A Prospective Phase 2 Trial of Transperineal Ultrasound-Guided Brachytherapy for Locally Recurrent Prostate Cancer after External Beam Radiation Therapy (NRG/RTOG0526): Initial Report of Late Toxicity Outcome

Abstract

Prior studies of low dose rate (LDR) prostate brachytherapy (BT) for salvage of local recurrence (LR) after external beam radiotherapy (EBRT) are limited by retrospective reporting. The primary objective of this prospective Phase II trial (NCT00450411) was to evaluate late gastrointestinal (GI) and genitourinary (GU) adverse events (AEs) after salvage LDR BT. Eligible patients had low or intermediate risk prostate cancer prior to EBRT and biopsy-proven LR >30 mos after EBRT, with PSA < 10 ng/mL and no regional or distant disease. Prescribed minimum target dose was 140 Gy with I-125, or 120 Gy with Pd-103. The primary endpoint was late GI/GU AEs occurring 9-24 mos after BT, Grade 3 or higher, and possibly, probably or definitely attributed to BT. These were projected to be < 10%, with > 20% considered unacceptable. With one-sided significance of 0.05 and 85% power, 87 evaluable patients were required under Fleming’s multiple testing procedure. Analyzable patients had a minimum 23 mos follow-up. All events were graded with CTCAE V3.0. Multivariate analyses sought associations of pre-treatment or treatment variables with AEs. Time to first occurrence of an AE was modelled by the Fine-Gray method. From 05/11/2007 to 01/21/2014, 100 patients were registered from 20 centers, of which 92 were analyzable. Median follow-up was 54 mos (range 4-97); median age 70 (IQR: 65-74). Initial Gleason score was 7 in 48%, and PSA >10 ng/ml in 16%. Median dose of EBRT was 74 Gy (IQR: 70-76). Androgen deprivation was combined with salvage BT in 16%. Median interval from prior EBRT was 85 mos (IQR: 60-119). The primary endpoint was evaluable in 87(95%) of the 92 patients. Twelve (14%) experienced late grade 3 GI/GU AEs (1 proctitis; 1 urethral fistula; the remainder being urinary frequency, incontinence, and retention). There were no treatment-related grade 4 or 5 AEs. No pre-treatment variable predicted late AEs, including prior EBRT dose and elapsed interval. Higher BT dose predicted both occurrence of late AE (OR 1.24: 95% CI 1.01-1.52; P = 0.04) and time to occurrence (HR 1.19: 95% CI 1.02-1.38; P = 0.03). Although median V150 (% ETV receiving >150% of prescribed dose) was 50%, the range was 18-90%. This is the first prospective multicenter trial to report outcomes of salvage LDR BT for post EBRT LR. The rate of late grade 3 AEs (14%) was not unacceptable by the predetermined protocol specification, without any grade 4-5 events, comparable to a study of primary EBRT + LDR (WR Lee 2007; RTOG 0019). The only factor predictive of late AEs was implant dose, underlining the need for meticulous planning and technique to limit the final delivered dose. Clinical outcomes for efficacy will be reported when minimum 5-yr follow-up is met.