Noninferiority of Hypofractionated vs Conventional Postprostatectomy Radiotherapy for Genitourinary and Gastrointestinal Symptoms: The NRG-GU003 Phase 3 Randomized Clinical Trial.

Importance: No prior trial has compared hypofractionated postprostatectomy radiotherapy (HYPORT) to conventionally fractionated postprostatectomy (COPORT) in patients primarily treated with prostatectomy. Objective: To determine if HYPORT is noninferior to COPORT for patient-reported genitourinary (GU) and gastrointestinal (GI) symptoms at 2 years. Design, Setting, and Participants: In this phase 3 randomized clinical trial, patients with a detectable prostate-specific antigen (PSA; ≥0.1 ng/mL) postprostatectomy with pT2/3pNX/0 disease or an undetectable PSA (<0.1 ng/mL) with either pT3 disease or pT2 disease with a positive surgical margin were recruited from 93 academic, community-based, and tertiary medical sites in the US and Canada. Between June 2017 and July 2018, a total of 296 patients were randomized. Data were analyzed in December 2020, with additional analyses occurring after as needed. Intervention: Patients were randomized to receive 62.5 Gy in 25 fractions (HYPORT) or 66.6 Gy in 37 fractions (COPORT). Main Outcomes and Measures: The coprimary end points were the 2-year change in score from baseline for the bowel and urinary domains of the Expanded Prostate Cancer Composite Index questionnaire. Secondary objectives were to compare between arms freedom from biochemical failure, time to progression, local failure, regional failure, salvage therapy, distant metastasis, prostate cancer-specific survival, overall survival, and adverse events. Results: Of the 296 patients randomized (median [range] age, 65 [44-81] years; 100% male), 144 received HYPORT and 152 received COPORT. At the end of RT, the mean GU change scores among those in the HYPORT and COPORT arms were neither clinically significant nor different in statistical significance and remained so at 6 and 12 months. The mean (SD) GI change scores for HYPORT and COPORT were both clinically significant and different in statistical significance at the end of RT (-15.52 [18.43] and -7.06 [12.78], respectively; P < .001). However, the clinically and statistically significant differences in HYPORT and COPORT mean GI change scores were resolved at 6 and 12 months. The 24-month differences in mean GU and GI change scores for HYPORT were noninferior to COPORT using noninferiority margins of -5 and -6, respectively, rejecting the null hypothesis of inferiority (mean [SD] GU score: HYPORT, -5.01 [15.10] and COPORT, -4.07 [14.67]; P = .005; mean [SD] GI score: HYPORT, -4.17 [10.97] and COPORT, -1.41 [8.32]; P = .02). With a median follow-up for censored patients of 2.1 years, there was no difference between HYPORT vs COPORT for biochemical failure, defined as a PSA of 0.4 ng/mL or higher and rising (2-year rate, 12% vs 8%; P = .28). Conclusions and Relevance: In this randomized clinical trial, HYPORT was associated with greater patient-reported GI toxic effects compared with COPORT at the completion of RT, but both groups recovered to baseline levels within 6 months. At 2 years, HYPORT was noninferior to COPORT in terms of patient-reported GU or GI toxic effects. HYPORT is a new acceptable practice standard for patients receiving postprostatectomy radiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT03274687.

Dosimetric Benefits of Omitting Primary Tumor Beds in Postoperative Radiotherapy After Transoral Robotic Surgery Using the Auto-Planning Technique.

INTRODUCTION: It has been suggested that post-transoral robotic surgery (post-TORS) radiotherapy (RT) might reduce the dose to organs at risk (OARs) adjacent to the primary tumor bed; however, the evidence supporting this has yet to be sufficient. This study examined the radiation dose reduction to OARs by omitting the primary tumor bed through the use of an Auto-Planning (AP)-based workflow. METHODS:  Twelve patients were identified who underwent post-TORS RT to the primary tumor bed and the unilateral/bilateral neck lymph nodes. In each patient, two treatment plans were designed: a Comprehensive (Comp)-plan treating the original planning target volume (PTV) including both the primary tumor bed and the lymph nodes, and a Neck-plan treating only the lymph nodes and omitting the primary tumor bed. Both plans were optimized using AP to ensure plan quality consistency. We compared the doses received by 95% of the primary tumor beds and lymph nodes (D95%) and our institutional dose constraints for the OARs between the Comp- and Neck-plans. Statistical analysis was performed using R Statistical Software (R Foundation for Statistical Computing, Vienna, Austria) with a two-tailed paired Wilcoxon signed-rank test. RESULTS:  All plans met target dose coverage requirements with at least 95% of the PTVs covered with the corresponding prescription doses. The primary tumor bed in the Neck-plans was spared with a significantly lower mean D95% (25.9 Gy vs. 60.0 Gy; p < 0.01; Wilcoxon test). The mean dose to the oral cavity (20.9 Gy vs. 28.1 Gy; p < 0.01) and the supraglottis (36.9 Gy vs. 28.2 Gy; p < 0.01) was significantly lower in the Neck-plans. CONCLUSION:  This study suggests that sparing the primary tumor bed during post-TORS RT offers dosimetric benefits to nearby OARs with significant dose reductions to the oral cavity and supraglottis. Further study of the clinical risks and benefits afforded by this strategy is needed.

Outcomes for prostate glands >60 cc treated with low-dose-rate brachytherapy.

