Long-Term Analysis of NRG Oncology RTOG 0415: A Randomized Phase III Noninferiority Study Comparing Two Fractionation Schedules in Patients With Low-Risk Prostate Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.NRG Oncology RTOG 0415 is a randomized phase III noninferiority (NI) clinical trial comparing conventional fractionation (73.8 Gy in 41 fractions) radiotherapy (C-RT) with hypofractionation (H-RT; 70 Gy in 28) in patients with low-risk prostate cancer. The study included 1,092 protocol-eligible patients initially reported in 2016 with a median follow-up of 5.8 years. Updated results with median follow-up of 12.8 years are now presented. The estimated 12-year disease-free survival (DFS) is 56.1% (95% CI, 51.5 to 60.5) for C-RT and 61.8% (95% CI, 57.2 to 66.0) for H-RT. The DFS hazard ratio (H-RT/C-RT) is 0.85 (95% CI, 0.71 to 1.03), confirming NI (P < .001). Twelve-year cumulative incidence of biochemical failure (BF) was 17.0% (95% CI, 13.8 to 20.5) for C-RT and 9.9% (95% CI, 7.5 to 12.6) for H-RT. The HR (H-RT/C-RT) comparing biochemical recurrence between the two arms was 0.55 (95% CI, 0.39 to 0.78). Late grade ≥3 GI adverse event (AE) incidence is 3.2% (C-RT) versus 4.4% (H-RT), with relative risk (RR) for H-RT versus C-RT 1.39 (95% CI, 0.75 to 2.55). Late grade ≥3 genitourinary (GU) AE incidence is 3.4% (C-RT) versus 4.2% (H-RT), RR 1.26 (95% CI, 0.69 to 2.30). Long-term DFS is noninferior with H-RT compared with C-RT. BF is less with H-RT. No significant differences in late grade ≥3 GI/GU AEs were observed between assignments (ClinicalTrials.gov identifier: NCT00331773).

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.

Long-term Outcomes of Chemoradiation for Muscle-invasive Bladder Cancer in Noncystectomy Candidates. Final Results of NRG Oncology RTOG 0524-A Phase 1/2 Trial of Paclitaxel + Trastuzumab with Daily Radiation or Paclitaxel Alone with Daily Irradiation.

BACKGROUND: Chemo-radiation is a well-established alternative to radical cystectomy in patients with muscle-invasive bladder cancer. Many patients due to age or medical comorbidity are unfit for either radical cystectomy, or standard cisplatin- or 5-fluorouracil-based chemoradiation, and do not receive appropriate treatment with curative intent. We treated patients with a less aggressive protocol employing seven weekly doses of paclitaxel and daily irradiation. In those whose tumors showed overexpression of her2/neu, seven weekly doses of trastuzumab were also administered. OBJECTIVE: To report the long-term survival outcomes and toxicity results of the of NRG Oncology RTOG 0524 study. DESIGN, SETTING, AND PARTICIPANTS: Seventy patients were enrolled and 65 (median age: 76 yr) were deemed eligible. Patients were assigned to daily radiation and weekly paclitaxel + trastuzumab (group 1, 20 patients) or to daily radiation plus weekly paclitaxel (group 2, 45 patients) based on tumor her2/neu overexpression. Radiation was delivered in 1.8 Gy fractions to a total dose of 64.8 Gy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was unresolved treatment-related toxicity. The secondary endpoints were complete response rate, protocol completion rate, and disease-free and overall survival. RESULTS AND LIMITATIONS: Protocol therapy was completed by 60% (group 1) and 76% (group 2); complete response rates at 12 wk were 62% in each group. Acute treatment-related adverse events (AEs) of grade ≥3 were observed in 80% in group 1 and 58% in group 2. There was one treatment-related grade 5 AE in group 1. Unresolved acute treatment-related toxicity was 35% in group 1 and 31% in group 2. The median follow-up was 2.3 yr in all patients and 7.2 yr in surviving patients. Overall survival at 5 yr was 25.0% in group 1 and 37.8% in group 2 (33.8% overall). At 5 yr, disease-free survival was 15.0% in group 1 and 31.1% in group 2. CONCLUSIONS: In a cohort of patients with muscle-invasive bladder cancer who are not candidates for cystectomy or cisplatin chemotherapy, chemoradiation therapy offers a treatment with a significant response rate and 34% 5-yr overall survival. While there were many AEs in this medically fragile group, there were few grade 4 events and one grade 5 event attributable to therapy. PATIENT SUMMARY: Patients with invasive bladder cancer who cannot tolerate surgery were treated with radiation and systemic therapy without surgically removing their bladders. Most patients tolerated the treatment, were able to keep their bladders, and showed a significant treatment response rate.

