Secondary analysis of late major gastrointestinal and genitourinary toxicities in unfavorable-risk prostate cancer patients receiving docetaxel: Insights from a randomized trial.

BACKGROUND: This study sought to evaluate the late toxicity associated with neoadjuvant and concurrent docetaxel and radiation therapy in patients with prostate cancer. METHODS: A secondary analysis was performed of the phase 3 multicenter randomized trial (Dana-Farber Cancer Institute 05-043) including 350 patients with nonmetastatic unfavorable-risk prostate cancer. Patients were randomized 1:1 to receive androgen deprivation therapy, radiation therapy, and docetaxel versus androgen deprivation therapy and radiation therapy. The study assessed the cumulative incidence rates of grade 2 and grade 3 or higher gastrointestinal, genitourinary, and sexual toxicity. A multivariable Fine and Gray's competing risks regression model adjusted for age at randomization and pelvic lymph node radiation therapy was used to evaluate the treatment effect of docetaxel on time to late genitourinary and gastrointestinal toxicities. RESULTS: The study included 338 patients who primarily had minimal or no comorbidity (74.9%) and median age 66 years (interquartile range: 61,71). At a median follow-up of 10.2 years, docetaxel was not associated with increased risk of any grade 3 or higher (adjusted hazard ratio [AHR], 0.98; 95% confidence interval [CI], 0.36-2.67; p = .96) or grade 2 gastrointestinal (p = .75), genitourinary (p = .44), and sexual (p = .29) toxicity. Age was associated with increased grade 3 or higher (AHR, 1.08; 95% CI, 1.01-1.16; p = .03) and grade 2 gastrointestinal toxicity (AHR, 1.11; 95% CI, 1.03-1.20; p = .005). A nonsignificant trend (p = .09) toward increased late grade 3 or higher toxicity was observed for pelvic radiation therapy use. CONCLUSIONS: Docetaxel combined with radiotherapy has an acceptable long-term toxicity profile.

Prostate-specific antigen nadir and testosterone level at prostate-specific antigen failure following radiation and androgen suppression therapy for unfavorable-risk prostate cancer and the risk of all-cause and prostate cancer-specific mortality.

BACKGROUND: Although both PSA nadir (PSAn) and testosterone levels at PSA failure are known prognostic factors in men undergoing radiation therapy (RT) and androgen deprivation therapy (ADT) for unfavorable-risk prostate cancer (PC), it is unclear whether their prognostic significance is independent or overlapping. METHODS: Seventy-five men treated with RT with or without 6 months of ADT for unfavorable-risk nonmetastatic PC enrolled in 2 prospective clinical trials between 1986 and 2001 formed the study cohort. Competing risks and Cox multivariable regression were used to assess whether low versus normal serum testosterone at the time of PSA failure and higher PSAn after initial therapy were independently associated with the risk of PC-specific (PCSM) and all-cause mortality (ACM) adjusting for PC prognostic factors. RESULTS: After a median follow-up of 15.34 years (interquartile range, 6.66-16.88 years), there were 53 deaths (73.3%): 30 (56.6%) were from PC. Low testosterone at PSA failure was significantly associated with an increased risk of PCSM (adjusted HR [AHR], 7.77; 95% CI, 1.14-52.99; P = .04) and ACM (AHR, 3.01; 95% CI, 1.01-8.96; P = .05), as was higher PSAn (PCSM AHR, 1.03; 95% CI, 1.01-1.05; P < .01; ACM AHR, 1.04; 95% CI, 1.02-1.07; P < .01), although the prognostic significance of PSAn was only noted in men with a normal testosterone at PSA failure. CONCLUSIONS: Low testosterone level at PSA failure in high-risk patients with PC treated with RT is associated with increased PCSM and ACM risk. In men with normal testosterone levels at the time of PSA failure, an elevated PSAn was associated with worse PCSM and ACM risk. LAY SUMMARY: This study investigates whether the prostate-specific antigen (PSA) nadir and normal versus low testosterone at the time of PSA failure provide mutually exclusive or overlapping prognostic information following treatment with radiation and androgen deprivation therapy for unfavorable-risk patients with prostate cancer using data from 2 prospective clinical trials. It was found that both provided prognostic information; however, higher PSA nadir was only found to be of prognostic significance in men with normal testosterone levels at PSA failure.

Impact of time to testosterone rebound and comorbidity on the risk of cause-specific mortality in men with unfavorable-risk prostate cancer.

