2261: Long-Term Outcome of Four Dose Schedules of Mixed 3-D Conformal Neutron and Photon Irradiation in the Treatment of Prostate Cancer

Abstract

When the Wayne State University experience with fast neutron irradiation (FNRT) began, FNRT had initially been shown to improve survival in locally advanced prostate cancer with no increase in risk (40% neutrons, RTOG 77–04) and subsequently to improve disease-free survival with a significant increase in late toxicity (100% Neutrons, RTOG 85–23). The purpose of the current report was to assess the long-term outcome of four dose regimens of mixed 3-Dimensional conformal neutron and photon irradiation in the treatment of non-metastatic prostate cancer to determine the optimal dose of delivery. Between January 1992 and December, 2004 956 men with Stage T1-T4, N0–1, M0 adenocarcinoma of the prostate received mixed neutron and photon RT at Wayne State University. Four mixed neutron/photon (N/P) levels were designed per LQ modeling to maintain a predicted late toxicity equivalent to about 72 Gy in 36 fractions while yielding a predicted tumor dose of ∼80 Gy, assuming a tumor RBE of 4 and a normal tissue RBE of ∼3.2 for the FNRT. The median follow-up was 6 years (range 1–12). Failure was defined as a PSA level > 2 ng/ml more than the nadir, any clinical or radiographic failure or the delivery of post-radiation salvage hormonal therapy. Late toxicity was graded according to the RTOG scale. Kaplan-Meier actuarial analyses were used to assess outcomes. The median age was 65 years (range 42 to 80). The Stages were: T1 a-c, 33%; T2a-b, 40%; T2c, 11%; T3–4, 16%. The Gleason Scores were: ≤ 6, 38%; 7, 44%; 8–10, 18%. Pre-RT PSA levels were : <10, 59%; 10–20, 22%; >20, 18% (mean 19.6). Thirty-four percent of the patients were African American and 38% received pre-RT hormones. The N/P doses were : 9 N Gy + 38 Gy, 78 (8%); 10 N Gy + 38–40 Gy, 724 (76%); 11 N Gy + 40 or 46 (bid) Gy, 86 (9%); 15 N Gy + 18 Gy, 68 (7%). Patients were grouped by the number of adverse risk factors (Stage > T2b, Gleason > 6, PSA > 10). The distribution of patients by risk factor were : 0 risk factors, 224 (24%);1 RF 342 (37%); 2 RF, 234 (26%); 3 RF, 115 (13%). The 5 and 10 year actuarial rates of freedom from biochemical relapse were 80 and 68%; overall survival (OS) were 84 and 57%; and disease-free survival (DFS) were 71 and 44%, respectively. Significant predictors of freedom from biochemical relapse, OS and DFS included: Stage, Gleason Score, Pre-RT PSA, Race (not FFBR), and the number of risk factors. The 5 and 10 year DFS by risk factor were : 0 RF 87 and 71%; 1 RF 78 and 49%: 2 RF 56 and 26%; and 3 RF 41 and 18%, respectively (p=0.001). At 10 years the actuarial rates of Grade 2 or greater GI complications by neutron dose were : 9 N GY - 23 %: 10 N Gy - 21 %, 11 NGY - 25 % and > 15 N Gy - 40%. For GU complications grade 2 or greater these rates were 10, 20, 35 and 35%, respectively. Grade 3–4 complications did not vary significantly by dose. This analysis demonstrated that 3-D mixed N/P irradiation could be delivered safely with toxicity levels comparable to conformal photon irradiation. The major prognostic factors (Stage, Grade and PSA) predicted for long-term DFS and overall survival both alone and in combination (Risk Groups). Late GI and GU complications demonstrated a dependence on Neutron dose. The optimal dose appears to be 10 N Gy + 40 Gy photons. Future work is focusing on developing image guided neutron IMRT and a prospective comparison with hypofractionated photon irradiation.