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).

Cardiovascular Mortality and Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-term Update of NRG/RTOG 9202.

BACKGROUND: Androgen deprivation therapy (ADT) has been associated with coronary heart disease and myocardial infarction (MI) in prostate cancer patients, but controversy persists regarding its effects on cardiovascular mortality (CVM). OBJECTIVE: We assessed the long-term relationship between ADT and CVM in a prostate cancer randomized trial (NRG Oncology/Radiation Therapy Oncology Group 9202). DESIGN, SETTING, AND PARTICIPANTS: From 1992 to 1995, 1554 men with locally advanced prostate cancer (T2c-T4, prostate-specific antigen <150 ng/ml) received radiotherapy with 4 mo (short-term [STADT]) versus 28 mo (longer-term [LTADT]) of ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Using the Fine-Gray and Cox regression models, the relationship between ADT and mortality was evaluated. RESULTS AND LIMITATIONS: With a median follow-up of 19.6 yr, LTADT was associated with improved overall survival (OS) versus STADT (adjusted hazard ratio [HR] 0.88; p = 0.03) and prostate cancer survival (subdistribution HR [sHR] 0.70, p = 0.003). Comparing LTADT with STADT, prostate cancer mortality improved by 6.0% (15.6% [95% confidence interval 13.0-18.3%] vs 21.6% [18.6-24.7%]) at 15 yr, while CVM increased by 2.2% (14.9% [12.4-17.6%] vs 12.7% [10.4-15.3%]). In multivariable analyses, LTADT was not associated with increased CVM versus STADT (sHR 1.22 [0.93-1.59]; p = 0.15). An association between LTADT and MI death was detected (sHR 1.58 [1.00-2.50]; p = 0.05), particularly in patients with prevalent cardiovascular disease (CVD; sHR 2.54 [1.16-5.58]; p = 0.02). CONCLUSIONS: With 19.6 yr of follow-up, LTADT was not significantly associated with increased CVM in men with locally advanced prostate cancer. Patients may have increased MI mortality with LTADT, particularly those with baseline CVD. Overall, there remained a prostate cancer mortality benefit and no OS detriment with LTADT. PATIENT SUMMARY: In a long-term analysis of a large randomized prostate cancer trial, radiation with 28 mo of hormone therapy did not increase the risk of cardiovascular death significantly versus 4 mo of hormone therapy. Future studies are needed for patients with pre-existing heart disease, who may have an increased risk of myocardial infarction death with longer hormone use.

Leveraging external control data in the design and analysis of neuro-oncology trials: Pearls and perils.

BACKGROUND: Randomized controlled trials have been the gold standard for evaluating medical treatments for many decades but they are often criticized for requiring large sample sizes. Given the urgent need for better therapies for glioblastoma, it has been argued that data collected from patients treated with the standard regimen can provide high-quality external control data to supplement or replace concurrent control arm in future glioblastoma trials. METHODS: In this article, we provide an in-depth appraisal of the use of external control data in the context of neuro-oncology trials. We describe several clinical trial designs with particular attention to how external information is utilized and address common fallacies that may lead to inappropriate adoptions of external control data. RESULTS: Using 2 completed glioblastoma trials, we illustrate the use of an assessment tool that lays out a blueprint for assembling a high-quality external control data set. Using statistical simulations, we draw caution from scenarios where these approaches can fall short on controlling the type I error rate. CONCLUSIONS: While this approach may hold promise in generating informative data in certain settings, this sense of optimism should be tampered with a healthy dose of skepticism due to a myriad of design and analysis challenges articulated in this review. Importantly, careful planning is key to its successful implementation.

Early Endpoints in High-risk Localized Prostate Cancer: Exploratory Analysis of Three Radiation Therapy Oncology Group Phase 3 Studies.

