A Prospective Phase 2 Trial of Transperineal Ultrasound-Guided Brachytherapy for Locally Recurrent Prostate Cancer After External Beam Radiation Therapy (NRG Oncology/RTOG-0526).

PURPOSE: Only retrospective data are available for low-dose-rate (LDR) salvage prostate brachytherapy for local recurrence after external beam radiation therapy (EBRT). The primary objective of this prospective phase 2 trial (NCT00450411) was to evaluate late gastrointestinal and genitourinary adverse events (AEs) after salvage LDR brachytherapy. METHODS AND MATERIALS: Eligible patients had low- or intermediate-risk prostate cancer before EBRT and biopsy-proven recurrence >30 months after EBRT, with prostate-specific antigen levels <10 ng/mL and no regional/distant disease. The primary endpoint was grade 3 or higher late treatment-related gastrointestinal or genitourinary AEs occurring 9 to 24 months after brachytherapy. These AEs were projected to be ≤10%, with ≥20% considered unacceptable. All events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Multivariate analyses investigated associations of pretreatment or treatment variables with AEs. RESULTS: One hundred patients from 20 centers were registered from May 2007 to January 2014. The 92 analyzable patients had a median follow-up of 54 months (range, 4-97) and a median age of 70 years (interquartile range [IQR], 65-74). The initial Gleason score was 7 in 48% of patients. The median dose of EBRT was 74 Gy (IQR, 70-76) at a median interval of 85 months previously (IQR, 60-119). Only 16% had androgen deprivation at study entry. Twelve patients (14%) had late grade 3 gastrointestinal/genitourinary AEs, with no treatment-related grade 4 or 5 AEs. No pretreatment variable predicted late AEs, including prior EBRT dose and elapsed interval. Higher V100 (percentage of prostate enclosed by prescription isodose) predicted both occurrence of late AEs (odds ratio, 1.24; 95% confidence interval, 1.02-1.52; P = .03) and earlier time to first occurrence (hazard ratio, 1.18; 95% CI, 1.03-1.34; P = .02). CONCLUSIONS: This prospective multicenter trial reports outcomes of salvage LDR brachytherapy for post-EBRT recurrence. The rate of late grade 3 AEs did not exceed the unacceptable threshold. The only factor predictive of late AEs was implant dosimetry reflected by V100. Efficacy outcomes will be reported at a minimum of 5-year follow-up.

Initial comparison of inverse optimization, modified peripheral technique, and geometric optimization as real-time intraoperative computer planning options for permanent seed implantation of the prostate.

PURPOSE: Comparison of inverse optimization (IO) to modified peripheral (MP) and geometric optimization (GO) intraoperative computer planning options for permanent seed implantation (PSI) of the prostate. METHODS AND MATERIALS: One hundred ten patients underwent PSI with iodine-125. Three computer planning options were compared including MP loading, GO, and IO. Preimplant dose goals (prescribed dose [PD] of 144 Gy) and normal tissue constraints were determined at the outset by the participating physicians before intraoperative computer planning. A single computer planning system was used for this comparison. Postimplant dosimetry was performed at 4-5 weeks and compared for V(100) and D(90), urethral V(150), and rectal V(110) of the PD. Acute urinary morbidity was evaluated and compared. RESULTS: All three options achieved a similar preimplant median V(100) (97%). The median number of needles and seeds implanted was greater with GO (29, 75) compared to MP (16, 66) and IO (17, 66) (p<0.0001 and p=0.0024, respectively). Postimplant dosimetry showed that IO achieved a higher percentage with V(100) >95% of the PD in multivariate analysis (p=0.04) and a lower percentage postimplant D(90) <140 Gy (7%) than for MP/GO (26%) (p = 0.01). IO predicted for lower urethral dose (p=0.0169), despite a higher median D(90) (169 Gy) than either MP (159 Gy) or GO (151 Gy) (p = 0.0025). The median percentage V(150) urethra for IO was 8% vs. 16% for MP and 23% for GO (p = 0.0005). With a median followup time of 6 months, acute Grade 2 urinary symptoms were higher with GO (81%) vs. MP (36%) and IO (53%) (p = 0.0019). CONCLUSIONS: Dosimetric outcomes for IO compare favorably to either MP or GO when performed in real time for PSI. In contrast to GO, IO and MP demonstrated excellent correlation between the intraoperative and postoperative plans while using fewer total and interior placed needles and seeds. IO appears feasible as an alternative intraoperative planning solution for PSI.

