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.

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.

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.

Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer.

BACKGROUND: Salvage radiation therapy is often necessary in men who have undergone radical prostatectomy and have evidence of prostate-cancer recurrence signaled by a persistently or recurrently elevated prostate-specific antigen (PSA) level. Whether antiandrogen therapy with radiation therapy will further improve cancer control and prolong overall survival is unknown. METHODS: In a double-blind, placebo-controlled trial conducted from 1998 through 2003, we assigned 760 eligible patients who had undergone prostatectomy with a lymphadenectomy and had disease, as assessed on pathological testing, with a tumor stage of T2 (confined to the prostate but with a positive surgical margin) or T3 (with histologic extension beyond the prostatic capsule), no nodal involvement, and a detectable PSA level of 0.2 to 4.0 ng per milliliter to undergo radiation therapy and receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary end point was the rate of overall survival. RESULTS: The median follow-up among the surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval, 0.59 to 0.99; P=0.04). The 12-year incidence of death from prostate cancer, as assessed by means of central review, was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (P<0.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (P=0.005). The incidence of late adverse events associated with radiation therapy was similar in the two groups. Gynecomastia was recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of those in the placebo group (P<0.001). CONCLUSIONS: The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo. (Funded by the National Cancer Institute and AstraZeneca; RTOG 9601 ClinicalTrials.gov number, NCT00002874 .).

Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features.

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.

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.

A randomized trial of bevacizumab for newly diagnosed glioblastoma.

BACKGROUND: Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, is currently approved for recurrent glioblastoma. Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known. METHODS: In this randomized, double-blind, placebo-controlled trial, we treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary end points, with the addition of bevacizumab. RESULTS: A total of 978 patients were registered, and 637 underwent randomization. There was no significant difference in the duration of overall survival between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; hazard ratio for death in the bevacizumab group, 1.13). Progression-free survival was longer in the bevacizumab group (10.7 months vs. 7.3 months; hazard ratio for progression or death, 0.79). There were modest increases in rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia in the bevacizumab group. Over time, an increased symptom burden, a worse quality of life, and a decline in neurocognitive function were more frequent in the bevacizumab group. CONCLUSIONS: First-line use of bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. Progression-free survival was prolonged but did not reach the prespecified improvement target. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00884741.).

Comparison of futility monitoring guidelines using completed phase III oncology trials.

BACKGROUND: Futility (inefficacy) interim monitoring is an important component in the conduct of phase III clinical trials, especially in life-threatening diseases. Desirable futility monitoring guidelines allow timely stopping if the new therapy is harmful or if it is unlikely to demonstrate to be sufficiently effective if the trial were to continue to its final analysis. There are a number of analytical approaches that are used to construct futility monitoring boundaries. The most common approaches are based on conditional power, sequential testing of the alternative hypothesis, or sequential confidence intervals. The resulting futility boundaries vary considerably with respect to the level of evidence required for recommending stopping the study. PURPOSE: We evaluate the performance of commonly used methods using event histories from completed phase III clinical trials of the Radiation Therapy Oncology Group, Cancer and Leukemia Group B, and North Central Cancer Treatment Group. METHODS: We considered published superiority phase III trials with survival endpoints initiated after 1990. There are 52 studies available for this analysis from different disease sites. Total sample size and maximum number of events (statistical information) for each study were calculated using protocol-specified effect size, type I and type II error rates. In addition to the common futility approaches, we considered a recently proposed linear inefficacy boundary approach with an early harm look followed by several lack-of-efficacy analyses. For each futility approach, interim test statistics were generated for three schedules with different analysis frequency, and early stopping was recommended if the interim result crossed a futility stopping boundary. For trials not demonstrating superiority, the impact of each rule is summarized as savings on sample size, study duration, and information time scales. RESULTS: For negative studies, our results show that the futility approaches based on testing the alternative hypothesis and repeated confidence interval rules yielded less savings (compared to the other two rules). These boundaries are too conservative, especially during the first half of the study (<50% of information). The conditional power rules are too aggressive during the second half of the study (>50% of information) and may stop a trial even when there is a clinically meaningful treatment effect. The linear inefficacy boundary with three or more interim analyses provided the best results. For positive studies, we demonstrated that none of the futility rules would have stopped the trials. CONCLUSION: The linear inefficacy boundary futility approach is attractive from statistical, clinical, and logistical standpoints in clinical trials evaluating new anti-cancer agents.

Assessing treatment benefit with competing risks not affected by the randomized treatment.