BACKGROUND: Early endpoints in clinical trials of high-risk localized prostate cancer (HRLPC) that resemble those monitored in real-world practice could expedite clinical development. OBJECTIVE: To assess the association of prostate-specific antigen (PSA) recurrence (PSA-R)-based early endpoints with metastasis-free survival (MFS), overall survival (OS), and prostate cancer (PC)-specific survival (PCSS), and to identify clinically undetectable disease. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of patients with HRLPC from Radiation Therapy Oncology Group studies 9202, 9902, and 0521 was performed. INTERVENTION: Long-term adjuvant androgen-deprivation therapy (ADT) and post-primary definitive radiotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Event-free survival (EFS; PSA-R, locoregional recurrence [LRR], distant metastasis [DM], or death), biochemical failure (PSA-R), general clinical failure (PSA-R, LRR, DM, ADT initiation, or death), and no evidence of disease (NED; alive patients without PSA-R, LRR, DM, and subsequent PC therapy, and with testosterone recovery) were assessed for association with MFS, OS, and PCSS using correlation and landmark analyses, Kaplan-Meier method, and Cox proportional-hazard model. PSA-R was defined as PSA nadir + 2 ng/ml; PSA nadir + 2 ng/ml and rising; PSA >5, 10, and 25 ng/ml; or PSA doubling time (PSADT) <6 mo. RESULTS AND LIMITATIONS: Among assessed early endpoints, EFS with PSA nadir + 2 ng/ml and rising, or with PSA >5 ng/ml was associated with MFS, OS, and PCSS. No development of EFS with PSADT <6 mo or ADT initiation event or achievement of NED at 3 yr was associated with prolonged OS, MFS, and PCSS (hazard ratio [95% confidence interval], 0.53 [0.45-0.64], 0.63 [0.52-0.76], and 0.26 [0.18-0.36], or 0.56 [0.48-0.66], 0.62 [0.52-0.74], and 0.26 [0.19-0.37]) after the landmark time. Older studies performed before the current guidance should be interpreted with caution. CONCLUSIONS: We identified EFS with PSA nadir + 2 ng/ml and rising, PSA >5 ng/ml, or PSADT <6 mo ± ADT initiation and NED as potentially promising early endpoints in HRLPC that should be validated further. PATIENT SUMMARY: We identified novel clinical measures that may expedite the development of new medicines for patients with localized prostate cancer at a high risk of progression. These measures, which took into account prostate-specific antigen assessments and other clinical characteristics, should be confirmed in future studies. We also defined a novel measure of no evidence of disease that can help treating physicians identify patients with clinically undetectable disease.

Predictors of Pneumonitis in Combined Thoracic Stereotactic Body Radiation Therapy and Immunotherapy.

PURPOSE: Thoracic stereotactic body radiation therapy (SBRT) is associated with high rates of local control but carries a risk of pneumonitis. Immunotherapy is a standard treatment for patients with metastatic disease but can also cause pneumonitis. To evaluate the feasibility and safety of thoracic SBRT with systemic immunotherapy, clinical outcomes of patients treated with immune checkpoint blockade (ICB) and SBRT on prospective trials were reviewed. METHODS AND MATERIALS: Three consecutive phase 1 trials of combination SBRT and ICB conducted between 2016 to 2020 for widely metastatic solid tumors were reviewed. The protocols mandated adherence to NRG BR001/BR002 organs at risk constraints, resulting in <100% coverage of some target volumes. ICB was administered either sequentially (within 7 days after completion of SBRT) or concurrently (before or at the start of SBRT), depending on protocol. End points included pneumonitis, dose-volume constraints, local failure, and overall survival. The cumulative incidence estimator and Kaplan-Meier method were used. RESULTS: In the study, 123 patients met eligibility with 311 metastases irradiated. The most common histologies included non-small cell lung cancer (33%) and colorectal cancer (12%). Median follow-up was 12 months. The overall rate of grade 3+ pneumonitis was 8.1%; 1-year local failure was 3.6%. Established dosimetric parameters were significantly associated with the development of pneumonitis (P < .05). In most patients, the lungs were not challenged with high doses of radiation, defined as receiving ≥75% of the maximum for a given lung dose-volume constraint. Patients who were challenged were not found to have a significantly higher risk of pneumonitis. CONCLUSIONS: In the largest series of thoracic SBRT and immunotherapy, local control was excellent with acceptable toxicity and support the conclusion that established dose-volume constraints for the lung are safe. However, these results highlight the potential value in reporting of organs at risk being challenged with doses approaching protocol specified limits.

Hematuria following Post-Prostatectomy Radiotherapy: Incidence Increases with Long-Term Followup.