BACKGROUND: Herein, the authors evaluated how the time to testosterone rebound (TTR) after radiotherapy (RT) and 6 months of androgen deprivation therapy (ADT) impacted the risk of prostate cancer-specific mortality (PCSM) and cardiovascular-specific mortality (CVM) among men with varying comorbidity extent. METHODS: Between 1995 and 2001, a total of 206 men who were randomized to receive RT either alone or with 6 months of ADT for unfavorable-risk PC and who had a comorbidity score assigned using the Adult Comorbidity Evaluation 27 metric comprised the study cohort. Multivariable competing risk regression was used to evaluate the impact of and possible interaction between comorbidity and TTR on PCSM and CVM. RESULTS: After a median follow-up of 18.19 years, 30 men (18.6%), 39 men (24.2%), and 92 men (57.1%), respectively, had died of PC, CV disease, or other causes. As TTR increased, PCSM significantly decreased in men with no or minimal (adjusted hazard ratio [AHR], 0.53, 95% confidence interval [95% CI], 0.34-0.84 [P =.007]) and moderate to severe (AHR, 0.37; 95% CI, 0.14-0.99 [P = .048]) comorbidity. However, increasing TTR significantly increased the risk of CVM among men with moderate to severe comorbidity (AHR, 1.87; 95% CI, 1.40-2.49 [P <.001]), but not those with no or minimal comorbidity (AHR, 0.86; 95% CI, 0.57-1.29 [P =.46]), leading to a significant interaction between TTR and comorbidity (P = .001). CONCLUSIONS: The results of the current study indicate that considering an intermittent course of ADT such that the TTR approaches 18 months, instead of continuous long-term administration of ADT, in men with moderate to severe comorbidity and high-risk PC may reduce the increased risk of CVM without increasing the risk of PCSM. Cancer 2018;124:1391-9. © 2018 American Cancer Society.

Low testosterone at first prostate-specific antigen failure and assessment of risk of death in men with unfavorable-risk prostate cancer treated on prospective clinical trials.

BACKGROUND: Low testosterone at the time of diagnosis of prostate cancer has been associated with a worse prognosis. Whether this is true and how to define the best treatment approach at the time of first prostate-specific antigen (PSA) failure to the authors' knowledge has not been elucidated to date and was studied herein. METHODS: Between 1995 and 2001, a total of 58 men with unfavorable-risk PC who were treated on clinical trials with radiotherapy and androgen deprivation therapy (ADT) had available testosterone levels at the time of PSA failure. Cox and Fine and Gray regressions were performed to ascertain whether low versus normal testosterone was associated with the risk of PC-specific mortality, other-cause mortality, and all-cause mortality adjusting for age, salvage ADT, and known PC prognostic factors. RESULTS: After a median follow-up of 6.68 years after PSA failure, 31 men (53.4%) had died; 10 of PC (32.3%), of which 8 of 11 (72.7%) versus 2 of 47 (4.3%) deaths occurred in men with low versus normal testosterone at the time of PSA failure, respectively. A significant increase in the risk of all-cause mortality (adjusted hazard ratio [AHR], 2.54; 95% confidence interval [95% CI], 1.04-6.21 [P = .04]) and PC-specific mortality (AHR, 13.71; 95% CI, 2.4-78.16 [P = .003]), with a reciprocal trend toward a decreased risk of other-cause mortality (AHR, 0.18; 95% CI, 0.02-1.55 [P = .12]) was observed in men with low versus normal testosterone. CONCLUSIONS: Low, but not necessarily castrate, testosterone levels at the time of PSA failure confer a very poor prognosis. These observations provide evidence to support testosterone testing at the time of PSA failure. Given prolonged survival when abiraterone or docetaxel is added to ADT in men with castrate-sensitive metastatic PC and possibly localized high-risk PC provides a rationale supporting their use with ADT in men with low testosterone in the setting of a phase 2 trial. Cancer 2018;124:1383-90. © 2017 American Cancer Society.

Early Versus Delayed Initiation of Salvage Androgen Deprivation Therapy and Risk of Prostate Cancer-Specific Mortality.

