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Purpose: The aim was to compare quality of life (QoL) of patients with testosterone recovery (TR) to patients without TR after the completion of either 18- or 36-month androgen deprivation therapy (ADT) for prostate cancer., Methods: From a Phase III trial, we selected all 630 randomised patients with testosterone measured at baseline (during screening, before randomisation) and follow-up and who completed baseline, 6-month and, at least, one further QoL questionnaire in follow-up (EORTC 30 - PR25). We estimated means and standard deviation of items and scales for each group at each time point. We analyzed items and scales scores with general linear model with repeated measures to evaluate changes between patients with or without TR to a normal level. p-values were adjusted for multiple comparisons with Benjamini-Hochberg's false discovery rate procedure (p adj ). A p adj < 0.05 was considered significant and mean differences of 10 points or more considered clinically relevant., Results: 494 patients retained for analysis (median follow-up 16.2 years). A significantly higher number of patients (177/314 vs 79/180, p = 0.008) recovered a normal testosterone level in a significantly shorter time [median (IQR): 3.06 (2.55-3.65) vs 5.00 years (4.5-5.96), p < 0.001] in the 18- vs the 36-month cohort. Patients with TR had a significantly better QoL: 37/55 items and 14/21 scales (p adj <0.05) in the 18-month and 25/55 items and 13/21 scales in the 36-month cohort. Moreover, 9 items and one scale reached clinical relevance in the 18-month cohort and 7 items and one scale in the 36-month cohort., Conclusions: TR is associated with significant regaining in QoL. A faster and significantly higher TR is seen in the shorter ADT schedule., Competing Interests: Declarations. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Comité d’éthique de la recherche du CIUSSS de l’Estrie – CHUS since October 10, 2000. FWA #00005894, IRB #00003849. Consent to participate: Informed consent was obtained from all individual participants included in the study. Competing interests: The authors declare that none of them have any direct or indirect conflicts of interest in relation to the present publication., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Current clinical risk stratification methods for localized prostate cancer are suboptimal, leading to over- and undertreatment. Recently, machine learning approaches using digital histopathology have shown superior prognostic ability in phase III trials. This study aims to develop a clinically usable risk grouping system using multimodal artificial intelligence (MMAI) models that outperform current National Comprehensive Cancer Network (NCCN) risk groups., Materials and Methods: The cohort comprised 9,787 patients with localized prostate cancer from eight NRG Oncology randomized phase III trials, treated with radiation therapy, androgen deprivation therapy, and/or chemotherapy. Locked MMAI models, which used digital histopathology images and clinical data, were applied to each patient. Expert consensus on cut points defined low-, intermediate-, and high-risk groups on the basis of 10-year distant metastasis rates of 3% and 10%, respectively. The MMAI's reclassification and prognostic performance were compared with the three-tier NCCN risk groups., Results: The median follow-up for censored patients was 7.9 years. According to NCCN risk categories, 30.4% of patients were low-risk, 25.5% intermediate-risk, and 44.1% high-risk. The MMAI risk classification identified 43.5% of patients as low-risk, 34.6% as intermediate-risk, and 21.8% as high-risk. MMAI reclassified 1,039 (42.0%) patients initially categorized by NCCN. Despite the MMAI low-risk group being larger than the NCCN low-risk group, the 10-year metastasis risks were comparable: 1.7% (95% CI, 0.2 to 3.2) for NCCN and 3.2% (95% CI, 1.7 to 4.7) for MMAI. The overall 10-year metastasis risk for NCCN high-risk patients was 16.6%, with MMAI further stratifying this group into low-, intermediate-, and high-risk, showing metastasis rates of 3.4%, 8.2%, and 26.3%, respectively., Conclusion: The MMAI risk grouping system expands the population of men identified as having low metastatic risk and accurately pinpoints a high-risk subset with elevated metastasis rates. This approach aims to prevent both overtreatment and undertreatment in localized prostate cancer, facilitating shared decision making.

Background and Purpose: To determine the rate and time of testosterone (T) recovery in patients (pts) with localised prostate cancer treated with radiotherapy plus 0-, 6-, 18- or 36-month of androgen deprivation therapy (ADT)., Materials and Methods: In 1230 pts with prostate cancer randomised into two phase III trials, serum T was measured at baseline, then regularly. T recovery rate was compared between normal vs. abnormal baseline T and with ADT duration with Chi-square test or Fisher's exact test. A multivariable logistic regression model to predict the probability of recovering normal T was performed., Results: Overall, 87.4 % (167/191), 75.9 % (293/386), 54.8 % (181/330) and 43.2 % (80/185) of pts, recovered normal T on the 0-, 6-, 18- or 36-month schedule, respectively (p < 0.001). In patients recovering normal T, the median time to T recovery increased with ADT duration ranging from 0.31, 1.64, 3.06 to 5.0 years for the 0-, 6-, 18- or 36-month schedules, respectively (p < 0.001) and was significantly faster for those with a normal T at baseline (p < 0.001). On multivariable analysis, older age and longer ADT duration are associated with a lower T recovery., Conclusions: Testosterone recovery rate after ADT depends on several factors including hormonal duration, normal baseline T, age and medical comorbidities. A longer ADT duration is the most important variable affecting T recovery. The data from this report might be a valuable tool to help physicians and patients in evaluating risks and benefits of ADT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Previous studies indicate that the benefit of short-term androgen deprivation therapy (ADT) with radiotherapy (RT) for prostate cancer depends on competing risks., Objective: To determine whether a quantitative method to stratify patients by risk for competing events (omega score) could identify subgroups that selectively benefit from ADT., Design, Setting, and Participants: An ancillary analysis of NRG/RTOG 9408 phase 3 trial (NCT00002597) involving 1945 prostate cancer patients was conducted., Intervention: Short-term ADT., Outcome Measurements and Statistical Analysis: We applied generalised competing event regression models incorporating age, performance status, comorbidity, T category, Gleason score (GS), and prostate-specific antigen (PSA), to stratify patients according to relative hazards for primary cancer-related events (distant metastasis or prostate cancer death) versus competing noncancer mortality. We tested interactions between ADT and subgroups defined by standard risk criteria versus relative risk (RR) using the omega score., Results and Limitations: T2b, higher GS, and higher PSA were associated with an increased RR for cancer-related versus competing mortality events (a higher omega score); increased age and comorbidity were associated with a decreased omega score. Of 996 patients with low-risk/favourable intermediate-risk (FIR) disease, 286 (28.7%) had a high omega score (≥0.314). Of 768 patients with unfavourable intermediate-risk disease, 175 (22.8%) had a low omega score. The overall discordance in risk classification was 26.1%. Both standard criteria and omega score identified significant interactions for the effect of ADT on cancer-related events and late mortality in low- versus high-risk subgroups. Within the low-risk/FIR subgroup, a higher omega score identified patients in whom ADT significantly reduced cancer events and improved event-free survival. Limitations are the need for external/prospective validation and lower RT doses than contemporary standards., Conclusions: Stratification based on competing event risk is useful for identifying prostate cancer patients who selectively benefit from ADT., Patient Summary: We analysed the effectiveness of androgen deprivation therapy (ADT) for localised prostate cancer among patients, defined by the relative risk (RR) for cancer versus noncancer events. Among patients with traditional low-risk/favourable intermediate-risk disease, those with a higher RR benefitted from short-term ADT., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: CyberKnife radiosurgery (RS), as an initial first treatment, is recognized as an efficient and safe modality for trigeminal neuralgia (TN). However, knowledge on repeat CyberKnife RS in refractory cases is limited. The objective was to evaluate the clinical outcomes of repeat CyberKnife RS for TN., Methods: A retrospective review of 33 patients with refractory TN treated a second time with CyberKnife RS from 2009 to 2021. The median follow-up period after the second RS was 26.0 months (range 0.3-115.8). The median dose for the repeat RS was 60 Gy (range 60.0-70.0). Pain relief after the intervention was assessed using the Barrow Neurological Institute scale for pain (I-V). Scores I to IIIb were classified as an adequate pain relief and scores IV-V were classified as a treatment failure., Results: After the second RS, initial adequate pain relief was achieved in 87.9% of cases. The actuarial probabilities of maintaining an adequate pain relief at 6, 12, 24, and 36 months were 92.1%, 74.0%, 58.2%, and 58.2%, respectively. Regarding sustained pain relief, there was no significant difference between the first and the second RS. Sensory toxicity after the first RS was predictive of a better outcome following the second RS. The onset of hypesthesia rate was the same after the first or the second RS (21%)., Conclusion: Repeat RS is an effective and safe method for the treatment of refractory TN.

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. Fine–Gray regression and restricted mean survival times were used to assess the interaction between treatment and the predictive model and within predictive model–positive, 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.)