Artificial Intelligence Predictive Model for Hormone Therapy Use in Prostate Cancer.

Background: Androgen deprivation therapy (ADT) with radiotherapy can benefit patients with localized prostate cancer. However, ADT can negatively impact quality of life and there remain no validated predictive models to guide its use. Methods: Digital pathology image and clinical data from pre-treatment prostate tissue from 5,727 patients enrolled on five phase III randomized trials treated with radiotherapy +/- ADT were used to develop and validate an artificial intelligence (AI)-derived predictive model to assess ADT benefit with the primary endpoint of distant metastasis. After the model was locked, validation was performed on NRG/RTOG 9408 (n = 1,594) that randomized men to radiotherapy +/- 4 months of ADT. Fine-Gray regression and restricted mean survival times were used to assess the interaction between treatment and predictive model and within predictive model positive and negative subgroup treatment effects. Results: In the NRG/RTOG 9408 validation cohort (14.9 years of median follow-up), ADT significantly improved time to distant metastasis (subdistribution hazard ratio [sHR] = 0.64, 95%CI [0.45-0.90], p = 0.01). The predictive model-treatment interaction was significant (p-interaction = 0.01). In predictive model positive patients (n = 543, 34%), ADT significantly reduced the risk of distant metastasis compared to radiotherapy alone (sHR = 0.34, 95%CI [0.19-0.63], p < 0.001). There were no significant differences between treatment arms in the predictive model negative subgroup (n = 1,051, 66%; sHR = 0.92, 95%CI [0.59-1.43], p = 0.71). Conclusions: Our data, derived and validated from completed randomized phase III trials, show that an AI-based predictive model was able to identify prostate cancer patients, with predominately intermediate-risk disease, who are likely to benefit from short-term ADT.

Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostate Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial.

BACKGROUND: Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer. OBJECTIVE: To provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT. DESIGN, SETTING, AND PARTICIPANTS: High-risk localized prostate cancer patients (>50% of patients had Gleason 9-10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS). RESULTS AND LIMITATIONS: After 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval [CI] 0.70-1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73-1.14), DM (HR = 0.84, 95% CI 0.73-1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74-1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm. CONCLUSIONS: After a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers. PATIENT SUMMARY: No significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.

Dose-Escalated Radiation Alone or in Combination With Short-Term Total Androgen Suppression for Intermediate-Risk Prostate Cancer: Patient-Reported Outcomes From NRG/Radiation Therapy Oncology Group 0815 Randomized Trial.