Background: This study sought to ascertain whether there is an association between prostate cancer (PC)-specific mortality (PCSM) and timing of salvage androgen deprivation therapy (ADT) among men with short versus long prostate-specific antigen doubling times (PSA-DTs). Methods: The study cohort was selected from 206 men with localized unfavorable-risk PC randomized to radiation therapy (RT) or RT plus 6 months of ADT between 1995 and 2001. A total of 54 men who received salvage ADT for PSA failure after a median follow-up of 18.72 years following randomization defined the study cohort. The Fine-Gray competing risks regression model was used to analyze whether the timing of salvage ADT was associated with an increased risk of PCSM after adjusting for age, comorbidity, known PC prognostic factors, and previously identified interactions. Results: After a median follow-up of 5.68 years (interquartile range, 3.05-9.56) following salvage ADT, 49 of the 54 men (91%) died, of which 27 from PC (54% of deaths). Increasing PSA-DT as a continuous covariate (per month increase) was associated with a decreasing risk of PCSM (adjusted hazard ratio [HR], 0.33; 95% CI, 0.13-0.82; P=.02). Among men with a long PSA-DT (≥6 months), initiating salvage ADT later (PSA level >12 ng/mL, upper quartile) versus earlier was associated with an increased risk of PCSM (adjusted HR, 8.84; 95% CI, 1.99-39.27; P=.004), whereas for those with a short PSA-DT (<6 months; adjusted HR, 1.16; 95% CI, 0.38-3.54; P=.79) this was not true. Conclusions: Early initiation of salvage ADT for post-RT PSA failure in men with a PSA-DT of ≥6 months may reduce the risk of PCSM.

The likelihood of death from prostate cancer in men with favorable or unfavorable intermediate-risk disease.

BACKGROUND: Recently, men with intermediate-risk prostate cancer (PC) were classified into favorable and unfavorable categories; however, whether the risk of PC-specific mortality (PCSM) among men with high-risk PC versus unfavorable intermediate-risk PC is increased is unknown. METHODS: In a prospective, randomized trial conducted between 1995 and 2001, 206 men with intermediate-risk or high-risk PC were randomized to receive 70 Gy with or without 6 months of androgen-suppression therapy (AST). The subgroup of 197 patients with information available on the percentage of positive biopsies formed the cohort. Fine and Gray regression analysis was used to assess whether men with high-risk PC versus unfavorable intermediate-risk PC had an increased risk of PCSM. RESULTS: After a median follow-up of 14.3 years, there were 127 deaths (64.5%), including 22 deaths (17.3%) from PC. There were no PC deaths in the favorable intermediate-risk group. There was an increase in the risk of PCSM among men with high-risk PC versus unfavorable intermediate-risk PC, but the difference was not significant (adjusted hazard ratio, 1.59; 95% confidence interval, 0.66-3.83; P = .30) after adjusting for age, randomized treatment arm, and comorbidity. CONCLUSIONS: The lack of PC deaths among men with favorable intermediate-risk PC suggests that adding AST may not reduce their risk of PCSM; whereas many men with unfavorable intermediate-risk PC are at risk for harboring occult PC with Gleason scores from 8 to 10 and, if proven, would benefit from long-term AST. Multiparametric magnetic resonance imaging and targeted biopsy of suspicious lesions should be considered to identify PC with Gleason scores from 8 to 10 in these men.

Elective Pelvic Lymph Node Radiation Therapy and the Risk of Death in Patients With Unfavorable-Risk Prostate Cancer: A Postrandomization Analysis.

PURPOSE: Although a contemporary randomized clinical trial has led to the use of whole-pelvic radiation therapy (WPRT), long-term data evaluating a potential reduction in mortality are lacking and are addressed in the current study. MATERIALS AND METHODS: From 2005 to 2015, 350 men with localized, unfavorable-risk prostate cancer (PC) were randomly assigned to receive androgen deprivation therapy (ADT) and RT plus docetaxel versus ADT and RT. Treatment of the pelvic lymph nodes was at the discretion of the treating physician. Multivariable Cox and Fine and Grays regression analyses were performed to assess whether a significant association existed between radiation treatment volume and all-cause mortality (ACM) and PC-specific mortality (PCSM), respectively, adjusting for known PC prognostic factors and comorbidity. An interaction term between age (categorized by dichotomization at 65 years to enable clinical interpretation and applicability of the results and which approximates the median (66 years [IQR, 61-70]) and radiation treatment volume was included in the analysis. RESULTS: After a median follow-up of 10.20 years (IQR, 7.96-11.41), 89 men died (25.43%); of these, 42 died of PC (47.19%). Of the 350 randomly assigned patients, 88 (25.14%) received WPRT. In men younger than 65 years, WPRT was associated with a significantly lower ACM risk (adjusted hazard ratio [AHR], 0.33 [95% CI, 0.11 to 0.97]; P = .04) and lower PCSM risk (AHR, 0.17 [95% CI, 0.02 to 1.35]; P = .09) after adjusting for covariates, whereas this was not the case for men 65 years or older. CONCLUSION: WPRT has the potential to reduce mortality in younger men with unfavorable-risk PC.