Purpose: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores., Methods and Materials: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 week and a day [twice a week]) or 12 fractions (4.3Gy in 2.5 weeks [5 times a week]). Secondary objectives assessed patient-reported toxicity at 5 years using the EPIC. Chi-square tests were used to assess the proportion of patients with a deterioration from baseline of >5 points for bowel, >2 points for urinary, and >11 points for sexual score., Results: The study enrolled 127 patients to 5 fractions (121 eligible) and 128 patients to 12 fractions (125 eligible). The median follow-up for all patients at the time of analysis was 5.38 years. The 5-year frequency for >5 point change in bowel score were 38.4% (P = .27) and 23.4% (P = 0.98) for 5 and 12 fractions, respectively. The 5-year frequencies for >2 point change in urinary score were 46.6% (P = .15) and 36.4% (P = .70) for 5 and 12 fractions, respectively. For 5 fractions, 49.3% (P = .007) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points; for 12 fractions, 54% (P < .001) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points. Disease-free survival at 5 years is 89.6% (95% CI: 84.0-95.2) in the 5-fraction arm and 92.3% (95% CI: 87.4-97.1) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity., Conclusions: This study confirms that, based on long-term changes in bowel and urinary domains and toxicity, the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: A recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline., Methods: In this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment., Results: The APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P < .01) and higher amyloid beta (Aβ 1-42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014)., Conclusions: Patients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To validate the association between body composition and mortality in men treated with radiation for localized prostate cancer (PCa). Secondarily, to integrate body composition as a factor to classify patients by risk of all-cause mortality., Materials and Methods: Participants of NRG/Radiation Therapy Oncology Group (RTOG) 9406 and NRG/RTOG 0126 with archived computed tomography were included. Muscle mass and muscle density were estimated by measuring the area and attenuation of the psoas muscles on a single slice at L4-L5. Bone density was estimated by measuring the attenuation of the vertebral body at mid-L5. Survival analyses, including Cox proportional hazards models, assessed the relationship between body composition and mortality. Recursive partitioning analysis (RPA) was used to create a classification tree to classify participants by risk of death., Results: Data from 2066 men were included in this study. In the final multivariable model, psoas area, comorbidity score, baseline prostate serum antigen, and age were significantly associated with survival. The RPA yielded a classification tree with four prognostic groups determined by age, comorbidity, and psoas area. Notably, the classification among older (≥70 years) men into prognostic groups was determined by psoas area., Conclusions: This study strongly supports that body composition is related to mortality in men with localized PCa. The inclusion of psoas area in the RPA classification tree suggests that body composition provides additive information to age and comorbidity status for mortality prediction, particularly among older men. More research is needed to determine the clinical impact of body composition on prognostic models in men with PCa., (© 2022 American Cancer Society.)

Importance: Long-term outcomes of radiotherapy are important in understanding the risks and benefits of therapies for patients with brain metastases., Objective: To determine how the use of postoperative whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) is associated with quality of life (QOL), cognitive function, and intracranial tumor control in long-term survivors with 1 to 4 brain metastases., Design, Setting, and Participants: This secondary analysis of a randomized phase 3 clinical trial included 48 institutions in the US and Canada. Adult patients with 1 resected brain metastases but limited to those with 1 to 4 brain metastasis were eligible. Unresected metastases were treated with SRS. Long-term survivors were defined as evaluable patients who lived longer than 1 year from randomization. Patients were recruited between July 2011 and December 2015, and data were first analyzed in February 2017. For the present study, intracranial tumor control, cognitive deterioration, QOL, and cognitive outcomes were measured in evaluable patients who were alive at 12 months from randomization and reanalyzed in June 2017., Interventions: Stereotactic radiosurgery or WBRT., Main Outcomes and Measures: Intracranial tumor control, toxic effects, cognitive deterioration, and QOL., Results: Fifty-four patients (27 SRS arm, 27 WBRT arm; female to male ratio, 65% vs 35%) were included for analysis with a median follow-up of 23.8 months. Cognitive deterioration was less frequent with SRS (37%-60%) compared with WBRT (75%-91%) at all time points. More patients declined by 2 or more standard deviations (SDs) in 1 or more cognitive tests for WBRT compared with SRS at 3, 6, and 9 months (70% vs 22%, 46% vs 19%, and 50% vs 20%, respectively). A 2 SD decline in at least 2 cognitive tests was associated with worse 12-month QOL in emotional well-being, functional well-being, general, additional concerns, and total scores. Overall QOL and functional independence favored SRS alone for categorical change at all time points. Total intracranial control for SRS alone vs WBRT at 12 months was 40.7% vs 81.5% (difference, -40.7; 95% CI, -68.1% to -13.4%), respectively. Data were first analyzed in February 2017., Conclusions and Relevance: The use of SRS alone compared with WBRT resulted in less cognitive deterioration among long-term survivors. The association of late cognitive deterioration with WBRT was clinically meaningful. A significant decline in cognition (2 SD) was associated with overall QOL. However, intracranial tumor control was improved with WBRT. This study provides detailed insight into cognitive function over time in this patient population., Trial Registration: ClinicalTrials.gov Identifier: NCT01372774; ALLIANCE/CCTG: N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group).

Purpose: Metastasis-free survival (MFS), but not event-free survival, is a validated surrogate end point for overall survival (OS) in men treated for localized prostate cancer. It remains unknown if this holds true in biochemically recurrent disease after radical prostatectomy. Leveraging NRG/RTOG 9601, we aimed to determine the performance of intermediate clinical end points (ICEs) as surrogate end points for OS in recurrent prostate cancer., Materials and Methods: NRG/RTOG 9601 randomly assigned 760 men with recurrence after prostatectomy to salvage radiation therapy with 2 years of placebo versus bicalutamide 150 mg daily. ICEs assessed were biochemical failure (BF) per NRG/RTOG 9601 (prostate-specific antigen nadir + 0.3-0.5 ng/mL or initiation of salvage hormone therapy; [BF1]) and NRG/RTOG 0534 (prostate-specific antigen nadir+2 ng/mL; [BF2]), distant metastasis (DM), and MFS (DM or death). Surrogacy was assessed by the Prentice criteria and a two-stage meta-analytic approach (condition one assessed at the patient level with Kendall's τ and condition two assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the average R 2 between treatment hazard ratios for ICE and OS)., Results: BF1, BF2, DM, and MFS satisfied the four Prentice criteria. However, with the two-condition meta-analytic approach, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF1 (τ = 0.25) or BF2 (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated ( R 2 = 0.67), but this was not true for BF1 ( R 2 = 0.09), BF2 ( R 2 = 0.12), or DM ( R 2 = 0.18) and OS., Conclusion: MFS is also a strong surrogate for OS in men receiving salvage radiation therapy for recurrence after prostatectomy. Caution should be used when inferring survival benefit from effects on BF in biochemically recurrent prostate cancer. Lack of comorbidity data did not allow us to assess whether BF in men with no/minimal comorbidity could serve as a surrogate for OS.

