Prostate-Specific Antigen After Neoadjuvant Androgen Suppression in Prostate Cancer Patients Receiving Short-Term Androgen Suppression and External Beam Radiation Therapy: Pooled Analysis of Four NRG Oncology Radiation Therapy Oncology Group Randomized Clinical Trials.

PURPOSE: To validate whether prostate-specific antigen (PSA) level after neoadjuvant androgen suppression (neoAS) is associated with long-term outcome after neoAS and external beam radiation therapy (RT) with concurrent short-term androgen suppression (AS) in patients with prostate cancer. METHODS AND MATERIALS: This study included 2404 patients. The patients were treated with neoAS before RT and concurrent AS (without post-RT AS) and were pooled from NRG Oncology/RTOG trials 9202, 9408, 9413, and 9910. Multivariable models were used to test associations between the prespecified dichotomized post-neoAS, pre-RT PSA level (≤0.1 vs >0.1 ng/mL) groupings, and clinical outcomes. RESULTS: The median follow-up for surviving patients was 9.4 years. The median post-neoAS, pre-RT PSA level was 0.3 ng/mL, with 32% of patients having levels ≤0.1 ng/mL. Race, Gleason score, tumor stage, node stage, pretreatment PSA level, and duration of neoAS were associated with the groups of patients with PSA levels ≤0.1 and >0.1 ng/mL. In univariate analyses, post-neoAS, pre-RT PSA level >0.1 ng/mL was associated with increased risks of biochemical failure (hazard ratio [HR], 2.04; P < .0001); local failure (HR, 2.51; P < .0001); distant metastases (HR, 1.73; P = .0006); cause-specific mortality (HR, 2.36; P < .0001); and all-cause mortality (HR, 1.24; P = .005). In multivariable models that also included baseline and treatment variables, post-neoAS, pre-RT PSA level >0.1 ng/mL was independently associated with increased risk of biochemical failure (HR, 2.00; P < .0001); local failure (HR, 2.33; P < .0001); and cause-specific mortality (HR, 1.75; P = .03). CONCLUSIONS: Patients with a PSA level >0.1 ng/mL after neoAS and before the start of RT had less favorable clinical outcomes than patients whose PSA level was ≤0.1 ng/mL. The role of post-neoAS, pre-RT PSA level relative to PSA levels obtained along the continuum of medical care is not presently defined but could be tested in future clinical trials.

Association of Gleason Grade With Androgen Deprivation Therapy Duration and Survival Outcomes: A Systematic Review and Patient-Level Meta-analysis.

Importance: Androgen deprivation therapy (ADT) improves survival outcomes in patients with high-risk prostate cancer (PCa) treated with radiotherapy (RT). Whether this benefit differs between patients with Gleason grade group (GG) 4 (formerly Gleason score 8) and GG 5 (formerly Gleason score 9-10) disease remains unknown. Objective: To determine whether the effectiveness of ADT duration varies between patients with GG 4 vs GG 5 PCa. Design, Setting, and Participants: Traditional and network individual patient data meta-analyses of 992 patients (593 GG 4 and 399 GG 5) who were enrolled in 6 randomized clinical trials were carried out. Main Outcomes and Measures: Multivariable Cox proportional hazard models were used to obtain hazard ratio (HR) estimates of ADT duration effects on overall survival (OS) and distant metastasis-free survival (DMFS). Cause-specific competing risk models were used to estimate HRs for cancer-specific survival (CSS). The interaction of ADT with GS was incorporated into the multivariable models. Traditional and network meta-analysis frameworks were used to compare outcomes of patients treated with RT alone, short-term ADT (STADT), long-term ADT (LTADT), and lifelong ADT. Results: Five hundred ninety-three male patients (mean age, 70 years; range, 43-88 years) with GG 4 and 399 with GG 5 were identified. Median follow-up was 6.4 years. Among GG 4 patients, LTADT and STADT improved OS over RT alone (HR, 0.43; 95% CI, 0.26-0.70 and HR, 0.59; 95% CI, 0.38-0.93, respectively; P = .03 for both), whereas lifelong ADT did not (HR, 0.84; 95% CI, 0.54-1.30; P = .44). Among GG 5 patients, lifelong ADT improved OS (HR, 0.48; 95% CI, 0.31-0.76; P = .04), whereas neither LTADT nor STADT did (HR, 0.80; 95% CI, 0.45-1.44 and HR, 1.13; 95% CI, 0.69-1.87; P = .45 and P = .64, respectively). Among all patients, and among those receiving STADT, GG 5 patients had inferior OS compared with GG 4 patients (HR, 1.25; 95% CI, 1.07-1.47 and HR, 1.40; 95% CI, 1.05-1.88, respectively; P = .02). There was no significant OS difference between GG 5 and GG 4 patients receiving LTADT or lifelong ADT (HR, 1.21; 95% CI, 0.89-1.65 and HR, 0.85; 95% CI, 0.53-1.37; P = .23 and P = .52, respectively). Conclusions and Relevance: These data suggest that prolonged durations of ADT improve survival outcomes in both GG 4 disease and GG 5 disease, albeit with different optimal durations. Strategies to maintain the efficacy of ADT while minimizing its duration (potentially with enhanced potency agents) should be investigated.