Defining the optimal approach to the patient with postradiation prostate-specific antigen recurrence using outcome data from a prospective randomized trial.

BACKGROUND: Optimal management remains unknown following prostate-specific antigen (PSA) failure when considering comorbidity and PSA kinetics at recurrence. In order to define randomized controlled trials (RCTs) that can address this issue, this study examined factors associated with the risk of death following PSA failure. METHODS: Of 206 men randomized to RT with or without 6 months of androgen suppression therapy (AST), 108 sustained PSA failure and began AST when PSA approached 10 ng/mL and formed the study cohort. Cox regression multivariable analysis was used to determine factors associated with death following PSA failure. RESULTS: After a median follow-up of 10.3 years of 108 men with PSA failure, 64 (59%) died, with 22 (34%) dying of prostate cancer (PC). Increasing PSA velocity at recurrence was associated with a significant increase in the risk of death (adjusted hazard ratio, 1.21; 95% confidence interval, 1.02-1.45; P = .03). Among men with no/minimal versus moderate/severe comorbidity, PC comprised 42% (20 of 48) versus 12.5% (2 of 16) of all deaths, respectively. Estimates of PC-specific and all-cause death were significantly higher when PSA velocity was greater than as compared with the median or less in men with no/minimal (P < .008) but not moderate/severe comorbidity (P > .15). CONCLUSIONS: Despite unfavorable PSA kinetics at recurrence, unhealthy men may not benefit from AST; RCTs examining intermittent AST versus surveillance are needed. For healthy men with unfavorable PSA kinetics at recurrence, PC death rates are high despite AST, which warrants RCTs to evaluate the impact on death when adding agents that prolong survival in men with metastatic castration-resistant PC to AST.

Surrogate endpoints for prostate cancer-specific mortality after radiotherapy and androgen suppression therapy in men with localised or locally advanced prostate cancer: an analysis of two randomised trials.

BACKGROUND: Androgen suppression therapy and radiotherapy are used to treat locally advanced prostate cancer. 3 years of androgen suppression confers a small survival benefit compared with 6 months of therapy in this setting, but is associated with more toxic effects. Early identification of men in whom radiotherapy and 6 months of androgen suppression is insufficient for cure is important. Thus, we assessed whether prostate-specific antigen (PSA) values can act as an early surrogate for prostate cancer-specific mortality (PCSM). METHODS: We systematically reviewed randomised controlled trials that showed improved overall and prostate cancer-specific survival with radiotherapy and 6 months of androgen suppression compared with radiotherapy alone and measured lowest PSA concentrations (PSA nadir) and those immediately after treatment (PSA end). We assessed a cohort of 734 men with localised or locally advanced prostate cancer from two eligible trials in the USA and Australasia that randomly allocated participants between Feb 2, 1996, and Dec 27, 2001. We used Prentice criteria to assess whether reported PSA nadir or PSA end concentrations of more than 0·5 ng/mL were surrogates for PCSM. FINDINGS: Men treated with radiotherapy and 6 months of androgen suppression in both trials were significantly less likely to have PSA end and PSA nadir values of more than 0·5 ng/mL than were those treated with radiotherapy alone (p<0·0001). Presence of candidate surrogates (ie, PSA end and PSA nadir values >0·5 ng/mL) alone and when assessed in conjunction with the randomised treatment group increased risk of PCSM in the US trial (PSA nadir p=0·0016; PSA end p=0·017) and Australasian trial (PSA nadir p<0·0001; PSA end p=0·0012). In both trials, the randomised treatment group was no longer associated with PCSM (p ≥ 0·20) when the candidate surrogates were included in the model. Therefore, both PSA metrics satisfied Prentice criteria for surrogacy. INTERPRETATION: After radiotherapy and 6 months of androgen suppression, men with PSA end values exceeding 0·5 ng/mL should be considered for long-term androgen suppression and those with localised or locally advanced prostate cancer with PSA nadir values exceeding 0·5 ng/mL should be considered for inclusion in randomised trials investigating the use of drugs that have extended survival in castration-resistant metastatic prostate cancer. FUNDING: None.