Prostate cancer is the most frequent cancer in men and a leading cause of cancer death. Determining a patient's optimal therapy is a challenge, where oncologists must select a therapy with the highest likelihood of success and the lowest likelihood of toxicity. International standards for prognostication rely on non-specific and semi-quantitative tools, commonly leading to over- and under-treatment. Tissue-based molecular biomarkers have attempted to address this, but most have limited validation in prospective randomized trials and expensive processing costs, posing substantial barriers to widespread adoption. There remains a significant need for accurate and scalable tools to support therapy personalization. Here we demonstrate prostate cancer therapy personalization by predicting long-term, clinically relevant outcomes using a multimodal deep learning architecture and train models using clinical data and digital histopathology from prostate biopsies. We train and validate models using five phase III randomized trials conducted across hundreds of clinical centers. Histopathological data was available for 5654 of 7764 randomized patients (71%) with a median follow-up of 11.4 years. Compared to the most common risk-stratification tool-risk groups developed by the National Cancer Center Network (NCCN)-our models have superior discriminatory performance across all endpoints, ranging from 9.2% to 14.6% relative improvement in a held-out validation set. This artificial intelligence-based tool improves prognostication over standard tools and allows oncologists to computationally predict the likeliest outcomes of specific patients to determine optimal treatment. Outfitted with digital scanners and internet access, any clinic could offer such capabilities, enabling global access to therapy personalization., (© 2022. The Author(s).)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: External beam radiation therapy (EBRT) dose escalation has been tested in multiple prospective trials. However, the impact on patient reported outcomes (PROs) associated with higher doses of EBRT remain poorly understood. We sought to assess the differences in PROs between men treated with a dose of 70.2 Gy versus 79.2 Gy of EBRT for prostate cancer., Methods and Materials: The phase 3 clinical trial RTOG 0126 randomized 1532 patients with prostate cancer between March 2002 and August 2008 to 79.2 Gy over 44 fractions versus 70.2 Gy over 39 fractions. Eligible patients participated in the PRO data collection. PROs completed included the International Index of Erectile Function Questionnaire (IIEF), Functional Alterations due to Changes in Elimination (FACE), and the Spitzer Quality of Life Index (SQLI). The timepoints for the IIEF were collected pre-entry and at 6, 12, and 24 months. The FACE and SQLI were collected pre-entry and at 3, 6, 12, 18, and 24 months. The impact of EBRT dose to normal structures (penile bulb, rectum, and bladder) on PROs was also examined. Mixed effects models were used to analyze trends across time., Results: In total, 1144 patients completed baseline IIEF forms and of these, 56%, 64%, and 61% completed the IIEF at 6, 12, and 24 months, respectively; 1123 patients completed the FACE score at baseline and 50%, 61%, 73%, 61%, and 65% completed all 15 items for the FACE metric at timepoints of 3, 6, 12, 18, and 24 months, respectively. Erectile dysfunction at 12 months based on the single question was not significantly different between arms (38.1% for the standard dose radiation therapy arm vs 49.7% for the dose escalated radiation therapy arm; P = .051). Treatment arm (70.2 vs 79.2) had no significant impact on any PRO metrics measured across all collected domains. Comprehensive dosimetric analyses are presented and reveal multiple significant differences to regional organs at risk., Conclusions: Compliance with PRO data collection was lower than anticipated in this phase 3 trial. Examining the available data, dose escalated EBRT did not appear to be associated with any detriment to PROs across numerous prospectively collected domains. These data, notwithstanding limitations, add to our understanding of the implications of EBRT dose escalation in prostate cancer. Furthermore, these results illustrate challenges associated with PRO data collection., (Published by Elsevier Inc.)

Purpose: This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX , CIC , FUBP1 , TERT , and TP53 , in NRG/RTOG 0424 using long-term follow-up data., Methods: Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics., Results: We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDH mutant/co-deleted, 28 (35%) were IDH mutant/non-co-deleted, and 26 (32.5%) were IDH wild-type. Upon single-marker MVA, both IDH mutant subgroups were associated with significantly better OS and PFS ( P values < .001), compared with the IDH wild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS ( P value < .001) and PFS ( P value = .003). In a multimarker MVA, one WHO subgroup comparison ( IDH mutant/co-deleted v IDH wild-type) was significant for OS ( P value = .045), whereas MGMT methylation did not retain significance., Conclusion: This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status., Competing Interests: Stephanie L. Pugh Research Funding: Pfizer, Millennium Glenn J. Lesser Honoraria: SDP Oncology Consulting or Advisory Role: Cancer Expert Now, Agios, Incysus Research Funding: Novocure, Oblato, Denovo Biopharma, Global Coalition for Adaptive Research Other Relationship: NCI, ASCO David R. Macdonald Research Funding: Celgene, Servier Erica H. Bell Patents, Royalties, Other Intellectual Property: US20180002762A1 Joseph P. McElroy Employment: Pfizer Cynthia D. Timmers Employment: Incyte Stock and Other Ownership Interests: Array BioPharma, Seattle Genetics, Exact Sciences, Incyte, Arbutus Biopharma, PDS Biotechnology Consulting or Advisory Role: Ventana Medical Systems C. Leland Rogers Employment: Barrow Neurological Institute, GammaWest Cancer Services Stock and Other Ownership Interests: GT Technologies Maria Werner-Wasik Stock and Other Ownership Interests: Illumina Honoraria: AstraZeneca Patents, Royalties, Other Intellectual Property: Signal transduction inhibitor in lymphoma Hsiang-Hsuan Michael Yu Honoraria: UpToDate, Elsevier, Sermo, Guidepoint Global Consulting or Advisory Role: Novocure Speakers' Bureau: BrainLAB Research Funding: Bristol Myers Squibb/Sanofi, Merck Travel, Accommodations, Expenses: BrainLAB David P. D'Souza Consulting or Advisory Role: AbbVie Nadia N. Laack Research Funding: Bristol Myers Squibb Minesh P. Mehta Leadership: Oncoceutics Stock and Other Ownership Interests: Chimerix Consulting or Advisory Role: Tocagen, Karyopharm Therapeutics, Mevion Medical Systems, ZappRx, Sapience Therapeutics Patents, Royalties, Other Intellectual Property: WARF patent 14/934,27, Topical Vasoconstritor Preparations and Methods for Protecting Cells During Cancer Chemotherapy and Radiotherapy Uncompensated Relationships: Xcision Medical Systems, ViewRay Arnab Chakravarti Research Funding: Varian Medical Systems No other potential conflicts of interest were reported. Stephanie L. Pugh Research Funding: Pfizer, Millennium Glenn J. Lesser Honoraria: SDP Oncology Consulting or Advisory Role: Cancer Expert Now, Agios, Incysus Research Funding: Novocure, Oblato, Denovo Biopharma, Global Coalition for Adaptive Research Other Relationship: NCI, ASCO David R. Macdonald Research Funding: Celgene, Servier Erica H. Bell Patents, Royalties, Other Intellectual Property: US20180002762A1 Joseph P. McElroy Employment: Pfizer Cynthia D. Timmers Employment: Incyte Stock and Other Ownership Interests: Array BioPharma, Seattle Genetics, Exact Sciences, Incyte, Arbutus Biopharma, PDS Biotechnology Consulting or Advisory Role: Ventana Medical Systems C. Leland Rogers Employment: Barrow Neurological Institute, GammaWest Cancer Services Stock and Other Ownership Interests: GT Technologies Maria Werner-Wasik Stock and Other Ownership Interests: Illumina Honoraria: AstraZeneca Patents, Royalties, Other Intellectual Property: Signal transduction inhibitor in lymphoma Hsiang-Hsuan Michael Yu Honoraria: UpToDate, Elsevier, Sermo, Guidepoint Global Consulting or Advisory Role: Novocure Speakers' Bureau: BrainLAB Research Funding: Bristol Myers Squibb/Sanofi, Merck Travel, Accommodations, Expenses: BrainLAB David P. D'Souza Consulting or Advisory Role: AbbVie Nadia N. Laack Research Funding: Bristol Myers Squibb Minesh P. Mehta Leadership: Oncoceutics Stock and Other Ownership Interests: Chimerix Consulting or Advisory Role: Tocagen, Karyopharm Therapeutics, Mevion Medical Systems, ZappRx, Sapience Therapeutics Patents, Royalties, Other Intellectual Property: WARF patent 14/934,27, Topical Vasoconstritor Preparations and Methods for Protecting Cells During Cancer Chemotherapy and Radiotherapy Uncompensated Relationships: Xcision Medical Systems, ViewRay Arnab Chakravarti Research Funding: Varian Medical Systems No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Medulloblastoma is an aggressive primary brain tumor that is extremely rare in adults; therefore, prospective studies are limited. We reviewed the information of all MB patients treated at the CHUM between 2006 and 2017. We divided our cohort by age and further divided adult patients (53%) in two groups, those diagnosed between 2006-2012 and 2013-2017. In our adult population, median follow up was 26 months and SHH-activated MB comprised 39% of tumors. Adult 5yOS was 80% and first-line therapy led to a 5yPFS of 77%. The absence of radiosensitizing chemotherapy (100% vs. 50%; p = 0.033) negatively influenced 5yPFS. 96% of adult patients received radiotherapy and 48% of them received concomitant radiosensitizing chemotherapy. Complete surgical resection was performed on 85% of adults, but the extent of resection did not have a discernable impact on survival and did not change with time. Adjuvant chemotherapy did not clearly affect prognosis (5yOS 80% vs. 67%, p = 0.155; 5yPFS 78% vs. 67%, p = 0.114). From 2006-2012, the most common chemotherapy regimen (69%) was Cisplatinum, Lomustine and Vincristine, which was replaced in 2013 by Cisplatinum, Etoposide and Cyclophosphamide (77%) with a trend for worse survival. Nine patients recurred and seven of these (78%) were treated with palliative chemotherapy. In conclusion, we did not identify prognostic demographic or tumor factors in our adult MB population. The presence of radiosensitizing chemotherapy was associated with a more favorable PFS. Cisplatinum, Lomustine and Vincristine regimen might be a better adjuvant chemotherapy regimen.

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.