PURPOSE: Hematuria following post-prostatectomy radiotherapy (PPRT) is inadequately characterized. We performed a consecutive cohort study of patients treated with PPRT at our institution to characterize this complication including impact on patient-reported quality of life. MATERIALS AND METHODS: Patients with potential followup ≥4 years following PPRT were identified. Freedom from ≥grade 2 hematuria (FFG2H; macroscopic blood) was estimated using the Kaplan-Meier method. Predictors of ≥grade 2 hematuria (G2H) were assessed via log-rank tests and the Cox model. Urinary patient-reported quality of life by EPIC-26 (26-question Expanded Prostate Cancer Index Composite) was compared for patients with/without hematuria using mixed-effects regression. RESULTS: A total of 216 men received PPRT (median 68.4 Gy, IQR 68.0-68.4) from 2007 to 2016 at a median of 20 months (IQR 9-45) after prostatectomy. Median followup was 72 months (IQR 54-99). A total of 85 men developed hematuria, of whom 49 (58%) underwent cystoscopy, 13 (15%) required intervention and 26 (31%) experienced recurrent hematuria. Eight-year FFG2H was 55%. G2H was highest in men treated with anticoagulation/antiplatelet therapy (HR 3.24, p <0.001), men with bladder V65 Gy ≥43% (HR 1.97, p=0.004) and men with medication allergies (HR 1.73, p=0.049). Age <65 years (HR 0.81, p=0.374) and diabetes mellitus (HR 0.49, p=0.098) were not associated with G2H. Change in urinary continence (mean -3.5, 95% CI: 10.1, 3.1) and irritation/obstruction (mean -3.0, 95% CI: 5.8, -0.3) domain scores did not exceed the minimally clinically important difference for men with/without hematuria. CONCLUSIONS: Hematuria following PPRT is common, especially among men with medication allergies and those on anticoagulation/antiplatelet therapy; however, PPRT-related hematuria is typically self-limited. Limiting bladder V65 Gy may reduce PPRT-related hematuria.

Appropriate Systemic Therapy Dosing for Obese Adult Patients With Cancer: ASCO Guideline Update.

PURPOSE: To provide recommendations for appropriate dosing of systemic antineoplastic agents in obese adults with cancer. METHODS: A systematic review of the literature collected evidence regarding dosing of chemotherapy, immunotherapy, and targeted therapies in obese adults with cancer. PubMed and the Cochrane Library were searched for randomized controlled trials, meta-analyses, or cohort studies published from November 1, 2010, through March 27, 2020. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: Sixty studies, primarily retrospective, were included in the review. Overall, the evidence supported previous findings that obese adult patients tolerate full, body-size-based dosing of chemotherapy as well as nonobese patients. Fewer studies have addressed the dosing of targeted therapies and immunotherapies in relation to safety and efficacy in obese patients. RECOMMENDATIONS: The Panel continues to recommend that full, weight-based cytotoxic chemotherapy doses be used to treat obese adults with cancer. New to this version of the guideline, the Panel also recommends that full, approved doses of immunotherapy and targeted therapies be offered to obese adults with cancer. In the event of toxicity, the consensus of the Panel is that dose modifications of systemic antineoplastic therapies should be handled similarly for obese and nonobese patients. Important areas for future research include the impact of sarcopenia and other measures of body composition on optimal antineoplastic dosing, and more customized dosing based on pharmacokinetic or pharmacogenetic factors.Additional information is available at www.asco.org/supportive-care-guidelines.

Statistical Considerations in the Evaluation of Continuous Biomarkers.

Discovery of biomarkers has been steadily increasing over the past decade. Although a plethora of biomarkers has been reported in the biomedical literature, few have been sufficiently validated for broader clinical applications. One particular challenge that may have hindered the adoption of biomarkers into practice is the lack of reproducible biomarker cut points. In this article, we attempt to identify some common statistical issues related to biomarker cut point identification and provide guidance on proper evaluation, interpretation, and validation of such cut points. First, we illustrate how discretization of a continuous biomarker using sample percentiles results in significant information loss and should be avoided. Second, we review the popular "minimal-P-value" approach for cut point identification and show that this method results in highly unstable P values and unduly increases the chance of significant findings when the biomarker is not associated with outcome. Third, we critically review a common analysis strategy by which the selected biomarker cut point is used to categorize patients into different risk categories and then the difference in survival curves among these risk groups in the same dataset is claimed as the evidence supporting the biomarker's prognostic strength. We show that this method yields an exaggerated P value and overestimates the prognostic impact of the biomarker. We illustrate that the degree of the optimistic bias increases with the number of variables being considered in a risk model. Finally, we discuss methods to appropriately ascertain the additional prognostic contribution of the new biomarker in disease settings where standard prognostic factors already exist. Throughout the article, we use real examples in oncology to highlight relevant methodologic issues, and when appropriate, we use simulations to illustrate more abstract statistical concepts.