PURPOSE: To report patient-reported outcomes (PROs) of a phase III trial evaluating total androgen suppression (TAS) combined with dose-escalated radiation therapy (RT) for patients with intermediate-risk prostate cancer. METHODS: Patients with intermediate-risk prostate cancer were randomly assigned to dose-escalated RT alone (arm 1) or RT plus TAS (arm 2) consisting of luteinizing hormone-releasing hormone agonist/antagonist with oral antiandrogen for 6 months. The primary PRO was the validated Expanded Prostate Cancer Index Composite (EPIC-50). Secondary PROs included Patient-Reported Outcome Measurement Information System (PROMIS)-fatigue and EuroQOL five-dimensions scale questionnaire (EQ-5D). PRO change scores, calculated for each patient as the follow-up score minus baseline score (at the end of RT and at 6, 12, and 60 months), were compared between treatment arms using a two-sample t test. An effect size of 0.50 standard deviation was considered clinically meaningful. RESULTS: For the primary PRO instrument (EPIC), the completion rates were ≥86% through the first year of follow-up and 70%-75% at 5 years. For the EPIC hormonal and sexual domains, there were clinically meaningful (P < .0001) deficits in the RT + TAS arm. However, there were no clinically meaningful differences by 1 year between arms. There were also no clinically meaningful differences at any time points between arms for PROMIS-fatigue, EQ-5D, and EPIC bowel/urinary scores. CONCLUSION: Compared with dose-escalated RT alone, adding TAS demonstrated clinically meaningful declines only in EPIC hormonal and sexual domains. However, even these PRO differences were transient, and there were no clinically meaningful differences between arms by 1 year.

Dose-Escalated Radiotherapy Alone or in Combination With Short-Term Androgen Deprivation for Intermediate-Risk Prostate Cancer: Results of a Phase III Multi-Institutional Trial.

PURPOSE: It remains unknown whether or not short-term androgen deprivation (STAD) improves survival among men with intermediate-risk prostate cancer (IRPC) treated with dose-escalated radiotherapy (RT). METHODS: The NRG Oncology/Radiation Therapy Oncology Group 0815 study randomly assigned 1,492 patients with stage T2b-T2c, Gleason score 7, or prostate-specific antigen (PSA) value >10 and ≤20 ng/mL to dose-escalated RT alone (arm 1) or with STAD (arm 2). STAD was 6 months of luteinizing hormone-releasing hormone agonist/antagonist therapy plus antiandrogen. RT modalities were external-beam RT alone to 79.2 Gy or external beam (45 Gy) with brachytherapy boost. The primary end point was overall survival (OS). Secondary end points included prostate cancer-specific mortality (PCSM), non-PCSM, distant metastases (DMs), PSA failure, and rates of salvage therapy. RESULTS: Median follow-up was 6.3 years. Two hundred nineteen deaths occurred, 119 in arm 1 and 100 in arm 2. Five-year OS estimates were 90% versus 91%, respectively (hazard ratio [HR], 0.85; 95% CI, 0.65 to 1.11]; P = .22). STAD resulted in reduced PSA failure (HR, 0.52; P <.001), DM (HR, 0.25; P <.001), PCSM (HR, 0.10; P = .007), and salvage therapy use (HR, 0.62; P = .025). Other-cause deaths were not significantly different (P = .56). Acute grade ≥3 adverse events (AEs) occurred in 2% of patients in arm 1 and in 12% for arm 2 (P <.001). Cumulative incidence of late grade ≥3 AEs was 14% in arm 1 and 15% in arm 2 (P = .29). CONCLUSION: STAD did not improve OS rates for men with IRPC treated with dose-escalated RT. Improvements in metastases rates, prostate cancer deaths, and PSA failures should be weighed against the risk of adverse events and the impact of STAD on quality of life.

Analysis of a Biopsy-Based Genomic Classifier in High-Risk Prostate Cancer: Meta-Analysis of the NRG Oncology/Radiation Therapy Oncology Group 9202, 9413, and 9902 Phase 3 Randomized Trials.