Risk of Short-Term Prostate-Specific Antigen Recurrence and Failure in Patients With Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: A shorter time interval to prostate-specific antigen (PSA) failure is associated with worse clinical outcomes; however, specific factors defining this state remain unknown. Objective: To evaluate the factors of a short time interval to PSA failure in order to identify patients for treatment escalation randomized clinical trials. Design, Setting, and Participants: This secondary analysis of a randomized clinical trial was a secondary analysis of the Dana-Farber Cancer Institute 05-043 trial and included 350 patients with nonmetastatic unfavorable risk prostate cancer (PC). Interventions: Patients were randomized 1:1 to receive androgen deprivation therapy (ADT) and radiation therapy (RT) plus docetaxel vs ADT and RT. Main Outcomes and Measures: Cumulative incidence rates curves of PSA failure, defined as PSA nadir plus 2 ng/mL or initiation of salvage therapies, and the Fine and Gray competing risks regression was used to assess the prognostic association between these factors and time to PSA failure. Results: The study included 350 males who primarily had a good performance status (330 [94.3%] with Eastern Cooperative Oncology Group score of 0), median (range) age of 66 (43-86) years, with 167 (46.6%) having Gleason scores of 8 to 10, and 195 (55.2%) presenting with a baseline PSA of more than 10 ng/mL. After a median (IQR) follow-up of 10.2 (8.0-11.4) years, having a PSA level of 10 ng/mL to 20 ng/mL (subdistribution hazard ratio [sHR], 1.98; 95% CI, 1.28-3.07; P = .002) and a Gleason score of 8 to 10 (sHR, 2.55; 95% CI, 1.63-3.99; P < .001) were associated with a shorter time to PSA failure, and older age (sHR, 0.82; 95% CI, 0.72-0.93; P = .002) was associated with reduced risk for PSA failure after adjusting for other baseline clinical factors. The high-risk category, defined by these 3 factors, was associated with a shorter time to PSA failure (sHR, 2.69; 95% CI, 1.84-3.93; P < .001). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial of males with unfavorable risk PC, young age, PSA of 10 ng/mL or more, and a Gleason score of 8 to 10 estimated a shorter time to PSA failure. A subgroup of males at very high-risk for early PSA failure, as defined by our study, may benefit from treatment escalation with androgen receptor signaling inhibitors or cytotoxic chemotherapy and should be the subject of a prospective randomized clinical trial. Trial Registration: NCT00116142.

Posttreatment prostate specific antigen nadir predicts prostate cancer specific and all cause mortality.

PURPOSE: We investigated whether the prostate specific antigen nadir predicts prostate cancer specific and all cause mortality in men treated in a randomized trial of radiation with or without 6 months of androgen deprivation therapy. MATERIALS AND METHODS: The study included 204 men with cT1b-T2bN0M0 prostate adenocarcinoma and at least 1 unfavorable factor, including prostate specific antigen less than 10 to 40 ng/ml, Gleason 7 or greater, or T3 on magnetic resonance imaging. We performed Fine and Gray regression, and Cox multivariable analysis to determine whether an increasing prostate specific antigen nadir was associated with prostate cancer specific and all cause mortality, adjusting for treatment, age, Adult Comorbidity Evaluation 27 score and cancer prognostic factors. RESULTS: At a 6.9-year median followup median prostate specific antigen nadir was 0.7 ng/ml for radiation alone and 0.1 ng/ml for radiation plus androgen deprivation therapy. The prostate specific antigen nadir (adjusted HR 1.18/ng/ml increase, 95% CI 1.07-1.31, p=0.001) and Gleason 8 or greater (adjusted HR 8.05, 95% CI 1.01-64.05, p=0.049) significantly predicted increased prostate cancer specific mortality. Moderate/severe comorbidity carried a decreased risk (adjusted HR 0.13, 95% CI 0.02-0.96, p=0.045). Higher prostate specific antigen nadir (adjusted HR 1.10/ng/ml increase, 95% CI 1.04-1.17), older age (adjusted HR 1.10/year, 95% CI 1.04-1.15) and interaction between comorbidity score and randomization arm (each p<0.001) increased the all cause mortality risk. Men who achieved a prostate specific antigen nadir of the median value or less had lower estimated prostate cancer specific and all cause mortality at 7 years (3.7% vs 18.3%, p=0.0005 and 31.5% vs 55.0%, p=0.002). CONCLUSIONS: Posttreatment prostate specific antigen nadir is significantly associated with the risk of prostate cancer specific and all cause mortality after radiation with or without androgen deprivation therapy. A suboptimal prostate specific antigen nadir may identify candidates for earlier intervention to prolong survival.

Biopsy Gleason score and the duration of testosterone suppression among men treated with external beam radiation and 6 months of combined androgen blockade.

UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? The return of testosterone to normal levels following short-course androgen blockade in prostate cancer is variable. Factors associated with a longer time to recovery include older age and lower baseline testosterone level. In this study, we found that among men treated with 6 months of combined androgen blockade and radiation therapy, higher biopsy Gleason grade was associated with a shorter time to testosterone normalization. OBJECTIVE: • To determine whether the biopsy Gleason score is associated with duration of testosterone suppression following 6 months of combined androgen blockade (CAB) and radiation therapy (RT) in men with prostate cancer (PCa). PATIENTS AND METHODS: • The study cohort consisted of 221 men with PCa treated with RT and 6 months of CAB between 1996 and 2005. • We defined the duration of testosterone suppression as the time between the last day of CAB and the date the testosterone returned to ≥ 252 ng/dL. We used Cox regression multivariable analysis to relate biopsy Gleason score to duration of testosterone suppression following cessation of CAB. RESULTS: • A biopsy Gleason score of 8-10 had an adjusted hazard ratio (AHR) of 1.56 (95% confidence interval [CI] 1.04, 2.34; P= 0.03) for a shorter time to testosterone normalization relative to Gleason 6. Specifically, the 51 men with biopsy Gleason score of 8-10 had a median time to testosterone normalization of 17.0 months compared with 22.1 months and 23.8 months for those with biopsy Gleason ≤ 6 and 7, respectively. • Increasing age was significantly associated with a longer duration of testosterone suppression (AHR of 0.95 [95% CI 0.92, 0.97; P < 0.001]) as was a higher baseline PSA (AHR 0.82 [95% CI 0.69, 0.97; P= 0.02]). CONCLUSION: • A biopsy Gleason score of 8-10 was associated with a shorter period of testosterone suppression following 6 months of CAB and RT. These data are consistent with the hypothesis that a factor released from high-grade PCa cells may impact on testosterone production.

Patient-reported quality of life during radiation treatment for localized prostate cancer: results from a prospective phase II trial.

UNLABELLED: Study Type--Therapy (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Patient-reported quality of life (QoL) in prostate cancer is recognized as an important outcome, and has been shown in multiple studies to capture the incidence and timing of patient symptoms more accurately than physician-graded toxicity reports. Although the long-term QoL after completing radiation therapy (RT) has been previously studied, patient experience during RT is not well described in the literature. The present study collected patient-reported QoL during RT in a prospective phase II clinical trial. The study describes in detail the time course and severity of gastrointestinal and genitourinary symptoms during radiation, providing clinically useful information for patients and physicians considering RT during the treatment decision-making process. OBJECTIVE: • To evaluate data collected from a phase II trial to describe the time course and trajectory of patient-reported acute urinary and bowel symptom development during radiation therapy (RT) for prostate cancer. PATIENTS AND METHODS: • In all, 100 patients with intermediate- or high-risk prostate cancer received 72 Gy of RT to the prostate and seminal vesicles, with 6 months of concurrent androgen deprivation therapy; a rectal balloon was used for prostate immobilization. • Patients completed the validated Prostate Cancer Symptom Indices questionnaire every 1-2 weeks, reporting urinary and bowel symptoms on a four- or five-point Likert scale. • A score of ≥ 3 in a symptom is associated with clinically meaningful distress. Cumulative incidence of each symptom is reported. Bonferroni corrections of P values were used to adjust for multiple comparisons. RESULTS: • Urinary symptoms were frequent at baseline and worsened during treatment. By the end of RT, 28-50% of patients developed clinically meaningful obstructive and irritative urinary symptoms. • Acute bowel symptoms were less frequent. Each bowel symptom increased in frequency by 9-26% from baseline to end of RT. • Urinary incontinence was rare. • Overall, symptom burden at the end of treatment was modest. CONCLUSIONS: • Urinary symptoms were common during RT, and bowel symptoms were less frequent. • These results inform patients and physicians during the decision-making process about potential patient quality of life experiences during RT, and also provide a benchmark for comparative effectiveness studies against newer treatments and technologies.

MRI-Based Radiotherapy Planning to Reduce Rectal Dose in Excess of Tolerance.

MATERIALS AND METHODS: This prospective single-arm study enrolled 15 men treated with IG-IMRT for localized prostate cancer. All participants received a dedicated 3 Tesla MRI examination of the prostate in addition to a pelvic CT examination for treatment planning. Two volumetric modulated arc therapy (VMAT) plans with a prescription dose of 79.2 Gy were designed using identical constraints based on CT- and MRI-defined consensus volumes. The volume of rectum exposed to 70 Gy or more was compared using the Wilcoxon paired signed rank test. RESULTS: For CT-based treatment plans, the median volume of rectum receiving 70 Gy or more was 9.3 cubic centimeters (cc) (IQR 7.0 to 10.2) compared with 4.9 cc (IQR 4.1 to 7.8) for MRI-based plans. This resulted in a median volume reduction of 2.1 cc (IQR 0.5 to 5.3, P < .001). CONCLUSIONS: Using MRI to plan prostate IG-IMRT to a dose of 79.2 Gy reduces the volume of rectum receiving radiation dose in excess of tolerance (70 Gy or more) and should be considered in men who are at high risk for late rectal toxicity and are not good candidates for other rectal sparing techniques such as hydrogel spacer. This trial is registered with NCT02470910.

