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.

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.

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.

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.

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.

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.

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.

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.

Surrogate End Points for All-Cause Mortality in Men With Localized Unfavorable-Risk Prostate Cancer Treated With Radiation Therapy vs Radiation Therapy Plus Androgen Deprivation Therapy: A Secondary Analysis of a Randomized Clinical Trial.

IMPORTANCE: Several surrogates for prostate cancer-specific mortality satisfying the Prentice criteria exist, but whether these are surrogates for all-cause mortality, and how their performance compares, is unknown. OBJECTIVE: To ascertain and compare the performance of 4 candidate surrogates (prostate-specific antigen [PSA] failure, PSA nadir >0.5 ng/mL, PSA doubling time <9 months, and interval to PSA failure <30 months) for all-cause mortality using the proportion of treatment-effect metric. DESIGN, SETTING, AND PARTICIPANTS: For this randomized clinical trial, 206 men with unfavorable-risk prostate cancer who were seen at a Harvard-affiliated academic hospital or an associated community hospital between December 1, 1995, to April 15, 2001, were identified, randomized to radiation therapy alone or radiation therapy followed by 6 months of androgen deprivation therapy, and followed for a median 16.62 years. This analysis looks at the subgroup of 157 men with minimal comorbidities or no comorbidity (median follow-up, 16.49 months). INTERVENTIONS: Patients were previously randomized to receive radiation therapy or radiation and 6 months of androgen deprivation therapy. MAIN OUTCOMES AND MEASURES: Risk of all-cause mortality. RESULTS: Overall, a cohort of 157 men (median [interquartile range] age, 72.43 [68.75-75.53]) with unfavorable-risk prostate cancer and minimal or no comorbidities were selected for this study. Three tested metrics met all 4 Prentice criteria for surrogacy for the surrogate covariate in the adjusted model for all-cause mortality: PSA nadir greater than 0.5 ng/mL (adjusted hazard ratio [aHR], 1.72; 95% CI, 1.17-2.52; P = .01), PSA doubling time less than 9 months (aHR, 2.06; 95% CI, 1.29-3.28; P = .003), and interval to PSA failure less than 30 months (aHR, 1.76; 95% CI, 1.06-2.92; P = .03); while PSA failure did not. For the 3 successful surrogates, the proportion of treatment effect values were 103.86%, 43.09%, and 41.26%, respectively. CONCLUSIONS AND RELEVANCE: A PSA nadir value of greater than 0.5 ng/mL following radiation and androgen deprivation therapy appears to identify men prior to PSA failure who are at high-risk for death. This could be used to select men for entry at the time of PSA nadir onto randomized trials evaluating the impact on survival of salvage androgen deprivation therapy with or without agents shown to prolong survival in men with castrate-resistant metastatic prostate cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00116220.

Prostate-Specific Antigen Failure and Risk of Death Within Comorbidity Subgroups Among Men With Unfavorable-Risk Prostate Cancer Treated in a Randomized Trial.

Purpose Physicians sometimes make management recommendations on the basis of early results from randomized controlled trials (RCTs) relating to reduced prostate-specific antigen (PSA) failure, yet whether this early end point is associated with all-cause mortality (ACM), particularly in men with competing risks, is unknown. Using a validated metric in men treated within the context of an RCT, we aimed to determine whether PSA failure is associated with the risk of ACM stratified by comorbidity score. Patients and Methods Between 1995 and 2001, 206 men with localized (T1b to 2b) intermediate- and high-risk prostate cancer (PC) were randomly assigned to receive radiation therapy or radiation therapy and 6 months of ADT. Cox regression analyses were performed to evaluate whether PSA failure modeled as a time-dependent covariate was associated with an increased risk of ACM among men with Adult Comorbidity Evaluation-27-defined no or minimal versus moderate-to-severe comorbidity adjusting for age, PC prognostic factors, and treatment. Results After a median follow-up of 16.62 years, 156 men (76%) died, 29 of whom (19%) died as a result of PC. PSA failure was associated with an increased ACM risk among men with no or minimal (adjusted hazard ratio, 1.59; 95% CI, 1.03 to 2.46; P = .04), but not moderate or severe comorbidity (adjusted hazard ratio, 1.75; 95% CI, 0.76 to 3.99; P = .19). Conclusion Recommending treatment on the basis of reduced PSA failure observed from early results of RCTs is unlikely to prolong survival in men with moderate-to-severe comorbidity but may prolong survival in men with no or minimal comorbidity, providing evidence to support discussing the early results with these men.