PURPOSE: Decipher is a genomic classifier (GC) prospectively validated postprostatectomy. We validated the performance of the GC in pretreatment biopsy samples within the context of 3 randomized phase 3 high-risk definitive radiation therapy trials. METHODS AND MATERIALS: A prespecified analysis plan (NRG-GU-TS006) was approved to obtain formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled in the NRG/Radiation Therapy Oncology Group (RTOG) 9202, 9413, and 9902 phase 3 randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability for the GC for distant metastases (DM), and secondary for prostate cancer-specific mortality (PCSM) and overall survival (OS) with Cox univariable and multivariable analyses. RESULTS: GC scores were obtained on 385 samples, of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9-13). In the pooled cohort, on univariable analysis, the GC was shown to be a prognostic factor for DM (per 0.1 unit; subdistribution hazard ratio [sHR], 1.29; 95% confidence interval [CI], 1.18-1.41; P < .001), PCSM (sHR, 1.28; 95% CI, 1.16-1.41; P < .001), and OS (hazard ratio [HR], 1.16; 95% CI, 1.08-1.22; P < .001). On multivariable analyses, the GC (per 0.1 unit) was independently associated with DM (sHR, 1.22; 95% CI, 1.09-1.36), PCSM (sHR, 1.23; 95% CI, 1.09-1.39), and OS (HR, 1.12; 95% CI, 1.05-1.20) after adjusting for age, Prostate Specific Antigen, Gleason score, cT stage, trial, and randomized treatment arm. GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy, but the absolute improvement in outcome varied by GC risk. CONCLUSIONS: This is the first validation of a gene expression biomarker on pretreatment prostate cancer biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state, and GC can improve risk stratification to help personalize shared decision making.

Artificial Intelligence Predictive Model for Hormone Therapy Use in Prostate Cancer.

BACKGROUND: Androgen deprivation therapy (ADT) with radiotherapy can benefit patients with localized prostate cancer. However, ADT can negatively impact quality of life, and there remain no validated predictive models to guide its use. METHODS: We used digital pathology images from pretreatment prostate tissue and clinical data from 5727 patients enrolled in five phase 3 randomized trials, in which treatment was radiotherapy with or without ADT, as our data source to develop and validate an artificial intelligence (AI)­derived predictive patient-specific model that would determine which patients would develop the primary end point of distant metastasis. The model used baseline data to provide a binary output that a given patient will likely benefit from ADT or not. After the model was locked, validation was performed using data from NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9408 (n=1594), a trial that randomly assigned men to radiotherapy plus or minus 4 months of ADT. Fine­Gray regression and restricted mean survival times were used to assess the interaction between treatment and the predictive model and within predictive model­positive, i.e., benefited from ADT, and ­negative subgroup treatment effects. RESULTS: Overall, in the NRG/RTOG 9408 validation cohort (14.9 years of median follow-up), ADT significantly improved time to distant metastasis. Of these enrolled patients, 543 (34%) were model positive, and ADT significantly reduced the risk of distant metastasis compared with radiotherapy alone. Of 1051 patients who were model negative, ADT did not provide benefit. CONCLUSIONS: Our AI-based predictive model was able to identify patients with a predominantly intermediate risk for prostate cancer likely to benefit from short-term ADT. (Supported by a grant [U10CA180822] from NRG Oncology Statistical and Data Management Center, a grant [UG1CA189867] from NCI Community Oncology Research Program, a grant [U10CA180868] from NRG Oncology Operations, and a grant [U24CA196067] from NRG Specimen Bank from the National Cancer Institute and by Artera, Inc. ClinicalTrials.gov numbers NCT00767286, NCT00002597, NCT00769548, NCT00005044, and NCT00033631.)

Salvage Low-Dose-Rate Prostate Brachytherapy: Clinical Outcomes of a Phase 2 Trial for Local Recurrence after External Beam Radiation Therapy (NRG Oncology/RTOG 0526).