Radiation and Androgen Deprivation Therapy With or Without Docetaxel in the Management of Nonmetastatic Unfavorable-Risk Prostate Cancer: A Prospective Randomized Trial.

PURPOSE: Although docetaxel is not recommended when managing men with unfavorable-risk prostate cancer (PC) given negative or inconclusive results from previous randomized trials, unstudied benefits may exist. METHODS: Between September 21, 2005, and January 13, 2015, we randomly assigned 350 men 1:1 with T1c-4N0M0 unfavorable-risk PC to receive radiation therapy (RT) and androgen deprivation therapy (ADT) plus docetaxel (60 mg/m2 once every 3 weeks for three cycles before RT and 20 mg/m2 once weekly during RT) versus ADT + RT. We evaluated the treatment effect of adding docetaxel to ADT + RT on the primary end point of overall survival (OS) and the incidence of RT-induced cancers and explored whether the impact of the treatment effect on OS differed within prostate-specific antigen (PSA) subgroups (< 4, > 20 v 4-20 ng/mL) using the interaction test for heterogeneity adjusted for age and PC prognostic factors. RESULTS: After a median follow-up of 10.2 years, 89 men died (25.43%); of these, 42 from PC (47.19%). Although OS was not significantly increased in the docetaxel arm (the restricted mean survival time over 10 years was 9.11 v 8.82 years; P = .22), significantly fewer RT-induced cancers were observed (10-year estimates: 0.61% v 4.90%; age-adjusted hazard ratio of 0.13; 95% CI, 0.02 to 0.97; P = .046). The treatment effect of adding docetaxel to ADT + RT on OS significantly differed in men with a PSA < 4 ng/mL versus 4-20 ng/mL (adjusted hazard ratio: 0.27 and 1.51, respectively) because of less PC-specific mortality on the docetaxel arm (0.00% v 28.57%) among men with PSA < 4 ng/mL. CONCLUSION: Adding docetaxel to ADT + RT did not prolong OS in men with unfavorable-risk PC, but decreased RT-induced cancer incidence, and may prolong OS in the subgroup of men with a PSA < 4 ng/mL by reducing PC-specific mortality.

Patient-reported quality of life after salvage brachytherapy for radio-recurrent prostate cancer: A prospective Phase II study.

BACKGROUND: Patient-reported quality of life (QOL) after salvage brachytherapy for radiorecurrent prostate cancer has not been well-characterized prospectively. METHODS: We examined 25 men who recurred after primary radiotherapy for prostate cancer and received MRI-guided salvage brachytherapy as part of a prospective Phase II study. These patients received prospectively a validated patient-reported QOL questionnaire to fill out at baseline, as well as 3, 15, and 27 months after re-irradiation to determine the degree of sexual, bowel, and urinary dysfunction (maximum dysfunction score=100). RESULTS: On average, sexual function continued to decline with time, and patients had significantly worse sexual function scores at 27 months than baseline (p=0.01). Although bowel and urinary symptoms worsened acutely at 3 or 15 months, they showed on average some improvement by 27 months, and there were no significant differences between baseline and 27-month urinary or bowel scores. An interval to re-irradiation less than 4.5 years and prior brachytherapy were each associated significantly with the largest decrements in bowel function (p=0.035). CONCLUSION: Similar to the patterns seen in the de novo setting, patients who receive salvage brachytherapy report a worsening of bowel and urinary symptoms followed by some improvement by 27 months, while sexual function steadily declines over time. Interval to re-irradiation and type of prior radiation received may be used to counsel and optimize selection of men for salvage brachytherapy with regard to QOL endpoints.

Time to Prostate-specific Antigen Nadir and the Risk of Death From Prostate Cancer Following Radiation and Androgen Deprivation Therapy.