Validation of a 22-Gene Genomic Classifier in Patients With Recurrent Prostate Cancer: An Ancillary Study of the NRG/RTOG 9601 Randomized Clinical Trial.

Importance: Decipher (Decipher Biosciences Inc) is a genomic classifier (GC) developed to estimate the risk of distant metastasis (DM) after radical prostatectomy (RP) in patients with prostate cancer. Objective: To validate the GC in the context of a randomized phase 3 trial. Design, Setting, and Participants: This ancillary study used RP specimens from the phase 3 placebo-controlled NRG/RTOG 9601 randomized clinical trial conducted from March 1998 to March 2003. The specimens were centrally reviewed, and RNA was extracted from the highest-grade tumor available in 2019 with a median follow-up of 13 years. Clinical-grade whole transcriptomes from samples passing quality control were assigned GC scores (scale, 0-1). A National Clinical Trials Network-approved prespecified statistical plan included the primary objective of validating the independent prognostic ability of GC for DM, with secondary end points of prostate cancer-specific mortality (PCSM) and overall survival (OS). Data were analyzed from September 2019 to December 2019. Intervention: Salvage radiotherapy (sRT) with or without 2 years of bicalutamide. Main Outcomes and Measures: The preplanned primary end point of this study was the independent association of the GC with the development of DM. Results: In this ancillary study of specimens from a phase 3 randomized clinical trial, GC scores were generated from 486 of 760 randomized patients with a median follow-up of 13 years; samples from a total of 352 men (median [interquartile range] age, 64.5 (60-70) years; 314 White [89.2%] participants) passed microarray quality control and comprised the final cohort for analysis. On multivariable analysis, the GC (continuous variable, per 0.1 unit) was independently associated with DM (hazard ratio [HR], 1.17; 95% CI, 1.05-1.32; P = .006), PCSM (HR, 1.39; 95% CI, 1.20-1.63; P < .001), and OS (HR, 1.17; 95% CI, 1.06-1.29; P = .002) after adjusting for age, race/ethnicity, Gleason score, T stage, margin status, entry prostate-specific antigen, and treatment arm. Although the original planned analysis was not powered to detect a treatment effect interaction by GC score, the estimated absolute effect of bicalutamide on 12-year OS was less when comparing patients with lower vs higher GC scores (2.4% vs 8.9%), which was further demonstrated in men receiving early sRT at a prostate-specific antigen level lower than 0.7 ng/mL (-7.8% vs 4.6%). Conclusions and Relevance: This ancillary validation study of the Decipher GC in a randomized trial cohort demonstrated association of the GC with DM, PCSM, and OS independent of standard clinicopathologic variables. These results suggest that not all men with biochemically recurrent prostate cancer after surgery benefit equally from the addition of hormone therapy to sRT. Trial Registration: ClinicalTrials.gov identifier: NCT00002874.

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.

Association of Presalvage Radiotherapy PSA Levels After Prostatectomy With Outcomes of Long-term Antiandrogen Therapy in Men With Prostate Cancer.