PURPOSE: We report efficacy of a prospective phase 2 trial (NCT00450411) of salvage low-dose-rate (LDR) prostate brachytherapy (BT) for local failure (LF) after prior external beam radiation therapy (EBRT) with minimum 5-years' follow-up. METHODS AND MATERIALS: Eligible patients had low/intermediate risk prostate cancer (PCa) before EBRT and biopsy-proven LF >30 months after EBRT, with prostate-specific antigen <10 ng/mL and no regional/distant disease. The primary endpoint, late gastrointestinal and genitourinary adverse events (Common Terminology Criteria for Adverse Events v3.0) grade ≥3 were 14%. With minimum 5-year follow-up after salvage BT, secondary clinical outcomes including disease-free survival (DFS; includes death from any cause), disease-specific survival, and overall survival (OS) were estimated using the Kaplan-Meier method and modelled using Cox proportional hazards regression. Local tumor progression (ie, LF), distant failure (DF), and biochemical failure (BF) were estimated using cumulative incidence. Time to LF, DF, and BF were modeled by cause-specific Cox proportional hazards regression. RESULTS: From May 2007 to January 2014, 20 centers registered 100 patients (92 analyzable). Median follow-up is 6.7 years (range, 0.3-11.2); median age 70 years (range, 55-82); median prior EBRT dose 74 Gy [interquartile range (IQR):70 - 76] at a median of 85 months prior (IQR 60-119 months). Androgen deprivation was combined with salvage BT in 16%. Ten-year OS is 70% [95% confidence interval (CI) 58% - 83%]. Nineteen patients died (5 PCa, 10 other, 4 unknown). Ten-year failure rates are local 5% (95% CI, 1-11), distant 19% (95% CI, 10-29), and biochemical 46% (95% CI, 34-57). DFS is 61% at 5 years and 33% at 10 years. No baseline characteristic was significantly associated with any clinical outcome. CONCLUSIONS: This is the first prospective multicenter trial reporting outcomes of salvage LDR BT for LF after EBRT. Five-year freedom from BF is 68%, comparable to other salvage modalities. Although further LF is rare (5%), BF climbs to 46% by 10 years.

Adding Short-Term Androgen Deprivation Therapy to Radiation Therapy in Men With Localized Prostate Cancer: Long-Term Update of the NRG/RTOG 9408 Randomized Clinical Trial.

PURPOSE: For men with localized prostate cancer, NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9408 demonstrated that adding short-term androgen deprivation therapy (ADT) to radiation therapy (RT) improved the primary endpoint of overall survival (OS) and improved disease-specific mortality (DSM), biochemical failure (BF), local progression, and freedom from distant metastases (DM). This study was performed to determine whether the short-term ADT continued to improve OS, DSM, BF, and freedom from DM with longer follow-up. METHODS AND MATERIALS: From 1994 to 2001, NRG/RTOG 9408 randomized 2028 men from 212 North American institutions with T1b-T2b, N0 prostate adenocarcinoma and prostate-specific antigen (PSA) ≤20ng/mL to RT alone or RT plus short-term ADT. Patients were stratified by PSA, tumor grade, and surgical versus clinical nodal staging. ADT was flutamide with either goserelin or leuprolide for 4 months. Prostate RT (66.6 Gy) was started after 2 months. OS was calculated at the date of death from any cause or at last follow-up. Secondary endpoints were DSM, BF, local progression, and DM. Acute and late toxic effects were assessed using RTOG toxicity scales. RESULTS: Median follow-up in surviving patients was 14.8 years (range, 0.16-21.98). The 10-year and 18-year OS was 56% and 23%, respectively, with RT alone versus 63% and 23% with combined therapy (HR 0.94; 95% confidence interval [CI], 0.85-1.05; P = .94). The hazards were not proportional (P = .003). Estimated restricted mean survival time at 18 years was 11.8 years (95% CI, 11.4-12.1) with combined therapy versus 11.3 years with RT alone (95% CI, 10.9-11.6; P = .05). The 10-year and 18-year DSM was 7% and 14%, respectively, with RT alone versus 3% and 8% with combined therapy (HR 0.56; 95% CI, 0.41-0.75; P < .01). DM and BF favored combined therapy at 18 years. Rates of late grade ≥3 hepatic, gastrointestinal, and genitourinary toxicity were ≤1%, 3%, and 8%, respectively, with combined therapy versus ≤1%, 2%, and 5% with RT alone. CONCLUSIONS: Further follow-up demonstrates that OS converges at approximately 15 years, by which point the administration of 4 months of ADT had conferred an estimated additional 6 months of life.