OBJECTIVE: To assess whether the time to prostate-specific antigen (PSA) nadir (TTN) has differential prognostic value in men who reach an undetectable vs detectable PSA nadir. METHODS: Two hundred and four men from a prospective randomized controlled trial involving radiation therapy with or without 6 months of androgen deprivation therapy in unfavorable risk Prostate cancer (CaP) at academic or community based centers in Massachusetts, enrolled between 1995 and 2001. Adjusted hazard ratios (AHR) of the risk of CaP-specific mortality calculated using Fine and Gray competing risk regression. RESULTS: After a median follow-up of 18.17years, 160 men died; 30 (18.75%) of CaP. Among men with a PSA nadir ≥ 0.2ng/ml, a TTN < median (12 months) was significantly associated with an increased CaP-specific mortality-risk vs the median or more (AHR 5.07, 95% CI 2.10-12.23, P <.001); whereas this association was not observed among men with a PSA nadir of < 0.2ng/mL, (AHR 9.9, 95% CI 0.23-433.8, P = .23). CONCLUSION: Men with both a short TTN and detectable PSA nadir could be considered for entry on randomized controlled trials at a novel entry point prior to PSA failure at the time of PSA nadir to completeplanned conventional androgen deprivation therapy vs that plus agent(s) shown to improve outcomes in men with or at high risk of having castrate-resistant CaP.

Tumor volume changes on 1.5 tesla endorectal MRI during neoadjuvant androgen suppression therapy for higher-risk prostate cancer and recurrence in men treated using radiation therapy results of the phase II CALGB 9682 study.

PURPOSE: We prospectively determined whether the change in tumor volume (TV) during 2 months of neoadjuvant androgen suppression therapy (nAST) measured using conventional 1.5 Tesla endorectal magnetic resonance imaging (eMRI) was associated with the risk of recurrence after radiation (RT) and 6 months of AST. PATIENTS AND METHODS: Between 1997 and 2001, 180 men with clinical stage T1c-T3cN0M0 adenocarcinoma of the prostate were registered. Fifteen were found to be ineligible and the institutional MR radiologist could not assess the TV in 32, leaving 133 for analysis. Multivariable Cox regression analysis was used to assess whether a significant association existed between eMRI-defined TV progression during nAST and time to recurrence adjusting for prostate-specific antigen (PSA) level, Gleason score (8 to 10 or 7 vs. 6 or less) and stage (T3 vs. T1-2). RESULTS: After a median follow up of 6.7 years and adjusting for known prognostic factors, there was a significant increase in the risk of PSA failure (HR, 2.3 [95% CI, 1.1-4.5; p = 0.025) in men with eMRI-defined TV progression during nAST. Specifically, adjusted estimates of PSA failure were significantly higher (p = 0.032) in men with, compared with men without, eMRI-defined TV progression reaching 38% vs. 19%, respectively, by 5 years. CONCLUSION: Eradicating intraprostatic hormone refractory prostate cancer (HRPC) by maximizing local control and randomized trials assessing whether survival is improved when agents active against HRPC are combined with maximal local therapy are needed in men who progress based on eMRI during nAST.

Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial.

CONTEXT: Comorbidities may increase the negative effects of specific anticancer treatments such as androgen suppression therapy (AST). OBJECTIVES: To compare 6 months of AST and radiation therapy (RT) to RT alone and to assess the interaction between level of comorbidity and all-cause mortality. DESIGN, SETTING, AND PATIENTS: At academic and community-based medical centers in Massachusetts, between December 1, 1995, and April 15, 2001, 206 men with localized but unfavorable-risk prostate cancer were randomized to receive RT alone or RT and AST combined. All-cause mortality estimates stratified by randomized treatment group and further stratified in a postrandomization analysis by the Adult Comorbidity Evaluation 27 comorbidity score were compared using a log-rank test. MAIN OUTCOME MEASURE: Time to all-cause mortality. RESULTS: As of January 15, 2007, with a median follow-up of 7.6 (range, 0.5-11.0) years, 74 deaths have occurred. A significant increase in the risk of all-cause mortality (44 vs 30 deaths; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.1-2.9; P = .01) was observed in men randomized to RT compared with RT and AST. However, the increased risk in all-cause mortality appeared to apply only to men randomized to RT with no or minimal comorbidity (31 vs 11 deaths; HR, 4.2; 95% CI, 2.1-8.5; P < .001). Among men with moderate or severe comorbidity, those randomized to RT alone vs RT and AST did not have an increased risk of all-cause mortality (13 vs 19 deaths; HR, 0.54; 95% CI, 0.27-1.10; P = .08). CONCLUSIONS: The addition of 6 months of AST to RT resulted in increased overall survival in men with localized but unfavorable-risk prostate cancer. This result may pertain only to men without moderate or severe comorbidity, but this requires further assessment in a clinical trial specifically designed to assess this interaction. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00116220.