Importance of Local Control in Early-Stage Prostate Cancer: Outcomes of Patients With Positive Post-Radiation Therapy Biopsy Results Treated in RTOG 9408.

PURPOSE: The purpose of this study was to assess the association between positive post-radiation therapy (RT) biopsy results and subsequent clinical outcomes in males with localized prostate cancer. METHODS AND MATERIALS: Radiation Therapy Oncology Group study 94-08 analyzed 1979 males with prostate cancer, stage T1b-T2b and prostate-specific antigen concentrations of ≤ 20 ng/dL, to investigate whether 4 months of total androgen suppression (TAS) added to RT improved survival compared to RT alone. Patients randomized to receive TAS received flutamide with luteinizing hormone releasing hormone (LHRH) agonist. According to protocol, patients without evidence of clinical recurrence or initiation of additional endocrine therapy underwent repeat prostate biopsy 2 years after RT completion. Statistical analysis was performed to evaluate the impact of positive post-RT biopsy results on clinical outcomes. RESULTS: A total of 831 patients underwent post-RT biopsy, 398 were treated with RT alone and 433 with RT plus TAS. Patients with positive post-RT biopsy results had higher rates of biochemical failure (hazard ratio [HR] = 1.7; 95% confidence interval [CI] = 1.3-2.1) and distant metastasis (HR = 2.4; 95% CI = 1.3-4.4) and inferior disease-specific survival (HR = 3.8; 95% CI = 1.9-7.5). Positive biopsy results remained predictive of such outcomes after correction for potential confounders such as Gleason score, tumor stage, and TAS administration. Prior TAS therapy did not prevent elevated risk of adverse outcome in the setting of post-RT positive biopsy results. Patients with Gleason score ≥ 7 with a positive biopsy result additionally had inferior overall survival compared to those with a negative biopsy result (HR = 1.56; 95% CI = 1.04-2.35). CONCLUSIONS: Positive post-RT biopsy is associated with increased rates of distant metastases and inferior disease-specific survival in patients treated with definitive RT and was associated with inferior overall survival in patients with high-grade tumors.

A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902.

PURPOSE: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). METHODS AND MATERIALS: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. RESULTS: A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). CONCLUSIONS: NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa.

Prostate implant dosimetric outcomes and migration patterns between bio-absorbable coated and uncoated brachytherapy seeds.

PURPOSE: To evaluate the lung and pelvic seed migration and intraprostatic dose variability for prostate seed implant (PSI) using bio-absorbable polymer "coated" seeds for intraoperative planning. METHODS AND MATERIALS: A total of 100 PSI patients were initially implanted with uncoated I-125 (STM 1251 or I125-SL, N = 85) or Pd-103 (mod 200, N = 15) seeds, and 105 PSI patients were implanted subsequently with coated seeds using inverse optimization with real-time planning. Implant technique, average number of needles, and dose objectives remained identical among the cohorts. RESULTS: Day 30 postimplant comparison of seed migration demonstrated a significant reduction in overall lung and pelvic seed migration from 25% (uncoated) to 4% (coated) (p < 0.0001). A measurable reduction in intraprostatic dose variability was observed in patients with the coated seeds when comparing 30 days dosimetry results for V100, V150, and D90 for prostate, and V110 for the rectum. A statistically significant reduction in the standard deviation from Day 0 to Day 30 for the above parameters for the prostate as well as for V110 of rectum was also observed. A significant improvement in implant quality at Day 30 was demonstrated using Radiation Therapy Oncology Group (RTOG) evaluation criteria range with the coated seeds cohort. CONCLUSIONS: PSI using coated seeds shows lower lung and pelvic seed migration compared with those using uncoated seeds and compares favorably to pelvic stranded seed migration reports. A higher concordance was observed with less dose variability in dosimetric parameters on Day 30 dosimetry compared with that on Day 0. Improvement in the implant quality was also observed using the RTOG criteria, suggesting reduced intraprostatic migration.