Do reminder emails and past due notifications improve patient completion and institutional data submission for patient-reported outcome measures?

PURPOSE: NRG Oncology, part of the National Cancer Institute's National Clinical Trials Network, took efforts to increase patient-reported outcome measures (PROMs) completion and institutional data submission rates within clinical trials. Lack of completion diminishes power to draw conclusions and can be a waste of resources. It is hypothesized that trials with automatic email reminders and past due notifications will have PROM forms submitted more timely with higher patient completion. METHODS: Automatic emails sent to the research associate were added to selected NRG Oncology trials. Comparisons between trials with and without automatic emails were analyzed using Chi-square tests with respect to patient completion and timeliness of form submission rates. Multivariable analyses were conducted using repeated measures generalized estimating equations. If PROMs were not completed, a form providing the reason why was submitted and counted towards form submission. RESULTS: For both disease sites, form submission was significantly higher within 1 month of the form's due date for the studies with automatic emails vs. those without (prostate: 79.7% vs. 75.7%, p < 0.001; breast: 59.2% vs. 31.3%, p < 0.001). No significant differences in patient completion were observed between the breast trials. The prostate trial with automatic emails had significantly higher patient completion but this result was not confirmed in the multivariable analysis. CONCLUSIONS: Although patient completion rates were higher on trials with automatic emails, there may be confounding factors requiring future study. The automatic emails appeared to have increased the timeliness of form submission, thus supporting their continued use on NRG Oncology trials.

Long-Term Results of NRG Oncology/RTOG 0321: A Phase II Trial of Combined High Dose Rate Brachytherapy and External Beam Radiation Therapy for Adenocarcinoma of the Prostate.

PURPOSE: To report the long-term outcome of patients with prostate cancer treated with external beam radiation therapy and high dose rate (HDR) brachytherapy from a prospective multi-institutional trial conducted by NRG Oncology/RTOG. METHODS AND MATERIALS: Patients with clinically localized (T1c-T3b) prostate cancer without prior history of transurethral resection of prostate or hip prosthesis were eligible for this study. All patients were treated with a combination of 45 Gy in 25 fractions from external beam radiation therapy and one HDR implant delivering 19 Gy in 2 fractions. Adverse events (AE) were collected using Common Toxicity Criteria for Adverse Events, version 3. Cumulative incidence was used to estimate time to severe late gastrointestinal (GI)/genitourinary (GU) toxicity, biochemical failure, disease-specific mortality, local failure, and distant failure. Overall survival was estimated using the Kaplan-Meier method. RESULTS: One hundred and twenty-nine patients were enrolled from July 2004 to May 2006. AE data was available for 115 patients. Patients were National Comprehensive Cancer Network (NCCN) intermediate to very high risk. The median age was 68, T1c-T2c 91%, T3a-T3b 9%, PSA ≤10 70%, PSA >10 to ≤20 30%, GS 6 10%, GS 7 72%, and GS 8 to 10 18%. Forty-three percent of patients received hormonal therapy. At a median follow-up time of 10 years, there were 6 (5%) patients with grade 3 GI and GU treatment-related AEs, and no late grade 4 to 5 GI and GU AEs. At 5 and 10 years, the rate of late grade 3 gastrointestinal and genitourinary AEs was 4% and 5%, respectively. Five- and 10-year overall survival rates were 95% and 76%. Biochemical failure rates per Phoenix definition at 5 and 10 years were 14% and 23%. The 10-year rate of disease-specific mortality was 6%. At 5 and 10 years, the rates of distant failure were 4% and 8%, respectively. The rates of local failure at 5 and 10 years were 2% at both time points. CONCLUSIONS: Combined modality treatment using HDR prostate brachytherapy leads to excellent long-term clinical outcomes in this prospective multi-institutional trial.