Introduction: We aimed to investigate whether patients on active surveillance (AS) had worse outcomes than patients who received immediate treatment with radiotherapy and whether a Gleason grade progression on repeat biopsy influenced outcome., Methods: From our institutional database, we identified 2001 patients treated between 2005 and 2019 with primary external beam radiation therapy or brachytherapy. Biochemical recurrence (BCR) was analyzed in relation to clinical factors such as a Gleason grade progression or having multiple biopsies vs. only one biopsy. Patients on AS were identified as those who had undergone ≥2 biopsies. We used log-rank tests for univariate analysis (UVA) and Cox regression analysis for multivariable analysis (MVA)., Results: Of 2001 patients, 374 (19%) patients had ≥2 biopsies before treatment, of which 48% presented with a Gleason grade progression of mostly to Gleason 3+4 (36%); 32% had a cancer volume increase on biopsy and 16% had no significant change on biopsy. For patients with ≥2 biopsies, median time from first biopsy to treatment was 22.0 months (interquartile range [IQR] 14.7-36.1). By UVA, patients with Gleason grade progression (n=105) had a worse BCR-free rate (p=0.02) than patients who had no grade progression on repeat biopsy or only one biopsy. On MVA, this effect was lost. Having ≥2 biopsies was not a significant negative prognostic factor on UVA (p=0.2) or MVA., Conclusions: In our experience, radiotherapy after a period of AS, even with Gleason grade progression, did not lead to worse outcomes compared to patients who had radiotherapy after only one biopsy.

We investigated whether there is an association between testosterone levels and prostate cancer aggressiveness in patients treated with radiation therapy who underwent a prostatectomy or prostate radiotherapy (EBRT). A total of 380 patients who received primary or post-operative radiotherapy were identified. At the time of radiotherapy, baseline testosterone levels and body mass index (BMI) measurements were available. On multivariate analysis (MVA), higher prostate-specific antigen (PSA) levels were predictive of testosterone ≥10.4  (OR = 1.3, p = .04) and testosterone ≥12.0 nmol/L (OR = 1.3, p = .04). Patients with a Gleason score ≥8 were more likely to have testosterone <8 nmol/L than patients with a lower score (31% vs. 20%, p = .043). On univariate analysis, a Gleason score ≥8 was associated with a lower likelihood of having a normal (≥8 nmol/L) testosterone level (OR = 0.51, 95% CI: 0.3-0.9, p = .02), and on MVA adjusted for post-surgical versus primary EBRT and BMI (≥30 kg/m 2 ), the Gleason score lost its statistical significance (p = .09). While higher PSA levels are associated with higher testosterone levels, the interaction between Gleason score and testosterone is unclear and merits further study., (© 2020 Blackwell Verlag GmbH.)

Purpose: To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT)., Methods and Materials: For this single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in 2015., Results: The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%-81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6-9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively., Conclusions: The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Whole brain radiation therapy (WBRT) remains a commonly used cancer treatment, although controversy exists regarding the optimal dose/fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits., Methods and Materials: NCCTG N107C [Alliance]/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the dose/fractionation that would be used for all patients treated at that site (either 30 Gy in 10 fractions or 37.5 Gy in 15 fractions). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher's exact tests., Results: Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fractions (53%), and 43 were treated with 37.5 Gy in 15 fractions (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology was more frequent with protracted WBRT: 72% vs 45%, P = .01), and 93% of patients completed the full course of WBRT. A more protracted WBRT dose regimen (37.5 Gy in 15 fractions) did not significantly affect time to cognitive failure (hazard ratio [HR], 0.9; 95% confidence interval [CI], 0.6-1.39; P = .66), surgical bed control (HR, 0.52 [95% CI, 0.22-1.25], P = .14), intracranial tumor control (HR, 0.56 [95% CI, 0.28-1.12], P = .09), or overall survival (HR, 0.72 [95% CI, 0.45-1.16], P = .18). Although there was no reported radionecrosis, there is a statistically significant increase in the risk of at least 1 grade ≥3 adverse event with 37.5 Gy in 15 fractions versus 30 Gy in 10 fractions (54% vs 31%, respectively, P = .03)., Conclusions: This post hoc analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with the lengthened course of WBRT. For patients with brain metastases where WBRT is recommended, shorter course hypofractionated regimens remain the current standard of care., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The progress of women in academic medicine appears to be curtailed. We evaluated gender differences in academia for residents in radiation oncology compared with 2 of its related specialties, radiology and medical oncology, across Canada., Methods and Materials: We analyzed abstracts presented between 2013 and 2016 at the annual meetings of the Canadian Association of Radiation Oncologists and compared it to the corresponding data for the meetings of the Canadian Association of Radiologists and Canadian Association of Medical Oncology. We further evaluated gender composition of abstracts, presentations, and publications available on PubMed. Conversion rates according to gender and to medical specialties were assessed. Proportions were compared using Fisher exact test or the chi-squared test., Results: Among the 198 presented abstracts, 103 (52%) were published. Radiation oncology had the highest publishing rate with 90% (oncology 56%, radiology 40%). The publication rate between the medical specialties was significantly different ( P < .001).Fifty-seven percent of abstracts presented by women were published versus 48% of abstracts presented by men. Overall, there was no significant difference between genders in terms of subsequent conversions into a scientific publication within each specialty ( P = .25-1.0).In radiation oncology, women presented 67% of abstracts and published 95% of their presented abstracts, and in medical oncology, 66% of abstracts were from women and 57% of the presented abstracts were published. Among the published abstracts, 83% had the same first author in the abstract and the publication. Among those who lost their first-authorship status, 59% were women. However, there was no statistically significant difference between specialties for loss of first-author status., Conclusions: We observed that from 2013 to 2016, women had the highest presentation and publication rate in radiation oncology. More prospective data are needed to monitor the progress of women in all specialties and their specific needs., (© 2019 The Author(s).)

Importance: The initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial-evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes-was not previously reported., Objective: To examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes., Design, Setting, and Participants: Specimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses., Main Outcomes and Measures: Progression-free survival (PFS) and overall survival (OS)., Results: Of all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1%) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0%] male): 57 (76.0%) methylated and 18 (24.0%) unmethylated. A total of 13 unmethylated patients (72.2%) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4%) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95% CI, 1.64-7.56; P < .001) and PFS (HR, 3.06; 95% CI, 1.55-6.04; P < .001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95% CI, 1.02-7.14; P = .045) and PFS (HR, 2.74; 95% CI, 1.19-6.33; P = .02)., Conclusions and Relevance: In this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status., Trial Registration: ClinicalTrials.gov Identifier: NCT00114140.

Introduction: Conflicting data exists on the influence of metformin on prostate cancer. We investigated the importance of metformin in patients treated with radiotherapy or brachytherapy., Materials and Methods: All patients from a large institutionalized database, treated for primary localized prostate cancer with either brachytherapy or external-beam radiotherapy ± androgen deprivation therapy were identified. Groups were compared by Kaplan-Meier analyses and Cox regression models. Multivariate analysis was adjusted for CAPRA-Score, type of treatment and age., Results: A total of 2441 patients with complete data was identified. Among the 382 patients (16% of total) were diabetic. Two-hundred and eighty-one of the 382 diabetics (74%) were treated with metformin and 101 were treated with other anti-diabetic medication. Median follow up was 48 months (interquartile range [IQR] 24-84). Two-hundred eighteen patients (9%) died and 150 (6%) experienced biochemical recurrence (BCR). On unadjusted univariate analysis for BCR-free survival, metformin users showed a 50% reduction in BCR compared to non-metformin users. The results remained significant on multivariate analysis comparing diabetic metformin users to non-metformin users (diabetics and non-diabetics combined) (hazard ratio [HR] 0.5-0.6, p = 0.03-0.04) but lost its significance when adjusting for cancer aggressiveness. On multivariate analysis, diabetics had worse overall survival (OS) than non-diabetics (HR 1.5, 95% confidence interval [CI] 1.08-2.06, p = 0.01), but diabetics on metformin fared better than diabetics not taking metformin (HR 0.5, 95% CI 0.26-0.86, p = 0.01)., Conclusion: Metformin use in this analysis appears to be associated with better BCR and OS. Larger datasets and prospective trials are warranted to validate these results.