Age, Comorbidity, and the Risk of Prostate Cancer-Specific Mortality in Men With Biopsy Gleason Score 4+3: Implications on Patient Selection for Multiparametric MRI.

BACKGROUND: Some men with biopsy Gleason score (GS) 7 prostate cancer (PC) harbor occult GS 8 to 10 PC and might be undertreated with short-term androgen deprivation therapy (ADT) and radiation therapy (RT). With advancing age associated with occult high-grade PC, we evaluated PC-specific mortality (PCSM) risk after RT and short-term ADT for older men with GS 4+3 PC and men of any age with GS 8 to 10 PC. PATIENTS AND METHODS: The study cohort comprised 206 men with unfavorable-risk PC treated with RT or RT and 6 months of ADT on a randomized trial between 1995 and 2001. Competing risks regression was used to compare PCSM risk for men with GS 8 to 10 PC to men with GS ≤ 3+4, GS 4+3 and age ≤ 73 years (median age), and GS 4+3 and age > 73 years, adjusting for PC risk factors, comorbidity, and treatment. RESULTS: After a median follow-up of 14.3 years, 135 men died (65.53%), 24 (17.78%) of PC. Men age > 73 years with GS 4+3 PC did not have significantly lower PCSM risk compared with men with GS 8 to 10 (adjusted hazard ratio [AHR], 1.08; 95% confidence interval [CI], 0.29-4.06; P = .91); whereas unhealthy men (AHR, 0.20; 95% CI, 0.04-0.93; P = .04) and men age ≤ 73 years with GS 4+3 (AHR, 0.09; 95% CI, 0.01-1.03; P = .05) fared better. CONCLUSION: Men age > 73 years with biopsy GS 4+3 did not have a significant difference in PCSM risk than men with GS 8 to 10, supporting further study of multiparametric magnetic resonance imaging in such men with no or minimal comorbidity before determining ADT duration.

Greatest Percentage Involved Core Length and Risk of Clinically Significant Prostate-Specific Antigen Failure After Radical Prostatectomy.

BACKGROUND: Radical prostatectomy (RP) can cure men with unfavorable intermediate- or high-risk prostate cancer (PC). However, some will experience short prostate-specific antigen (PSA) doubling time (PSADT) failure that requires additional treatment with increased toxicity. The present study investigated whether the greatest percentage of involved biopsy core length (GPC) can preoperatively identify men at risk of short PSADT failure. PATIENTS AND METHODS: A total of 503 men with biopsy-proven PC underwent RP at an academic institution from January 2005 to December 2008. Men with incomplete pathologic information, those who had received neoadjuvant or adjuvant hormonal therapy or chemotherapy, and those who had undergone adjuvant radiation therapy were excluded. The median follow-up period was 4.89 years (interquartile range, 1.97-5.68 years). A competing risk regression was used to assess whether an increasing GPC value was associated with an increased PSADT at < 10-month failure risk, adjusting for age, percentage of positive biopsy results, and risk group. RESULTS: Of the 402 men, 34 (8.46%) developed PSA failure, 17 (50.0%) of whom had a PSADT of < 10 months. An increasing GPC value was significantly associated with an increased PSADT of < 10-month failure risk (adjusted hazard ratio, 1.03; 95% confidence interval, 1.01-1.06; P = .015). Men with a GPC > 30% (median) versus ≤ 30% and unfavorable intermediate- or high-risk PC (P = .011), but not low or favorable intermediate-risk PC (P = .57), had a significantly greater incidence of PSADT < 10-month failure estimates (30% vs. 0% at 5 years). CONCLUSION: Men planning to undergo RP for unfavorable intermediate- or high-risk PC with a GPC of > 30% should be considered for randomized trials evaluating the effect on survival of the neoadjuvant use of treatment that extends survival in those with castrate-resistant metastatic PC.