Risk factors for late bowel and bladder toxicities in NRG Oncology prostate cancer trials of high-risk patients: A meta-analysis of physician-rated toxicities.

PURPOSE: A meta-analysis of sociodemographic variables and their association with late (>180 days from start of radiation therapy[RT]) bowel, bladder, and clustered bowel and bladder toxicities was conducted in patients with high-risk (clinical stages T2c-T4b or Gleason score 8-10 or prostate-specific antigen level >20) prostate cancer. METHODS AND MATERIALS: Three NRG trials (RTOG 9202, RTOG 9413, and RTOG 9406) that accrued from 1992 to 2000 were used. Late toxicities were measured with the Radiation Therapy Oncology Group Late Radiation Morbidity Scale. After controlling for study, age, Karnofsky Performance Status, and year of accrual, sociodemographic variables were added to the model for each outcome variable of interest in a stepwise fashion using the Fine-Gray regression models with an entry criterion of 0.05. RESULTS: A total of 2432 patients were analyzed of whom most were Caucasian (76%), had a KPS score of 90 to 100 (92%), and received whole-pelvic RT+HT (67%). Of these patients, 13 % and 16% experienced late grade ≥2 bowel and bladder toxicities, respectively, and 2% and 3% experienced late grade ≥3 bowel and bladder toxicities, respectively. Late grade ≥2 clustered bowel and bladder toxicities were seen in approximately 1% of patients and late grade ≥3 clustered toxicities were seen in 2 patients (<1%). The multivariate analysis showed that patients who received prostate-only RT+HT had a lower risk of experiencing grade ≥2 bowel toxicities than those who received whole-pelvic RT+long-term (LT) HT (hazard ratio: 0.36; 95% confidence interval, 0.18-0.73; P = .0046 and hazard ratio: 0.43; 95% confidence interval, 0.23-0.80; P = .008, respectively). Patients who received whole-pelvic RT had similar chances of having grade ≥2 bowel or bladder toxicities no matter whether they received LT or short-term HT. CONCLUSIONS: Patients with high-risk prostate cancer who receive whole-pelvic RT+LT HT are more likely to have a grade ≥2 bowel toxicity than those who receive prostate-only RT. LT bowel and bladder toxicities were infrequent. Future studies will need to confirm these findings utilizing current radiation technology and patient-reported outcomes.

Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-Term Update of NRG Oncology RTOG 9202.

PURPOSE: Trial RTOG 9202 was a phase 3 randomized trial designed to determine the optimal duration of androgen deprivation therapy (ADT) when combined with definitive radiation therapy (RT) in the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate. Long-term follow-up results of this study now available are relevant to the management of this disease. METHODS AND MATERIALS: Men (N=1554) with adenocarcinoma of the prostate (cT2c-T4, N0-Nx) with a prostate-specific antigen (PSA) <150 ng/mL and no evidence of distant metastasis were randomized (June 1992 to April 1995) to short-term ADT (STAD: 4 months of flutamide 250 mg 3 times per day and goserelin 3.6 mg per month) and definitive RT versus long-term ADT (LTAD: STAD with definitive RT plus an additional 24 months of monthly goserelin). RESULTS: Among 1520 protocol-eligible and evaluable patients, the median follow-up time for this analysis was 19.6 years. In analysis adjusted for prognostic covariates, LTAD improved disease-free survival (29% relative reduction in failure rate, P<.0001), local progression (46% relative reduction, P=.02), distant metastases (36% relative reduction, P<.0001), disease-specific survival (30% relative reduction, P=.003), and overall survival (12% relative reduction, P=.03). Other-cause mortality (non-prostate cancer) did not differ (5% relative reduction, P=.48). CONCLUSIONS: LTAD and RT is superior to STAD and RT for the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate and should be considered the standard of care.

Effect of Long-Term Hormonal Therapy (vs Short-Term Hormonal Therapy): A Secondary Analysis of Intermediate-Risk Prostate Cancer Patients Treated on NRG Oncology RTOG 9202.