Purpose: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores., Methods and Materials: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 weeks) or 12 fractions (4.3 Gy in 2.5 weeks). The co-primary endpoints were the proportion of patients with a change in EPIC-50 bowel score at 1 year (baseline to 1 year) >5 points and in EPIC-50 urinary score >2 points tested with a 1-sample binomial test., Results: The study enrolled 127 patients to 5 fractions (121 analyzed) and 128 patients to 12 fractions (125 analyzed). Median follow-up for all patients at the time of analysis was 3.8 years. The 1-year frequency for >5 point change in bowel score were 29.8% (P < .001) and 28.4% (P < .001) for 5 and 12 fractions, respectively. The 1-year frequencies for >2 point change in urinary score were 45.7% (P < .001) and 42.2% (P < .001) for 5 and 12 fractions, respectively. For 5 fractions, 32.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥11 points (P = .34); for 12 fractions, 30.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥ 11 points (P = .20). Disease-free survival at 2 years is 99.2% (95% confidence interval: 97.5-100) in the 5-fraction arm and 97.5% (95% confidence interval: 94.6-100) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity., Conclusions: This study confirms that, based on changes in bowel and urinary domains and toxicity (acute and late), the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for patients with localized high-risk prostate cancer (HRPC). However, the optimal duration of ADT is not yet defined., Objective: The aim of this superiority randomized trial was to compare outcomes of RT combined with either 36 or 18 mo of ADT., Design, Setting and Participants: From October 2000 to January 2008, 630 patients with HRPC were randomized, 310 to pelvic and prostate RT combined with 36 mo (long arm) and 320 to the same RT with 18 mo (short arm) of ADT., Outcome Measurements and Statistical Analysis: Overall survival (OS) and quality of life (QoL) were primary end points. OS rates were compared with Cox Regression model and QoL data were analyzed through mixed linear model., Results and Limitations: With a median follow-up of 9.4 yr, 290 patients had died (147 long arm vs 143 short arm). The 5-yr OS rates (95% confidence interval) were 91% for long arm (88-95%) and 86% for short arm (83-90%), p=0.07. QoL analysis showed a significant difference (p<0.001) in six scales and 13 items favoring 18 mo ADT with two of them presenting a clinically relevant difference in mean scores of ≥10 points., Conclusions: In localized HRPC, our results support that 36 mo is not superior to 18 mo of ADT. ADT combined with RT can potentially be reduced to 18 mo in selected men without compromising survival or QoL. Thus, 18 mo of ADT appears to represent a valid option in HRPC., Patient Summary: In this study, we report outcomes from high-risk prostate cancer patients treated with radiotherapy and either 36 or 18 mo of androgen deprivation therapy. There was no difference in survival between the two groups, with the 18-mo group experiencing a better quality of life., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: A prostate-specific antigen (PSA) nadir <0.2 ng/mL is generally considered as tissue ablative and at low risk for recurrence. After attaining such a low PSA nadir, we analyzed risk factors for recurrence., Methods and Materials: We identified patients from our institutionalized database with either D'Amico low- or intermediate-risk prostate cancer that was treated with either low-dose-rate prostate brachytherapy or external beam radiotherapy as monotherapy. We compared patients who attained a nadir <0.2 ng/mL and subsequently developed biochemical failure to patients who did not experience biochemical failure by using χ 2 test and Student t test. Survival analysis was performed using the Kaplan-Meier method (log-rank test)., Results: Of 892 patients, 560 (63%) achieved a nadir <0.2 ng/mL. Only 23 (4.1%) later developed a biochemical recurrence. The 7-year Kaplan-Meier biochemical recurrence-free survival after a PSA nadir of <0.2 ng/mL was 96%. Patients who later experienced biochemical recurrence were more likely to have Cancer of the Prostate Risk Assessment Score intermediate- or high-risk cancer: (74% vs. 40%, p < 0.001). Patients were more likely to have a diagnostic PSA >6.0 ng/mL: (66% vs. 43% p < 0.001) and have a Gleason score ≥ 3  + 4: (52% vs. 34%, p = 0.005). They were also more likely to be older (p = 0.003): mean (SD) 70.3 (6.4) vs. 66.2 (6.5) and have a time to PSA nadir that was significantly shorter (p = 0.013): mean (SD) 51.8 (29.6) vs. 65.2 (25.1)., Conclusions: Biochemical recurrence after attaining a PSA nadir <0.2 ng/mL is rare and more frequent in patients with intermediate risk cancer and older patients. These patients can benefit from a prolonged followup with specialized physicians., (Copyright © 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Importance: Optimizing radiation therapy techniques for localized prostate cancer can affect patient outcomes. Dose escalation improves biochemical control, but no prior trials were powered to detect overall survival (OS) differences., Objective: To determine whether radiation dose escalation to 79.2 Gy compared with 70.2 Gy would improve OS and other outcomes in prostate cancer., Design, Setting, and Participants: The NRG Oncology/RTOG 0126 randomized clinical trial randomized 1532 patients from 104 North American Radiation Therapy Oncology Group institutions March 2002 through August 2008. Men with stage cT1b to T2b, Gleason score 2 to 6, and prostate-specific antigen (PSA) level of 10 or greater and less than 20 or Gleason score of 7 and PSA less than 15 received 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions., Main Outcomes and Measures: Time to OS measured from randomization to death due to any cause. American Society for Therapeutic Radiology and Oncology (ASTRO)/Phoenix definitions were used for biochemical failure. Acute (≤90 days of treatment start) and late radiation therapy toxic effects (>90 days) were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0, and the RTOG/European Organisation for the Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme, respectively., Results: With a median follow-up of 8.4 (range, 0.02-13.0) years in 1499 patients (median [range] age, 71 [33-87] years; 70% had PSA <10 ng/mL, 84% Gleason score of 7, 57% T1 disease), there was no difference in OS between the 751 men in the 79.2-Gy arm and the 748 men in the 70.2-Gy arm. The 8-year rates of OS were 76% with 79.2 Gy and 75% with 70.2 Gy (hazard ratio [HR], 1.00; 95% CI, 0.83-1.20; P = .98). The 8-year cumulative rates of distant metastases were 4% for the 79.2-Gy arm and 6% for the 70.2-Gy arm (HR, 0.65; 95% CI, 0.42-1.01; P = .05). The ASTRO and Phoenix biochemical failure rates at 5 and 8 years were 31% and 20% with 79.2 Gy and 47% and 35% with 70.2 Gy, respectively (both P < .001; ASTRO: HR, 0.59; 95% CI, 0.50-0.70; Phoenix: HR, 0.54; 95% CI, 0.44-0.65). The high-dose arm had a lower rate of salvage therapy use. The 5-year rates of late grade 2 or greater gastrointestinal and/or genitourinary toxic effects were 21% and 12% with 79.2 Gy and 15% and 7% with 70.2 Gy (P = .006 [HR, 1.39; 95% CI, 1.10-1.77] and P = .003 [HR, 1.59; 95% CI, 1.17-2.16], respectively)., Conclusions and Relevance: Despite improvements in biochemical failure and distant metastases, dose escalation did not improve OS. High doses caused more late toxic effects but lower rates of salvage therapy., Trial Registration: clinicaltrials.gov Identifier: NCT00033631.

Purpose: The aim of this study was to compare early prostate-specific antigen (PSA) decline patterns and PSA nadirs between low-dose-rate seed prostate brachytherapy (LDR-PB) and different fractionations of external beam radiotherapy (EBRT) and their predictive importance for biochemical failure (bF)., Methods and Materials: Patients with D'Amico low- or intermediate-risk prostate cancer who underwent a single-modality treatment without androgen deprivation were included in this study. Three different treatment groups were compared: (1) normofractionation EBRT up to 70.2-79.2 Gy/1.8-2.0 Gy, (2) LDR-PB, and (3) EBRT with hypofractionation 60 Gy/3 Gy daily or 5-7.25 Gy once a week over 9-5 weeks, to a total dose of 45-36.25 Gy, respectively. The log-rank test, Cox regression analysis, and nonparametric tests were used., Results: We analyzed 892 patients: the median followup for patients without bF was 84 months (interquartile range 60-102 months), with 12% of patients experiencing bF. The PSA decline within the first 15 months was generally exponential. LDR-PB showed a faster early exponential decline compared with EBRT treatments, but whether decline was fast or slow had no influence on recurrence. The only factors that were positive predictive factors in univariate and multivariate analyses were the time to nadir >48 months (median), PSA nadir <0.5 ng/mL, and <0.2 ng/mL (all p < 0.001)., Conclusions: Although there are significant differences in early exponential PSA decline between different treatments, only the PSA nadir and longer time to nadir were predictive factors for bF., (Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background: Procarbazine, lomustine, and vincristine (pcv) significantly improve survival outcomes in lgg (low-grade gliomas). Administration of pcv to lgg patients increased tremendously over the past years as it went from 2 patients per year between 2005 and 2012 to 23 patients in 2015 only in our centre. However, serious hematological and non-hematological adverse events may occur. The purpose of this study was to evaluate the toxicity of pcv and its clinical relevance in our practice., Methods: We retrospectively reviewed the charts of 57 patients with lgg who received pcv at the Centre hospitalier de l'Université de Montréal between 1 January 2005 and 27 July 2016., Results: Procarbazine, lomustine, and vincristine were associated with severe hematological toxicity as clinically significant grade 3 anemia, neutropenia, and thrombocytopenia occurred in 7%, 10%, and 28% of patients, respectively. Other frequent adverse events such as the increase of liver enzymes, cutaneous rash, neurotoxicity, and vomiting occurred in 65%, 26%, 60%, and 40% of patients, respectively. Patients with prophylactic trimethoprim/sulfamethoxazole had more grade 3 hematological toxicity with pcv, especially anemia ( p = 0.040) and thrombocytopenia ( p = 0.003) but we found no increase in pcv toxicity in patients on concurrent anticonvulsants. Patients with grade 3 neutropenia had a significantly lower survival (median survival 44.0 months vs. 114.0 months, p = 0.001). Patients who were given pcv at diagnosis had more grade 3 anemia than those who received it at subsequent lines of treatment ( p = 0.042)., Conclusion: Procarbazine, lomustine, and vincristine increase survival in lgg but were also associated with major hematologic, hepatic, neurologic, and cutaneous toxicity. Anti- Pneumocystis jiroveci pneumonia (pjp) prophylaxis, but not anticonvulsants, enhances hematologic toxicity.