Importance: In men with recurrent prostate cancer, addition of long-term antiandrogen therapy to salvage radiotherapy (SRT) was associated with overall survival (OS) in the NRG/RTOG 9601 study. However, hormone therapy has associated morbidity, and there are no validated predictive biomarkers to identify which patients derive most benefit from treatment. Objective: To examine the role of pre-SRT prostate-specific antigen (PSA) levels to personalize hormone therapy use with SRT. Interventions: Men were randomized to SRT plus high-dose nonsteroidal antiandrogen (bicalutamide, 150 mg/d) or placebo for 2 years. Design, Setting, and Participants: In this secondary analysis of the multicenter RTOG 9601 double-blind, placebo-controlled randomized clinical trial conducted from 1998 to 2003 by a multinational cooperative group, men with a positive surgical margin or pathologic T3 disease after radical prostatectomy with pre-SRT PSA of 0.2 to 4.0 ng/mL were included. Analysis was performed between March 4, 2019, and December 20, 2019. Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary end points included distant metastasis (DM), other-cause mortality (OCM), and grades 3 to 5 cardiac and neurologic toxic effects. Subgroup analyses were performed using the protocol-specified PSA stratification variable (1.5 ng/mL) and additional PSA cut points, including test for interaction. Competing risk analyses were performed for DM and other-cause mortality (OCM). Results: Overall, 760 men with PSA elevation after radical prostatectomy for prostate cancer were included. The median (range) age of particpants was 65 (40-83) years. Antiandrogen assignment was associated with an OS benefit in the PSA stratum greater than 1.5 ng/mL (n = 118) with a 25% 12-year absolute benefit (hazard ratio [HR], 0.45; 95% CI, 0.25-0.81), but not in the PSA of 1.5 ng/mL or less stratum (n = 642) (1% 12-year absolute difference; HR, 0.87; 95% CI, 0.66-1.16). In a subanalysis of men with PSA of 0.61 to 1.5 (n = 253), there was an OS benefit associated with antiandrogen assignment (HR, 0.61; 95% CI, 0.39-0.94). In those receiving early SRT (PSA ≤0.6 ng/mL, n = 389), there was no improvement in OS (HR, 1.16; 95% CI, 0.79-1.70), an increased OCM hazard (subdistribution HR, 1.94; 95% CI, 1.17-3.20; P = .01), and an increased odds of late grades 3 to 5 cardiac and neurologic toxic effects (odds ratio, 3.57; 95% CI, 1.09-15.97; P = .05). Conclusions and Relevance: These results suggest that pre-SRT PSA level may be a prognostic biomarker for outcomes of antiandrogen treatment with SRT. In patients receiving late SRT (PSA >0.6 ng/mL, hormone therapy was associated with improved outcomes. In men receiving early SRT (PSA ≤0.6 ng/mL), long-term antiandrogen treatment was not associated with improved OS. Future randomized clinical trials are needed to determine hormonal therapy benefit in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT00002874.

A Systematic Review and Recommendation for Reporting of Surrogate Endpoint Evaluation Using Meta-analyses.

BACKGROUND: Meta-analysis of randomized controlled trials (RCTs) has been widely conducted for the evaluation of surrogate endpoints in oncology, but little attention has been given to the adequacy of reporting and interpretation. This review evaluated the reporting quality of published meta-analyses on surrogacy evaluation and developed recommendations for future reporting. METHODS: We searched PubMed through August 2017 to identify studies that evaluated surrogate endpoints using the meta-analyses of RCTs in oncology. Both individual patient data (IPD) and aggregate data (AD) meta-analyses were included for the review. RESULTS: Eighty meta-analyses were identified: 22 used IPD and 58 used AD from multiple RCTs. We observed variability and reporting deficiencies in both IPD and AD meta-analyses, especially on reporting of trial selection, endpoint definition, study and patient characteristics for included RCTs, and important statistical methods and results. Based on these findings, we proposed a checklist and recommendations to improve completeness, consistency, and transparency of reports of meta-analytic surrogacy evaluation. We highlighted key aspects of the design and analysis of surrogate endpoints and presented explanations and rationale why these items should be clearly reported in surrogacy evaluation. CONCLUSIONS: Our reporting of surrogate endpoint evaluation using meta-analyses (ReSEEM) guidelines and recommendations will improve the quality in reporting and facilitate the interpretation and reproducibility of meta-analytic surrogacy evaluation. Also, they should help promote greater methodological consistency and could also serve as an evaluation tool in the peer review process for assessing surrogacy research.

Association of Black Race With Prostate Cancer-Specific and Other-Cause Mortality.