Obesity and the Odds of Weight Gain following Androgen Deprivation Therapy for Prostate Cancer.

Background. Increasing body mass index (BMI) is associated with increased risk of mortality; however, quantifying weight gain in men undergoing androgen deprivation therapy (ADT) for prostate cancer (PC) remains unexplored. Methods. Between 1995 and 2001, 206 men were enrolled in a randomized trial evaluating the survival difference of adding 6 months of ADT to radiation therapy (RT). BMI measurements were available in 171 men comprising the study cohort. The primary endpoint was weight gain of ≥10 lbs by 6-month followup. Logistic regression analysis was performed to assess whether baseline BMI or treatment received was associated with this endpoint adjusting for known prognostic factors. Results. By the 6-month followup, 12 men gained ≥10 lbs, of which 10 (83%) received RT + ADT and, of these, 7 (70%) were obese at randomization. Men treated with RT as compared to RT + ADT were less likely to gain ≥10 lbs (adjusted odds ratio (AOR): 0.18 [95% CI: 0.04-0.89]; P = 0.04), whereas this risk increased with increasing BMI (AOR: 1.15 [95% CI: 1.01-1.31]; P = 0.04). Conclusions. Consideration should be given to avoid ADT in obese men with low- or favorable-intermediate risk PC where improved cancer control has not been observed, but shortened life expectancy from weight gain is expected.

Evaluating the Impact of PSA as a Selection Criteria for Nerve Sparing Radical Prostatectomy in a Screened Cohort.

Purpose. We investigated whether NS-RP increased risk of PSA failure and whether PSA should be included as a selection criterion for NS. Methods. We evaluated 357 consecutive men with screen-detected PC who underwent open RP without adjuvant radiotherapy between 9/11/2001 and 12/30/2008. Criteria for NS included Gleason score ≤3 + 4, percentage of positive biopsies (PPB) ≤50%, percentage of core involvement ≤50%, nonapical location, no perineural invasion, and no palpable disease on pre- or intraoperative exam but did not include a PSA threshold. Cox multivariable regression assessed whether increasing PSA or unilateral- or bilateral-NS versus non-NS-RP was associated with PSA failure adjusting for prognostic factors. Results. After a median follow-up of 3.96 years, 34 men sustained PSA failure (9.5%). Increasing PSA was significantly associated with increased risk of PSA failure in the interaction model (adjusted hazard ratio (AHR): 1.09 [95% CI: 1.03-1.16]; P = 0.005), whereas unilateral (AHR: 1.24 [95% CI: 0.36-4.34]; P = 0.73) or bilateral NS (AHR: 0.41 [95% CI: 0.06-2.59]; P = 0.34) versus non-NS RP was not. Conclusion. NS-RP in a screened cohort did not increase risk of PSA failure using NS criteria not including PSA.

Maximum tumor diameter and the risk of prostate-specific antigen recurrence after radical prostatectomy.