Objective: To investigate the impact of 5‑alpha-reductase inhibitor (5-ARI) use on radiotherapy outcomes for localized prostate cancer., Patients and Methods: We included 203 patients on a 5-ARI from our institutional database comprising over 2500 patients who had been treated with either external beam radiotherapy (EBRT) or brachytherapy for localized prostate cancer. Patients received a 5-ARI for urinary symptoms or active surveillance. Cancer progressions at the time of definitive treatment were analyzed according to the following criteria: (a) progression of Gleason score or increase in cancer volume on biopsy, (b) first biopsy positive for cancer after being treated for urinary symptoms with a 5-ARI, and (c) prostate-specific antigen (PSA) progression with or without a previous cancer diagnosis. Biochemical failure (BF) was defined by the Phoenix definition. Log-rank test was used for survival analysis., Results: At a median follow-up of 38.2 months (standard deviation 22.2 months), 10 (4.9%) patients experienced BF. Concerning prostate cancer progression criteria, 52% of men demonstrated none, 37% showed only one criterion, and 11% showed two. Using univariate analysis, PSA progression (p = 0.004) and appearance of a positive biopsy (p < 0.001) were significant predictive factors for BF, while Gleason progression (p = 0.3) was not. In multivariate analysis adjusted for cancer aggressiveness, rising PSA (hazard ratio, HR, 5.7; 95% confidence interval, CI, 1.1-28.8; p = 0.04) and the number of cancer progression factors (HR 2.9, 95% CI 1.2-7.0, p = 0.02) remained adverse risk factors., Conclusion: PSA progression experienced during 5‑ARI treatment before radiotherapy is predictive of worse biochemical outcome. Such details should be considered when counseling men prior to radiation therapy.

Background: It has been shown that neutrophil count or an elevated neutrophil-to-lymphocyte ratio (NLR) as well as testosterone levels are separately associated with increased mortality in patients with localized prostate cancer., Objective: We tested a combination of testosterone levels and white blood cell (WBC) counts to predict overall survival (OS) in a prospective cohort of patients treated with radiotherapy for localized prostate cancer., Patients and Methods: The 381 patients included in this study were prospectively enrolled in phase 2 or 3 studies. Multivariate Cox proportional hazards models were used to analyze the influence of WBC count and testosterone level on biochemical recurrence and OS. Cutoff levels of ≤10.4 nmol/L (300 ng/dL) for testosterone and a median value of 6.2 (×10 9 /L) for WBC count were used., Results: The median follow-up for biochemical recurrence and OS were 72 and 78 months, respectively. A WBC count of ≥6.2 alone was not associated with OS (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.30-1.46). When combined with a testosterone level of >10.3 nmol/L, a WBC count of ≥6.2 was associated with increased mortality (HR 2.96; 95% CI 1.45-6.06) when compared with a WBC count of <6.2 (p-interaction = 0.01). The HR for biochemical recurrence for patients with a testosterone level >10.3 nmol/L combined with a lymphocyte level above or equal to the median was nearly identical to the HR of a testosterone level >10.3 nmol/L with a WBC above or equal to the median. There was no association between testosterone level and the NLR., Conclusions: A high WBC and lymphocyte count combined with normal testosterone levels increases the overall mortality of patients treated with radiotherapy for localized prostate cancer within the first 6-7 years post-treatment. Validation in larger cohorts is necessary.

Objectives: We reviewed testosterone changes for patients who were treated with radiation therapy (RT) alone on NRG oncology RTOG 9408., Methods and Materials: Patients (T1b-T2b, prostate-specific antigen <20 ng/mL) were randomized between RT alone and RT plus 4 months of androgen ablation. Serum testosterone (ST) levels were investigated at enrollment, RT completion, and the first follow-up 3 months after RT. The Wilcoxon signed rank test was used to compare pre- and post-treatment ST levels in patients who were randomized to the RT-alone arm., Results: Of 2028 patients enrolled, 992 patients were randomized to receive RT alone and 917 (92.4%) had baseline ST values available and completed RT. Of these 917 patients, immediate and 3-month post-RT testosterone levels were available for 447 and 373 patients, respectively. Excluding 2 patients who received hormonal therapy off protocol after RT, 447 and 371 patients, respectively, were analyzed. For all patients, the median change in ST values at completion of RT and at 3-month follow-up were -30.0 ng/dL (p5-p95; -270.0 to 162.0; P  < .001) and -34.0 ng/dL (p5-p95, -228.0 to 160.0; P  < .01), respectively., Conclusion: RT for prostate cancer was associated with a median 9.2% decline in ST at completion of RT and a median 9.3% decline 3 months after RT. These changes were statistically significant.