Importance: Black men are more likely to die of prostate cancer than white men. In men with similar stages of disease, the contribution of biological vs nonbiological differences to this observed disparity is unclear. Objective: To quantify the association of black race with long-term survival outcomes after controlling for known prognostic variables and access to care among men with prostate cancer. Design, Setting, and Participants: This multiple-cohort study included updated individual patient-level data of men with clinical T1-4N0-1M0 prostate cancer from the following 3 cohorts: Surveillance, Epidemiology, and End Results (SEER [n = 296 273]); 5 equal-access regional medical centers within the Veterans Affairs health system (VA [n = 3972]); and 4 pooled National Cancer Institute-sponsored Radiation Therapy Oncology Group phase 3 randomized clinical trials (RCTs [n = 5854]). Data were collected in the 3 cohorts from January 1, 1992, through December 31, 2013, and analyzed from April 27, 2017, through April 13, 2019. Exposures: In the VA and RCT cohorts, all patients received surgery and radiotherapy, respectively, with curative intent. In SEER, radical treatment, hormone therapy, or conservative management were received. Main Outcomes and Measures: Prostate cancer-specific mortality (PCSM). Secondary measures included other-cause mortality (OCM). To adjust for demographic-, cancer-, and treatment-related baseline differences, inverse probability weighting (IPW) was performed. Results: Among the 306 100 participants included in the analysis (mean [SD] age, 64.9 [8.9] years), black men constituted 52 840 patients (17.8%) in the SEER cohort, 1513 (38.1%) in the VA cohort, and 1129 (19.3%) in the RCT cohort. Black race was associated with an increased age-adjusted PCSM hazard (subdistribution hazard ratio [sHR], 1.30; 95% CI, 1.23-1.37; P < .001) within the SEER cohort. After IPW adjustment, black race was associated with a 0.5% (95% CI, 0.2%-0.9%) increase in PCSM at 10 years after diagnosis (sHR, 1.09; 95% CI, 1.04-1.15; P < .001), with no significant difference for high-risk men (sHR, 1.04; 95% CI, 0.97-1.12; P = .29). No significant differences in PCSM were found in the VA IPW cohort (sHR, 0.85; 95% CI, 0.56-1.30; P = .46), and black men had a significantly lower hazard in the RCT IPW cohort (sHR, 0.81; 95% CI, 0.66-0.99; P = .04). Black men had a significantly increased hazard of OCM in the SEER (sHR, 1.30; 95% CI, 1.27-1.34; P < .001) and RCT (sHR, 1.17; 95% CI, 1.06-1.29; P = .002) IPW cohorts. Conclusions and Relevance: In this study, after adjustment for nonbiological differences, notably access to care and standardized treatment, black race did not appear to be associated with inferior stage-for-stage PCSM. A large disparity remained in OCM for black men with nonmetastatic prostate cancer.

Quality of Life in Patients With Low-Risk Prostate Cancer Treated With Hypofractionated vs Conventional Radiotherapy: A Phase 3 Randomized Clinical Trial.

IMPORTANCE: Hypofractionated radiotherapy (HRT) would be more convenient for men with low-risk prostate cancer and cost less than conventional radiotherapy (CRT) as long as HRT is noninferior to CRT in terms of survival and quality of life (QOL) is not found to be worse. OBJECTIVE: To assess differences in QOL between men with low-risk prostate cancer who are treated with HRT vs CRT. DESIGN, SETTING, AND PARTICIPANTS: In this phase 3 randomized clinical trial, men with low-risk prostate cancer were enrolled from sites within the National Cancer Institute's National Clinical Trials Network in the United States, Canada, and Switzerland. INTERVENTIONS: Random assignment to CRT (73.8 Gy in 41 fractions over 8.2 weeks) or to HRT (70 Gy in 28 fractions over 5.6 weeks). MAIN OUTCOMES AND MEASURES: Quality of life was assessed using the Expanded Prostate Index Composite questionnaire measuring bowel, urinary, sexual, and hormonal domains; the 25-item Hopkins Symptom Checklist measuring anxiety and depression; and the EuroQol-5 Dimension questionnaire measuring global QOL. All data were collected at baseline and 6, 12, 24, and 60 months. Change scores were compared between treatment arms using the Wilcoxon signed rank test. A significance level of .0125 to adjust for multiple comparisons was used for an overall 2-sided type 1 error of .05. Clinical significance was determined for the Expanded Prostate Index Composite change scores by an effect size of 0.5. RESULTS: Of 1092 patients analyzable for the primary end point, 962 (mean [SD] age, 66.6 [7.4] years) consented to the QOL component. No statistically significant differences with regard to baseline characteristics nor any of the QOL baseline domains were measured between arms. There were no differences in change score between arms with respect to any of the Expanded Prostate Index Composite questionnaire domain scores except at 12 months when the HRT arm had a larger decline than the CRT arm in the bowel domain (mean score, -7.5 vs -3.7, respectively; P<.001), but it did not reach clinical significance (effect size = 0.29). There were no differences between arms at any time point for the Hopkins Symptom Checklist nor EuroQol-5 Dimension questionnaire. CONCLUSIONS AND RELEVANCE: Treatment with HRT is noninferior to CRT in men with low-risk prostate cancer in terms of disease-free survival and, as shown in the present study, in prostate cancer-specific (eg, bowel, bladder, sexual) and general QOL, as well as in anxiety and depression. This study provides evidence to affirm that HRT is a practice standard for men with low-risk prostate cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00331773.