The comparison of overall survival curves between treatment arms will always be of interest in a randomized clinical trial involving a life-shortening disease. In some settings, the experimental treatment is only expected to affect the deaths caused by the disease, and the proportion of deaths caused by the disease is relatively low. In these settings, the ability to assess treatment-effect differences between Kaplan-Meier survival curves can be hampered by the large proportion of deaths in both arms that are unrelated to the disease. To address this problem, frequently displayed are cause-specific survival curves or cumulative incidence curves, which respectively censor and immortalize events (deaths) not caused by the disease. However, the differences between the experimental and control treatment arms for these curves overestimate the difference between the overall survival curves for the treatment arms and thus could result in overestimation of the benefit of the experimental treatment for the patients. To address this issue, we propose new estimators of overall survival for the treatment arms that are appropriate when the treatment does not affect the non-disease-related deaths. These new estimators give a more precise estimate of the treatment benefit, potentially enabling future patients to make a more informed decision concerning treatment choice. We also consider the case where an exponential assumption allows the simple presentation of mortality rates as the outcome measures. Applications are given for estimating overall survival in a prostate-cancer treatment randomized clinical trial, and for estimating the overall mortality rates in a prostate-cancer screening trial.

Multiple imputation methods for nonparametric inference on cumulative incidence with missing cause of failure.

We propose a nonparametric approach for cumulative incidence estimation when causes of failure are unknown or missing for some subjects. Under the missing at random assumption, we estimate the cumulative incidence function using multiple imputation methods. We develop asymptotic theory for the cumulative incidence estimators obtained from multiple imputation methods. We also discuss how to construct confidence intervals for the cumulative incidence function and perform a test for comparing the cumulative incidence functions in two samples with missing cause of failure. Through simulation studies, we show that the proposed methods perform well. The methods are illustrated with data from a randomized clinical trial in early stage breast cancer.

Bayesian approach for flexible modeling of semicompeting risks data.

Semicompeting risks data arise when two types of events, non-terminal and terminal, are observed. When the terminal event occurs first, it censors the non-terminal event, but not vice versa. To account for possible dependent censoring of the non-terminal event by the terminal event and to improve prediction of the terminal event using the non-terminal event information, it is crucial to model their association properly. Motivated by a breast cancer clinical trial data analysis, we extend the well-known illness-death models to allow flexible random effects to capture heterogeneous association structures in the data. Our extension also represents a generalization of the popular shared frailty models that usually assume that the non-terminal event does not affect the hazards of the terminal event beyond a frailty term. We propose a unified Bayesian modeling approach that can utilize existing software packages for both model fitting and individual-specific event prediction. The approach is demonstrated via both simulation studies and a breast cancer data set analysis.

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.

Risk Factors for Hospital Readmission in Patients With Interstitial Lung Disease.

BACKGROUND: Little is known about the rates, causes, or risk factors for hospital readmission among patients with interstitial lung disease (ILD). We investigated the prevalence, features, and comorbidities of subjects hospitalized with ILD and their subsequent re-hospitalizations in this retrospective study. METHODS: A retrospective analysis of subjects enrolled in the University of Chicago ILD Natural History registry was conducted. Demographic data, comorbidities, and timing and cause of subsequent hospitalizations were collected from the medical record. The primary outcome was time to first readmission via a cause-specific Cox hazards model with a sensitivity analysis with the Fine-Gray cumulative hazard model; the secondary outcome was the number of hospitalizations per subject via a Poisson multivariable model. RESULTS: Among 1,796 patients with ILD, 443 subjects were hospitalized, with 978 total hospitalizations; 535 readmissions were studied, 282 (53%) for a respiratory indication. For the outcome of time to readmission, Black race was the only subject characteristic associated with an increased hazard of readmission in the Cox model (hazard ratio 1.50, P = .03) while Black race, hypersensitivity pneumonitis, and sarcoidosis were associated with increased hazard of readmission in the Fine-Gray model. Black race, female sex, atrial fibrillation, obstructive lung disease, and pulmonary hypertension were associated with an increased number of hospitalizations in the Poisson model. CONCLUSIONS: We demonstrated that hospital readmission from any cause was a common occurrence in subjects with ILD. Further efforts to improve quality of life among these subjects could focus on risk scores for readmission, mitigating racial health disparities, and treatment of comorbidities.

Prognostic factors in post-prostatectomy salvage radiotherapy setting with and without hormonotherapy: An individual patient data analysis of randomized trials from ICECaP database.