Background: Whole brain radiotherapy (WBRT) is the standard of care to improve intracranial control following resection of brain metastasis. However, stereotactic radiosurgery (SRS) to the surgical cavity is widely used in an attempt to reduce cognitive toxicity, despite the absence of high-level comparative data substantiating efficacy in the postoperative setting. We aimed to establish the effect of SRS on survival and cognitive outcomes compared with WBRT in patients with resected brain metastasis., Methods: In this randomised, controlled, phase 3 trial, adult patients (aged 18 years or older) from 48 institutions in the USA and Canada with one resected brain metastasis and a resection cavity less than 5·0 cm in maximal extent were randomly assigned (1:1) to either postoperative SRS (12-20 Gy single fraction with dose determined by surgical cavity volume) or WBRT (30 Gy in ten daily fractions or 37·5 Gy in 15 daily fractions of 2·5 Gy; fractionation schedule predetermined for all patients at treating centre). We randomised patients using a dynamic allocation strategy with stratification factors of age, duration of extracranial disease control, number of brain metastases, histology, maximal resection cavity diameter, and treatment centre. Patients and investigators were not masked to treatment allocation. The co-primary endpoints were cognitive-deterioration-free survival and overall survival, and analyses were done by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT01372774., Findings: Between Nov 10, 2011, and Nov 16, 2015, 194 patients were enrolled and randomly assigned to SRS (98 patients) or WBRT (96 patients). Median follow-up was 11·1 months (IQR 5·1-18·0). Cognitive-deterioration-free survival was longer in patients assigned to SRS (median 3·7 months [95% CI 3·45-5·06], 93 events) than in patients assigned to WBRT (median 3·0 months [2·86-3·25], 93 events; hazard ratio [HR] 0·47 [95% CI 0·35-0·63]; p<0·0001), and cognitive deterioration at 6 months was less frequent in patients who received SRS than those who received WBRT (28 [52%] of 54 evaluable patients assigned to SRS vs 41 [85%] of 48 evaluable patients assigned to WBRT; difference -33·6% [95% CI -45·3 to -21·8], p<0·00031). Median overall survival was 12·2 months (95% CI 9·7-16·0, 69 deaths) for SRS and 11·6 months (9·9-18·0, 67 deaths) for WBRT (HR 1·07 [95% CI 0·76-1·50]; p=0·70). The most common grade 3 or 4 adverse events reported with a relative frequency greater than 4% were hearing impairment (three [3%] of 93 patients in the SRS group vs eight [9%] of 92 patients in the WBRT group) and cognitive disturbance (three [3%] vs five [5%]). There were no treatment-related deaths., Interpretation: Decline in cognitive function was more frequent with WBRT than with SRS and there was no difference in overall survival between the treatment groups. After resection of a brain metastasis, SRS radiosurgery should be considered one of the standards of care as a less toxic alternative to WBRT for this patient population., Funding: National Cancer Institute., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Previous studies have examined testosterone levels after external beam radiation (EBRT) monotherapy, but since 2002 only sparse contemporary data have been reported., Aim: To examine testosterone kinetics in a large series of contemporary patients after EBRT., Methods: The study was conducted in 425 patients who underwent definitive EBRT for localized prostate cancer from 2002 through 2014. Patients were enrolled in several phase II and III trials. Exclusion criteria were neoadjuvant or adjuvant androgen-deprivation therapy or missing data. Testosterone was recorded at baseline and then according to each study protocol (not mandatory in all protocols). Statistical analyses consisted of means and proportions, Kaplan-Meier plots, and logistic and Cox regression analyses., Outcomes: Testosterone kinetics after EBRT monotherapy and their influence on biochemical recurrence., Results: Median follow-up of 248 assessable patients was 72 months. One hundred eighty-six patients (75.0%) showed a decrease in testosterone. Median time to first decrease was 6.4 months. Median percentage of decrease to the nadir was 30% and 112 (45.2%) developed biochemical hypogonadism (serum testosterone < 8 nmol/L). Of all patients with testosterone decrease, 117 (62.9%) recovered to at least 90% of baseline levels. Advanced age, increased body mass index, higher baseline testosterone level, and lower nadir level were associated with a lower chance of testosterone recovery. Subgroup analyses of 166 patients treated with intensity-modulated radiotherapy confirmed the results recorded for the entire cohort. In survival analyses, neither testosterone decrease nor recovery was predictive for biochemical recurrence., Clinical Implications: EBRT monotherapy influences testosterone kinetics, and although most patients will recover, approximately 45% will have biochemical hypogonadism., Strengths and Limitations: We report on the largest contemporary series of patients treated with EBRT monotherapy in whom testosterone kinetics were ascertained. Limitations are that testosterone follow-up was not uniform and the study lacked information on health-related quality-of-life data., Conclusion: Our findings indicate that up to 75% of patients will have a profound testosterone decrease, with up to a 40% increase in rates of biochemical hypogonadism, although the latter events will leave biochemical recurrence unaffected. Pompe RS, Karakrewicz PI, Zaffuto E, et al. External Beam Radiotherapy Affects Serum Testosterone in Patients With Localized Prostate Cancer. J Sex Med 2017;14:876-882., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose Men with localized prostate cancer often are treated with external radiotherapy (RT) over 8 to 9 weeks. Hypofractionated RT is given over a shorter time with larger doses per treatment than standard RT. We hypothesized that hypofractionation versus conventional fractionation is similar in efficacy without increased toxicity. Patients and Methods We conducted a multicenter randomized noninferiority trial in intermediate-risk prostate cancer (T1 to 2a, Gleason score ≤ 6, and prostate-specific antigen [PSA] 10.1 to 20 ng/mL; T2b to 2c, Gleason ≤ 6, and PSA ≤ 20 ng/mL; or T1 to 2, Gleason = 7, and PSA ≤ 20 ng/mL). Patients were allocated to conventional RT of 78 Gy in 39 fractions over 8 weeks or to hypofractionated RT of 60 Gy in 20 fractions over 4 weeks. Androgen deprivation was not permitted with therapy. The primary outcome was biochemical-clinical failure (BCF) defined by any of the following: PSA failure (nadir + 2), hormonal intervention, clinical local or distant failure, or death as a result of prostate cancer. The noninferiority margin was 7.5% (hazard ratio, < 1.32). Results Median follow-up was 6.0 years. One hundred nine of 608 patients in the hypofractionated arm versus 117 of 598 in the standard arm experienced BCF. Most of the events were PSA failures. The 5-year BCF disease-free survival was 85% in both arms (hazard ratio [short v standard], 0.96; 90% CI, 0.77 to 1.2). Ten deaths as a result of prostate cancer occurred in the short arm and 12 in the standard arm. No significant differences were detected between arms for grade ≥ 3 late genitourinary and GI toxicity. Conclusion The hypofractionated RT regimen used in this trial was not inferior to conventional RT and was not associated with increased late toxicity. Hypofractionated RT is more convenient for patients and should be considered for intermediate-risk prostate cancer.

Introduction: We tested different classification systems in order to separate intermediate-risk prostate cancers into prognostic groups. We then examined which groups were most suited for either prostate seed brachytherapy (PB) or external beam radiotherapy (EBRT)., Materials and Methods: We selected patients with D'Amico intermediate-risk prostate cancer who were treated exclusively with either PB or EBRT. Patients were excluded if they had received androgen deprivation therapy in combination with EBRT or a follow up of < 30 months without recurrence. The Kaplan-Meier method was used to compare groups., Results: Our sample consisted of 475 patients treated from July 2002-September 2013. Median follow up for patients without biochemical failure (BF) was 56 months (interquartile range 44-78); 222 patients (47%) were treated with PB exclusively (D90 interquartile range 145-176 Gy) and 253 (53%) with EBRT exclusively (dose interquartile range 76-80 Gy). The rate of BF was significantly lower in patients treated with PB (5.4%) than in patients treated with EBRT (14.2%) (p = 0.036, log-rank test). Upon univariate analysis, significant predictors of BF included the number of unfavorable intermediate-risk factors (0, 1, 2, 3) (p = 0.024) as well as the Cancer of the Prostate Risk Assessment (CAPRA) score (p = 0.002). After adjusting for the type of treatment, only the CAPRA score remained predictive (p = 0.025). For patients with a CAPRA score of 0-2, those with PB fared better than those treated with EBRT (p = 0.042). This difference disappeared in patients with a CAPRA score of 3-5 (p = 0.5)., Conclusions: Using our current selection criteria for monotherapy, we found that PB or EBRT as monotherapy are equally effective treatment options for intermediate-risk prostate cancer.

Background: The NRG Oncology RTOG 9402 trial showed significant survival benefit in patients with 1p/19q co-deleted anaplastic oligodendrogliomas (AO) who received both radiation (RT) and chemotherapy (PCV regimen) versus RT alone. Substantial separation of the survival curves was only seen after 7.3 years. We aimed to determine whether there are specific genetic alterations that distinguish co-deleted AO patients who benefit from the addition of PCV from those who do not., Methods: We performed whole exome sequencing on matched tumor and normal DNA from all available short-term (STS) and long-term survivors (LTS) who received RT+PCV. hTERT status and rs55705857 genotypes (G-allele) were analyzed in both cohorts., Results: Six STS (survival of <7.3y) and 7 LTS (survival of ≥7.3y and no progression) had sufficient material for analysis. There was no significant difference between the groups regarding age, performance status and extent of resection. On average, STS had 7 and LTS 4 mutations. Most common mutations in STS vs. LTS were: IDH1 (67 vs. 86%), CIC (50 vs. 71%) and FUBP1 (17 vs. 71%). The hTERT promoter was mutated in 83% STS and 86% LTS. Genotyping of rs55705857 showed a higher prevalence of G allele carriers in LTS than STS (43 vs. 17%)., Conclusions: These findings confirm that IDH, CIC, FUBP1 mutations and rs55705857 genotype are common in AO. No distinct genetic signature was identified to differentiate STS and LTS.

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 .).