PURPOSE: We sought to analyze whether outcomes of biochemical relapse-free survival (bRFS), late genitourinary (GU), and late gastrointestinal toxicity are different for prostate cancer patients with small (≤60 cc) vs. large (>60 cc) prostates following low dose-rate brachytherapy. METHODS AND MATERIALS: The bRFS outcomes for 2076 low- or intermediate-risk prostate cancer patients from 1996 to 2012 were determined from a review of a prospectively maintained database. All patients were treated with (125)I monotherapy without androgen deprivation therapy. Biochemical failure was defined per the Phoenix definition. Patient-related factors and dosimetric values were examined in Cox regression analyses for bRFS and late toxicity. Late toxicity was scored according to a modified Common Terminology Criteria for Adverse Events version 4.0 scale. RESULTS: The median followup for all patients was 55 months. The 5-year bRFS rates for all patients, prostates >60 cc, and prostates ≤60 cc were 93.4% (95% confidence interval [CI]: 92.1%, 94.7%), 96.7% (95% CI: 94.4%, 98.9%), and 92.9% (95% CI: 91.4%, 94.3%), respectively. On multivariable analysis, prostate size >60 cc was significantly associated with improved bRFS (p = 0.01), as were initial prostate-specific antigen and biopsy Gleason score (p < 0.0001 and p = 0.0002, respectively). Patients with prostates >60 cc had significantly higher rates of Grade 3-4 late GU toxicity at 5 years than patients with smaller prostates; 7.2% (95% CI: 4.0%, 10.4%) and 3.2% (95% CI: 2.3%, 4.1%), respectively (p = 0.0007). The overall late gastrointestinal toxicity rate for all patients was 0.7% at 5 years with no significant difference between the two groups. CONCLUSIONS: Implantation of large prostates >60 cc results in favorable bRFS outcomes and is associated with increased but acceptable rates of Grade 3 and higher late GU toxicities.

Long-Term Efficacy and Toxicity of Low-Dose-Rate ¹²5I Prostate Brachytherapy as Monotherapy in Low-, Intermediate-, and High-Risk Prostate Cancer.

PURPOSE/OBJECTIVES: To report long-term efficacy and toxicity for a single-institution cohort of patients treated with low-dose-rate prostate brachytherapy permanent implant (PI) monotherapy. METHODS AND MATERIALS: From 1996 to 2007, 1989 patients with low-risk (61.3%), intermediate-risk (29.8%), high-intermediate-risk (4.5%), and high-risk prostate cancer (4.4%) were treated with PI and followed up prospectively in a registry. All patients were treated with (125)I monotherapy to 144 Gy. Late toxicity was coded retrospectively according to a modified Common Terminology Criteria for Adverse Events 4.0 scale. The rates of biochemical relapse-free survival (bRFS), distant metastasis-free survival (DMFS), overall survival (OS), and prostate cancer-specific mortality (PCSM) were calculated. We identified factors associated with late grade ≥3 genitourinary (GU) and gastrointestinal (GI) toxicity, bRFS, DMFS, OS, PCSM, and incontinence. RESULTS: The median age of the patients was 67 years, and the median overall and prostate-specific antigen follow-up times were 6.8 years and 5.8 years, respectively. The overall 5-year rates for bRFS, DMFS, OS, and PCSM were 91.9%, 97.8%, 93.7%, and 0.71%, respectively. The 10-year rates were 81.5%, 91.5%, 76.1%, and 2.5%, respectively. The overall rates of late grade ≥3 GU and GI toxicity were 7.6% and 0.8%, respectively. On multivariable analysis, age and prostate length were significantly associated with increased risk of late grade ≥3 GU toxicity. The risk of incontinence was highly correlated with both pre-PI and post-PI transurethral resection of the prostate. CONCLUSIONS: Prostate brachytherapy as monotherapy is an effective treatment for low-risk and low-intermediate-risk prostate cancer and appears promising as a treatment for high-intermediate-risk and high-risk prostate cancer. Significant long-term toxicities are rare when brachytherapy is performed as monotherapy.

Safety and efficacy of iodine-125 permanent prostate brachytherapy in patients with J-pouch anastomosis after total colectomy for ulcerative colitis.

PURPOSE: To ascertain the safety and efficacy of permanent prostate brachytherapy (PPB) in early prostate cancer patients who have undergone previous total proctocolectomy and J-pouch anastomosis for inflammatory bowel disease. METHODS AND MATERIALS: We identified 10 patients with a previous history of prostate cancer and J-pouch anastomosis from our institutional review board-approved database. Seven patients had PPB and 3 had prostatectomy. Only patients treated with PPB were included. Patient records were reviewed to collect data on treatment-related toxicity and oncological outcomes. RESULTS: All 7 patients who underwent PPB had low- to intermediate-risk prostate cancer. The mean prostatic volume was 24.40 mL and the average number of iodine-125 seeds implanted was 84. Postimplant dosimetric calculations showed a mean prostate volume receiving 100% of the prescribed dose (V100) of 88.76%, V150 of 45.23%, V200 of 16.79%, radiation dose delivered to 90% of the prostate of 147.89 Gy, volume of ileal pouch receiving 100% of the prescribed dose of 0.164 mL, and volume of ileal pouch receiving 50% of the prescribed dose of 1.38 mL. After a mean follow-up of 19 months, none of the patients had evidence of biochemical failure or clinical failure. There were no long-term genitourinary side effects detected. Two patients had Common Terminology Criteria for Adverse Events version 4.0 grade II gastrointestinal side effects, of which symptoms resolved to baseline in 1 patient, whereas the other patient progressed to chronic active enteritis (pouchitis). CONCLUSION: Low- to intermediate-risk prostate cancer patients with J-pouch anastomosis after total colectomy for inflammatory bowel disease are candidates for definitive treatment with PPB. Caution should be exercised while deploying the most posterior row of seeds to minimize enteral pouch radiation doses.