BACKGROUND: Early salvage radiotherapy (SRT) is the standard of care for biochemical recurrence post-prostatectomy but outcomes are heterogeneous. OBJECTIVE: To develop a risk scoring system based on relevant standard-of-care clinico-pathological prognostic factors for patients treated with SRT with and without hormonal therapy (HT). DESIGN, SETTING, AND PARTICIPANTS: The Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) database included three randomized trials (Individual patients' data from 1647 subjects) assessing SRT (GETUG-AFU-16; NRG/RTOG-9601, and a subset of EORTC-22911). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were clinical progression (CP). metastasis free-survival (MFS) and overall survival (OS). Clinico-pathological factors, including pathological Gleason Score (GS), PSA at SRT start, margin status, persistent PSA post-RP and time from RP to SRT were evaluated by multivariable models stratified by type of treatment. RESULTS AND LIMITATIONS: On multivariable analysis PSA ≥ 0.5 ng/mL at SRT start, GS ≥ 8 and negative margin status were the three strongest prognostic factors. Three prognostic groups defined by number of these risk features (high risk: 2 or 3; intermediate risk: 1 and low risk: 0) were strongly associated with OS, MFS and CP outcomes with SRT alone or with HT. This prognostic group definition was also relevant for patients with persistent PSA post RP and for patients treated < 1 year from RP to SRT and with and without HT. CONCLUSION: A risk score for patients receiving SRT with or without HT, using three standard-of-care clinico-pathological risk factors provides refined prognostic information for individual patient counselling. PATIENT SUMMARY: By using a composite score of pathology grading (Gleason Score), PSA at start of salvage radiation and margin status data, physicians can provide patients with more refined information on the risk of a second relapse after receiving radiation to the prostate bed after a prostatectomy for a rising or persistent PSA, both with and without hormonal therapy.

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.

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).

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.

Race and the prognostic influence of p53 in women with breast cancer.

BACKGROUND: Prior study suggests that p53 status behaves as an independent marker of prognosis in African American (AA) women with breast cancer. We investigate whether the influence of p53 is unique to AAs or is present in other race/ethnic groups, and how this compares with known prognostic factors. METHODS: Cox regression models [hazard ratios (HRs), 95% confidence intervals (CIs)] were used to select and evaluate factors prognostic for all-cause mortality in 331 AA and 203 non-AA consecutively treated women. RESULTS: Statistically significant baseline prognostic factors were as follows. For AAs: stage [(III/I) HR 5.57; 95% CI 3.08-10.09], grade [(higher/low) HR 1.55; 95% CI 1.14-2.11], estrogen receptor (ER)/progesterone receptor (PR) status [(-/+) HR 2.01; 95% CI 1.38-2.93], triple negative (ER-, PR-, HER2-) subtype [(+/-) HR 1.95; 95% CI 1.33-2.85], and p53 status [(+/-) HR 1.69; 95% CI 1.10-2.58]. For non-AAs: stage [HR 11.93; 95% CI 2.80-50.84], grade [HR 1.61; 95% CI 0.96-2.71], and ER/PR status [HR 2.13; 95% CI 1.19-3.81]. There was a differential effect of race within p53 groups (P=0.05) and in multivariate modeling p53-positive status remained an adverse prognostic factor in AAs only [HR 1.82; 95% CI 1.04-3.17]. Compared to non-AAs, 5-year unadjusted survival was worse for AAs overall (73.4% vs. 63.6%; P=0.032), and also for AAs with p53-positive status (80.3% vs. 54.2%; P=0.016), but not for AAs with p53-negative disease (68.4% vs. 67.9%; P=0.81). CONCLUSIONS: Among women with breast cancer of different race/ethnicity, an adverse prognostic effect as a result of p53 positivity was only observed in AA women.

Integrated phase II/III clinical trials in oncology: a case study.

BACKGROUND: Integrated phase II/III trial designs implement the phase II and phase III aspects of oncology studies into a single trial. Despite a body of literature discussing the merits of integrated phase II/III clinical trial designs within the past two decades, implementation of this design has been limited in oncology studies. PURPOSE: We provide a brief discussion of the potential advantages and disadvantages of integrated phase II/III clinical trial designs in oncology and provide an example of the operating characteristics of a Radiation Therapy Oncology Group (RTOG) trial. METHODS: We review the differences among proposed integrated phase II/III designs. Then, we illustrate the use of the design in a brain tumor trial to be conducted by the RTOG and examine the impact of association between endpoints on design performance in terms of type I error, power, study duration, and expected sample size. RESULTS: Although integrated phase II/III designs should not be used in all situations, under appropriate conditions, significant gains can be achieved when using integrated phase II/III designs, including smaller sample size, time and resources savings, and shorter study duration. LIMITATIONS: Data submission without delay and sufficient evaluation of intermediate endpoints are assumed. CONCLUSIONS: Although there are potential benefits in using phase II/III designs, there also may be disadvantages. We recommend running design simulations incorporating theoretical and practical issues before implementing an integrated phase II/III design.