INTRODUCTION/BACKGROUND: The aim of this study was to investigate whether the MTD could identify men at low risk of PSA recurrence after RP who might not benefit from ART despite other adverse features. PATIENTS AND METHODS: The study cohort consisted of 354 men with T1c to T2 prostate cancer diagnosed between September 2001 and December 2008 who underwent RP without adjuvant therapy. Multivariable Cox regression was used to assess the effect of MTD on the risk of PSA recurrence (> 0.1 ng/mL and verified), adjusting for known predictors. RESULTS: After a median follow-up of 4.0 years, 34 men (9.6%) experienced PSA failure. In multivariable analysis, increasing MTD was significantly associated with an increased PSA recurrence risk (hazard ratio, 2.74; 95% confidence interval, 1.23-6.10; P = .01) within the interaction model. Estimates of PSA recurrence-free survival stratified around the median MTD value (1.2 cm) were significantly different in men with a pre-RP PSA > 4 ng/mL (P < .001; 5-year estimate: 74.5% vs. 99.0%) but not in men with PSA ≤ 4 ng/mL (P = .59; 5-year estimate: 89.6% vs. 92.6%), consistent with the significant interaction (P = .004) between PSA and MTD. Moreover, in men with a pre-RP PSA > 4 ng/mL these estimates were significantly different if at least 1 adverse feature (pT3, R1, or Gleason score ≥ 8) was present at RP (P = .01; 5-year estimate: 46.6% vs. 100%) versus none (P = .09; 5-year estimate: 93.4% vs. 98.9%). CONCLUSION: Men with a low MTD (≤ 1.2 cm) appear to be at low risk of PSA recurrence despite adverse features at RP and might not benefit from ART.

Natural history of untreated prostate specific antigen radiorecurrent prostate cancer in men with favorable prognostic indicators.

Background and Purpose. Life expectancy data could identify men with favorable post-radiation prostate-specific antigen (PSA) failure kinetics unlikely to require androgen deprivation therapy (ADT). Materials and Methods. Of 206 men with unfavorable-risk prostate cancer in a randomized trial of radiation versus radiation and ADT, 53 experienced a PSA failure and were followed without salvage ADT. Comorbidity, age and established prognostic factors were assessed for relationship to death using Cox regression analyses. Results. The median age at failure, interval to PSA failure, and PSA doubling time were 76.6 years (interquartile range [IQR]: 71.8-79.3), 49.1 months (IQR: 37.7-87.4), and 25 months (IQR: 13.1-42.8), respectively. After a median follow up of 4.0 years following PSA failure, 45% of men had died, none from prostate cancer and no one had developed metastases. Both increasing age at PSA failure (HR: 1.14; 95% CI: 1.03-1.25; P = 0.008) and the presence of moderate to severe comorbidity (HR: 12.5; 95% CI: 3.81-41.0; P < 0.001) were significantly associated with an increased risk of death. Conclusions. Men over the age of 76 with significant comorbidity and a PSA doubling time >2 years following post-radiation PSA failure appear to be good candidates for observation without ADT intervention.

The effect of differing Gleason scores at biopsy on the odds of upgrading and the risk of death from prostate cancer.

INTRODUCTION/BACKGROUND: The GS is an established prostate cancer prognostic factor. Whether the presence of differing GSs at biopsy (eg, 4+3 and 3+3), which we term ComboGS, improves the prognosis that would be predicted based on the highest GS (eg, 4+3) because of decreased upgrading is unknown. Therefore, we evaluated the odds of upgrading at time of radical prostatectomy (RP) and the risk of PCSM when ComboGS was present versus absent. PATIENTS AND METHODS: Logistic and competing risks regression were performed to assess the effect that ComboGS had on the odds of upgrading at time of RP in the index (n = 134) and validation cohorts (n = 356) and the risk of PCSM after definitive therapy in a long-term cohort (n = 666), adjusting for known predictors of these end points. We calculated and compared the area under the curve using a receiver operating characteristic analysis when ComboGS was included versus excluded from the upgrading models. RESULTS: ComboGS was associated with decreased odds of upgrading (index: adjusted odds ratio [AOR], 0.14; 95% confidence interval [CI], 0.04-0.50; P = .003; validation: AOR, 0.24; 95% CI, 0.11-0.51; P < .001) and added significantly to the predictive value of upgrading for the in-sample index (P = .02), validation (P = .003), and out-of-sample prediction models (P = .002). ComboGS was also associated with a decreased risk of PCSM (adjusted hazard ratio, 0.40; 95% CI, 0.19-0.85; P = .02). CONCLUSION: Differing biopsy GSs are associated with a lower odds of upgrading and risk of PCSM. If validated, future randomized noninferiority studies evaluating deescalated treatment approaches in men with ComboGS could be considered.