Characteristics of Participation in Patient-Reported Outcomes and Electronic Data Capture Components of NRG Oncology Clinical Trials.

PURPOSE: To assess the reasons why patients do not consent to patient-reported outcome (PRO) and electronic PRO data capture components of clinical trials and potential selection bias by having a separate consent. METHODS AND MATERIALS: Selected NRG Oncology trials were included based on disease site and inclusion of PROs and electronic PRO data capture via VisionTree Optimal Care as separate consent questions. Reasons for not participating were assessed. Pretreatment characteristics between patients who did and did not consent were tested using χ2 and t tests for univariate comparisons and logistic regression for multivariable analyses. RESULTS: Ten trials were selected in head and neck, prostate, gynecologic, breast, lung, and gastrointestinal cancers, with 4 of these trials having electronic PRO data capture. Most patients consented to the PRO component (75.3%) but not electronic PRO data capture (37.8%). More white patients consented to PROs than nonwhite patients across all trials (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.45-0.63; P < .001), and more patients with education after high school consented compared with those with less education (OR, 1.71; 95% CI, 1.46-2.02; P < .001). Patients who are younger (OR, 0.63; 95% CI, 0.47-0.85; P = .002), white (OR, 0.60; 95% CI, 0.44-0.82; P = .001), and a never or former smoker (OR, 0.57; 95% CI, 0.41-0.78; P = .001) are more likely to participate in electronic PRO data capture. CONCLUSIONS: These results suggest that a patient's race, age, and education can affect whether a patient chooses to consent or is offered to participate in PRO or electronic PRO data capture components. More investigation is needed, but this analysis provides support for making PROs integrated in the trial.

Bladder Preservation With Twice-a-Day Radiation Plus Fluorouracil/Cisplatin or Once Daily Radiation Plus Gemcitabine for Muscle-Invasive Bladder Cancer: NRG/RTOG 0712-A Randomized Phase II Trial.

PURPOSE: Fluorouracil plus cisplatin and radiation twice a day (FCT) is an established chemoradiation (CRT) regimen for selective bladder-sparing treatment of muscle-invasive bladder cancer. Gemcitabine and once daily radiation (GD) is a well-supported alternative. The current trial evaluates these regimens. METHODS: Patients with cT2-4a muscle-invasive bladder cancer were randomly assigned to FCT or GD. Patients underwent transurethral resection and induction CRT to 40 Gy. Patients who achieved a complete response (CR) received consolidation CRT to 64 Gy and others underwent cystectomy. We administered adjuvant gemcitabine/cisplatin chemotherapy. The primary end point was the rate of freedom from distant metastasis at 3 years (DMF3). The trial was not statistically powered to compare regimens, but to assess whether either regimen exceeded a DMF3 benchmark of 75%. Toxicity and efficacy end points, including CR and bladder-intact distant metastasis free survival at 3 years (BI-DMFS3), were assessed. RESULTS: From December 2008 to April 2014, 70 patients were enrolled, of which 66 were eligible for analysis, 33 per arm. Median follow-up was 5.1 years (range, 0.4 to 7.8 years) for eligible living patients. DMF3 was 78% and 84% for FCT and GD, respectively. BI-DMFS3 was 67% and 72%, respectively. Postinduction CR rates were 88% and 78%, respectively. Of 33 patients in the FCT arm, 21 (64%) experienced treatment-related grade 3 and 4 toxicities during protocol treatment, with 18 (55%), two (6%), and two patients (6%) experiencing grade 3 and 4 hematologic, GI, and genitourinary toxicity, respectively. For the 33 patients in the GD arm, these figures were 18 (55%) overall and 14 (42%), three (9%) and two patients (6%), respectively. CONCLUSION: Both regimens demonstrated DMF3 greater than 75%. There were fewer toxicities observed in the GD arm. Either gemcitabine and once daily radiation or a cisplatin-based regimen could serve as a base for future trials of systemic therapy.