Background: The primary objective of this study was to compare the overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU). Secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome., Methods: Eligible patients with centrally reviewed, histologically confirmed, newly diagnosed AA were randomized to receive either RT+TMZ (n = 97) or RT+NU (n = 99). The study closed early because the target accrual rate was not met., Results: Median follow-up time for patients still alive was 10.1 years (1.9-12.6 y); 66% of the patients died. Median survival time was 3.9 years in the RT/TMZ arm (95% CI, 3.0-7.0) and 3.8 years in the RT/NU arm (95% CI, 2.2-7.0), corresponding to a hazard ratio (HR) of 0.94 (P = .36; 95% CI, 0.67-1.32). The differences in progression-free survival (PFS) and TTP between the 2 arms were not statistically significant. Patients in the RT+NU arm experienced more grade ≥3 toxicity (75.8% vs 47.9%, P < .001), mainly related to myelosuppression. Of the 196 patients, 111 were tested for IDH1-R132H status (60 RT+TMZ and 51 RT+NU). Fifty-four patients were IDH negative and 49 were IDH positive with a better OS in IDH-positive patients (median survival time 7.9 vs 2.8 y; P = .004, HR = 0.50; 95% CI, 0.31-0.81)., Conclusions: RT+TMZ did not appear to significantly improve OS or TTP for AA compared with RT+ NU. RT+TMZ was better tolerated. IDH1-R132H mutation was associated with longer survival., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Introduction: To estimate the contribution of the prostate gland and prostatic urethral inflammation to urinary symptoms after radiation therapy for prostate cancer, we performed a secondary analysis of urinary toxicity after primary radiation to an intact prostate vs. postprostatectomy radiation to the prostatic fossa in protocols RTOG 94-08 and 96-01, respectively., Materials and Methods: Patients randomized to the radiation-alone arms (without hormone therapy) of the 2 trials were evaluated, including 104 men receiving primary prostate radiation to 68.4Gy on RTOG 94-08 and 371 men receiving 64.8Gy to the prostatic fossa on RTOG 96-01. Acute and late urinary toxicity were scored prospectively by RTOG scales. Chi-square test/logistic regression and cumulative incidence approach/Fine-Gray regression model were used for analyses of acute and late toxicity, respectively., Results: Grade≥2 acute urinary toxicity was significantly higher after primary prostatic radiation compared with postprostatectomy radiation (30.8% vs. 14.0%; P<0.001), but acute grade≥3 toxicity did not differ (3.8% vs. 2.7%; P = 0.54). After adjusting for age, primary radiation resulted in significantly higher grade≥2 acute urinary toxicity (odds ratio = 3.72; 95% CI: 1.65-8.37; P = 0.02). With median follow-up of 7.1 years, late urinary toxicity was not significantly different with primary vs. postprostatectomy radiation (5-year grade≥2: 16.7% vs. 18.3%; P = 0.65; grade≥3: 6.0% vs. 3.3%; P = 0.24)., Conclusions: Primary radiation to an intact prostate resulted in higher grade≥2 acute urinary toxicity than radiation to the prostatic fossa, with no difference in late urinary toxicity. Thus, a proportion of acute urinary toxicity in men with an intact prostate may be attributable to inflammation of the prostatic gland or urethra., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: To report the long-term toxicities and sexual quality of life of a once-weekly hypofractionated radiation therapy schedule for low-risk prostate cancer., Materials and Methods: A multi-institutional phase II trial was conducted, using a three-dimensional conformal radiation therapy (3D-CRT) approach for low-risk prostate cancer (T1a-T2a, Gleason ≤ 6 and prostate-specific antigen ≤ 10 ng/ml). Forty-five Gray (Gy) were delivered in nine fractions of 5 Gy given on a weekly basis. Acute and late genitourinary and gastrointestinal toxicities were graded according to the Radiation Therapy Oncology Group toxicity scale. Sexual function and sexual bother were assessed with the Expanded Prostate Cancer Index Composite (EPIC) questionnaire., Results: Between March 2006 and August 2008, 80 patients were treated, with a median age of 69 years (interquartile range 64-72). The median follow-up was 83 months (interquartile range 73-85 months). At 7 years, overall survival was 88%. No patients died of prostate cancer. Cumulative grade ≥2 genitourinary and gastrointestinal late toxicity was reported for 31.3% and 30% of our patients, respectively. Cumulative grade ≥3 genitourinary and gastrointestinal late toxicity was seen in 3.8% and 12.5% of cases, respectively. Late genitourinary grade 2 toxicity was correlated with the occurrence of acute genitourinary grade 2 toxicity (P = 0.006). The occurrence of late gastrointestinal toxicity was not correlated with acute gastrointestinal toxicity. Pre-treatment EPIC sexual function was low (37.5%) and the mean EPIC sexual function score at 7 years after treatment was 14%. On the other hand, pre-treatment EPIC sexual bother reached 80.5%, meaning little bother, and remained stable during follow-up., Conclusions: Once-weekly 3D-CRT leads to excellent biochemical disease-free survival and acceptable toxicities. Pre-treatment EPIC sexual function dropped by 42% at 5 years of follow-up. This functional deficit did not bother patients, possibly due to the already low sexual function at baseline., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Grade 2 gliomas occur most commonly in young adults and cause progressive neurologic deterioration and premature death. Early results of this trial showed that treatment with procarbazine, lomustine (also called CCNU), and vincristine after radiation therapy at the time of initial diagnosis resulted in longer progression-free survival, but not overall survival, than radiation therapy alone. We now report the long-term results., Methods: We included patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma who were younger than 40 years of age and had undergone subtotal resection or biopsy or who were 40 years of age or older and had undergone biopsy or resection of any of the tumor. Patients were stratified according to age, histologic findings, Karnofsky performance-status score, and presence or absence of contrast enhancement on preoperative images. Patients were randomly assigned to radiation therapy alone or to radiation therapy followed by six cycles of combination chemotherapy., Results: A total of 251 eligible patients were enrolled from 1998 through 2002. The median follow-up was 11.9 years; 55% of the patients died. Patients who received radiation therapy plus chemotherapy had longer median overall survival than did those who received radiation therapy alone (13.3 vs. 7.8 years; hazard ratio for death, 0.59; P=0.003). The rate of progression-free survival at 10 years was 51% in the group that received radiation therapy plus chemotherapy versus 21% in the group that received radiation therapy alone; the corresponding rates of overall survival at 10 years were 60% and 40%. A Cox model identified receipt of radiation therapy plus chemotherapy and histologic findings of oligodendroglioma as favorable prognostic variables for both progression-free and overall survival., Conclusions: In a cohort of patients with grade 2 glioma who were younger than 40 years of age and had undergone subtotal tumor resection or who were 40 years of age or older, progression-free survival and overall survival were longer among those who received combination chemotherapy in addition to radiation therapy than among those who received radiation therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00003375.).

Background: Androgen deprivation therapy (ADT) is associated with coronary heart disease and diabetes in men with prostate cancer (PCa); however, controversy exists regarding ADT and cardiovascular mortality (CVM) with limited data for lower risk disease., Objective: We conducted a hypothesis-generating retrospective analysis to evaluate the relationship between short-course ADT and CVM in patients with clinically localized PCa enrolled in a phase III trial., Design, Setting, and Participants: A total of 1979 men with clinically localized (T1b-2b, prostate-specific antigen [PSA] <20 ng/ml) PCa enrolled in Radiation Therapy Oncology Group (RTOG) 94-08 from 1994 to 2001. Patients were randomized to radiation therapy (RT) with or without short-course ADT (4 mo of gonadotropin-releasing hormone (GnRH) agonist therapy and antiandrogen). Median follow-up was 9.1 yr for survivors., Outcome Measurements and Statistical Analysis: The Cox proportional hazards model assessed overall survival. The Fine-Gray proportional hazards model assessed disease-specific survival (DSS) and CVM. Covariates included age, race, weight, baseline cardiovascular disease, baseline diabetes, baseline hypertension, Gleason score, T stage, and PSA., Results and Limitations: Short-course ADT improved overall survival and DSS and was not associated with an increased risk of CVM. Overall, 191 cardiovascular-related deaths were observed. At 10 yr, 83 patients (cumulative incidence rate: 10%) receiving RT and ADT versus 95 patients (cumulative incidence rate: 11%) receiving RT alone experienced CVM. The treatment arm was not associated with increased CVM (unadjusted hazard ratio: 1.07; confidence interval, 0.81-1.42; p=0.62). Increased CVM was not observed in patients at low risk of PCa death or at high risk of cardiac-related death., Conclusions: Data from patients enrolled in RTOG 94-08 support the hypothesis that ADT does not increase CVM risk in men with clinically localized PCa treated with short-course GnRH agonist therapy. These data support ADT use in settings with proven survival benefit., Patient Summary: We investigated the controversial relationship between hormone therapy and cardiovascular mortality in men with prostate cancer (PCa) treated with radiation in a large randomized trial. Our data suggest that hormone therapy does not increase the risk of cardiovascular death in patients with clinically localized PCa and support the use of such therapy in settings with proven survival benefit., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The authors analyzed a preliminary report of patient-reported outcomes (PROs) among men who received high-dose radiation therapy (RT) on Radiation Therapy Oncology Group study 0126 (a phase 3 dose-escalation trial) with either 3-dimensional conformal RT (3D-CRT) or intensity-modulated RT (IMRT)., Methods: Patients in the 3D-CRT group received 55.8 gray (Gy) to the prostate and proximal seminal vesicles and were allowed an optional field reduction; then, they received 23.4 Gy to the prostate only. Patients in the IMRT group received 79.2 Gy to the prostate and proximal seminal vesicles. PROs were assessed at 0 months (baseline), 3 months, 6 months, 12 months, and 24 months and included bladder and bowel function assessed with the Functional Alterations due to Changes in Elimination (FACE) instrument and erectile function assessed with the International Index of Erectile Function (IIEF). Analyses included the patients who completed all data at baseline and for at least 1 follow-up assessment, and the results were compared with an imputed data set., Results: Of 763 patients who were randomized to the 79.2-Gy arm, 551 patients and 595 patients who responded to the FACE instrument and 505 patients and 577 patients who responded to the IIEF were included in the completed and imputed analyses, respectively. There were no significant differences between modalities for any of the FACE or IIEF subscale scores or total scores at any time point for either the completed data set or the imputed data set., Conclusions: Despite significant reductions in dose and volume to normal structures using IMRT, this robust analysis of 3D-CRT and IMRT demonstrated no difference in patient-reported bowel, bladder, or sexual functions for similar doses delivered to the prostate and proximal seminal vesicles with IMRT compared with 3D-CRT delivered either to the prostate and proximal seminal vesicles or to the prostate alone., (© 2015 American Cancer Society.)