Biomarker-Driven Oncology Clinical Trials: Key Design Elements, Types, Features, and Practical Considerations.

In this precision oncology era, where molecular profiling at the individual patient level becomes increasingly accessible and affordable, more and more clinical trials are now driven by biomarkers, with an overarching objective to optimize and personalize disease management. As compared with the conventional clinical development paradigms, where the key is to evaluate treatment effects in histology-defined populations, the choices of biomarker-driven clinical trial designs and analysis plans require additional considerations that are heavily dependent on the nature of biomarkers (eg, prognostic or predictive, integral or integrated) and the credential of biomarkers' performance and clinical utility. Most recently, another major paradigm change in biomarker-driven trials is to conduct multi-agent and/or multihistology master protocols or platform trials. These trials, although they may enjoy substantial infrastructure and logistical advantages, also face unique operational and conduct challenges. Here we provide a concise overview of design options for both the setting of single-biomarker/single-disease and the setting of multiple-biomarker/multiple-disease types. We focus on explaining the trial design and practical considerations and rationale of when to use which designs, as well as how to incorporate various adaptive design components to provide additional flexibility, enhance logistical efficiency, and optimize resource allocation. Lessons learned from real trials are also presented for illustration.

Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial.

BACKGROUND: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity. METHODS: RTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (≤10 pack-years vs >10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m2 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m2 weekly for seven doses (total 2150 mg/m2), or cisplatin 100 mg/m2 on days 1 and 22 of radiotherapy (total 200 mg/m2). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1·45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with ClinicalTrials.gov, number NCT01302834. FINDINGS: Between June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio [HR] 1·45, one-sided 95% upper CI 1·94; p=0·5056 for non-inferiority; one-sided log-rank p=0·0163). Estimated 5-year overall survival was 77·9% (95% CI 73·4-82·5) in the cetuximab group versus 84·6% (80·6-88·6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1·72, 95% CI 1·29-2·29; p=0·0002; 5-year progression-free survival 67·3%, 95% CI 62·4-72·2 vs 78·4%, 73·8-83·0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2·05, 95% CI 1·35-3·10; 5-year proportions 17·3%, 95% CI 13·7-21·4 vs 9·9%, 6·9-13·6). Proportions of acute moderate to severe toxicity (77·4%, 95% CI 73·0-81·5 vs 81·7%, 77·5-85·3; p=0·1586) and late moderate to severe toxicity (16·5%, 95% CI 12·9-20·7 vs 20·4%, 16·4-24·8; p=0·1904) were similar between the cetuximab and cisplatin groups. INTERPRETATION: For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma. FUNDING: National Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation.

Smoking, age, nodal disease, T stage, p16 status, and risk of distant metastases in patients with squamous cell cancer of the oropharynx.

BACKGROUND: With an expectation of excellent locoregional control, ongoing efforts to de-intensify therapy for patients with human papillomavirus-associated squamous cell oropharyngeal cancer necessitate a better understanding of the metastatic risk for patients with this disease. The objective of this study was to determine what factors affect the risk of metastases in patients with squamous cell cancers of the oropharynx. METHODS: Under a shared use agreement, 547 patients from Radiation Therapy Oncology Group 0129 and 0522 with nonmetastatic oropharyngeal squamous cell cancers who had a known p16 status and smoking status were analyzed to assess the association of clinical features with the development of distant metastases. The analyzed factors included the p16 status, sex, T stage, N stage, age, and smoking history. RESULTS: A multivariate analysis of 547 patients with a median follow-up of 4.8 years revealed that an age ≥ 50 years (hazard ratio [HR], 3.28; P = .003), smoking for more than 0 pack-years (HR, 3.09; P < .001), N3 disease (HR, 2.64; P < .001), T4 disease (HR, 1.63; P = .030), and a negative p16 status (HR, 1.60; P = .044) were all factors associated with an increased risk of distant disease. CONCLUSIONS: Age, smoking, N3 disease, T4 disease, and a negative p16 status were associated with the development of distant metastases in patients with squamous cell cancers of the oropharynx treated definitively with concurrent chemoradiation.