gleason score <7, Pre-treatment PSA<10) were treated with combined radio-genetherapy. A mean dose of 76Gy was delivered to the prostate with intensity modulated radiotherapy. Four intra-prostatic injections were given delivering 5 × 10e11 viral particles. Oral valacyclovir (2 gm tid) was taken for fourteen days. Injection was given on Days 0 and 14. Radiotherapy started on Day 2. Arm B: high risk patients (T2b-T3, Gleason score >6, Pre-treatment PSA>10) were treated with combined radio-gene therapy and hormonal therapy. Three separate gene therapy injections were given on Days 0, 56 and 70, each followed by 14 days of valacyclovir. LHRH-agonist (30 mg lupron-4 month-depot) was given on Day 0. Anti-androgen (flutamide) 250 mg tid was given for fourteen days. Radiotherapy started on Day 58. Arm C: stage D1 (positive lymph node) received the same regimen as Arm B with the additional 45 Gy to pelvic lymphatics. PSA and biopsy were performed before, during and after treatment. ASTRO consensus definition (three consecutive rises in PSA) was used for PSA failure. Results: 59 patients (29 in Arm A, 26 in Arm B and 4 in Arm C) have completed the trial. Median age was 68 years (39 -85). Median follow-up for the entire group was 13.5 months (1.4 -27.8 months). Only Arm A patients were observed to have an increase of PSA (mean of 126% compared to controls receiving only radiotherapy) on Day 14. The PSA then declined appropriately. All patients in Arm A (median follow-up 13.4 months) and Arm B (median follow-up of 13.9 months) have had biochemical control thus far. Three patients in Arm C (with pre-treatment PSA of 335, 19.6 and 2.5 and Gleason combined score of 8, 9 and 9) had biochemical failure at 3, 3 and 7.7 months. Two patients failed distantly in bone and one patient failed in para-aortic lymph node outside radiotherapy portal. Six to twelve prostate biopsies performed in these three patients reviewed no evidence of residual carcinoma. In Arm A, biopsy showed evidence of carcinoma in 33.3% (9/27), 7.7% (2/26), 8.3% (1/12), 0% (0/8) and 0% (0/6) at 6 weeks, 4 months, 12 months, 18 months and 24 months after treatment respectively. In Arm B, biopsy proven carcinoma was noted in 4% (1/25), 9.5% (2/21), 0% (0/14), 0% (0/7) and 0% (0/2) respectively in the same time interval after treatment. Conclusions: The initial transient PSA rise in Arm A patients may be due to local immunological response or inflammation elicited by in-situ gene therapy or injection. Further investigation to elucidate the mechanisms is needed. Hormonal therapy may have obliterated this rise in Arm B and C patients. Biopsy data were encouraging and appeared to show no evidence of malignancy earlier than historical data. Combined radiotherapy, short course hormonal therapy and in-situ gene therapy appeared to provide good local control but inadequate systemic control in patients with positive pelvic lymph nodes. Longer term use of hormonal therapy in addition to gene therapy and radiotherapy is currently adopted for this group of patients to maximize both local and systemic control.