PURPOSE: NRG Oncology RTOG 9202 was a randomized trial testing long-term adjuvant androgen deprivation (LTAD) versus initial androgen deprivation only (STAD) with external beam radiation therapy (RT) in mostly high-risk and some intermediate-risk prostate cancer patients. RTOG 9408 found an overall survival (OS) advantage in patients with cT1b-T2b disease and prostate-specific antigen (PSA) <20 ng/mL, with benefit observed mostly among intermediate-risk patients. It was still unknown whether intermediate-risk patients would experience an additional survival benefit with LTAD; thus, we performed a secondary analysis to explore whether LTAD had any incremental benefit beyond STAD among the intermediate-risk subset of RTOG 9202. The study endpoints were OS, disease-specific survival (DSS), and PSA failure (PSAF). METHODS AND MATERIALS: An analysis was performed for all patients enrolled in RTOG 9202 defined as intermediate-risk (cT2 disease, PSA<10 ng/mL, and Gleason score = 7 or cT2 disease, PSA 10-20 ng/mL, and Gleason score <7). This review yielded 133 patients: 74 (STAD) and 59 (LTAD). The Kaplan-Meier method was used to estimate OS; the cumulative incidence approach was used to estimate DSS and PSAF. A 2-sided test was used, with significance level defined to be .05. RESULTS: With over 11 years of median follow-up, 39 STAD patients were alive and 33 LTAD patients were alive. There was no difference in OS (10-year estimates, 61% STAD vs 65% LTAD; P=.53), DSS (10-year DSS, 96% vs 97%; P=.72), or PSAF (10-year PSAF, 53% vs 55%; P=.99) between groups. CONCLUSION: LTAD did not confer a benefit in terms of OS, DSS, or PSAF rates in the intermediate-risk subset in this study. Whereas the subset was relatively small, treatment assignment was randomly applied, and a trend in favor of LTAD would have been of interest. Given the small number of disease-specific deaths observed and lack of benefit with respect to our endpoints, this secondary analysis does not suggest that exploration of longer hormonal therapy is worth testing in the intermediate-risk prostate cancer subset.

Impact of biochemical failure classification on clinical outcome: a secondary analysis of Radiation Therapy Oncology Group 9202 and 9413.

BACKGROUND: Biochemical failure (BF) after radiation therapy is defined on the basis of a rising prostate-specific antigen (PSA) level (A1 failure) or any event that prompts the initiation of salvage androgen-deprivation therapy without PSA failure (A2). It was hypothesized that A2 failure may have a different prognosis. METHODS: Data for 2799 eligible patients from Radiation Therapy Oncology Group (RTOG) 9202 and RTOG 9413 were analyzed. BF was defined according to the 1997 American Society for Therapeutic Radiology and Oncology consensus definition as A1 for PSA failure or as A2 for the start of salvage hormone therapy before 3 consecutive PSA rises. RESULTS: Rates of all-cause mortality (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.5-2.0; P < .0001) and distant metastasis (DM; HR, 1.6; 95% CI, 1.3-2.0; P < .0001) were greater with A2 failure. The 5-year overall survival (OS) rates were 88.2% and 74.6% for A1 and A2, respectively (P < .0001), and the DM rates were 15.7% and 29.0%, respectively (P < .0001). The DM rate was greater at 5 years for A2 patients with DM as the first sign of failure versus patients with other A2 failures (87.3% vs 11.7%, P < .001), and this also correlated with worse OS at 5 years: 81.1% for A2 failure without DM and 52.8% with DM (P < .001). After the removal of patients with DM, the difference between A1 and A2 BF persisted for OS (P = .002) but not for DM (P = .16) CONCLUSIONS: These results suggest that patients with rising PSA levels alone have less risk than those with A2 failures; although DM was the largest contributor of adverse risk to A2 failure, it did not account for all excess risk in A2 failure.

A tissue biomarker-based model that identifies patients with a high risk of distant metastasis and differential survival by length of androgen deprivation therapy in RTOG protocol 92-02.

PURPOSE: To examine the relationship between the expression of 7 promising apoptotic/cell proliferation proteins (Ki-67, p53, MDM2, bcl-2, bax, p16, and Cox-2) and risk of distant metastasis. EXPERIMENTAL DESIGN: RTOG 92-02 compared external beam radiotherapy (EBRT) to approximately 70 Gy + short-term androgen deprivation therapy (STADT) with EBRT + long-term ADT (LTADT). Immunohistochemical analysis was available for ≥4 biomarkers in 616 of 1,521 assessable cases. Biomarkers were evaluated individually and jointly via multivariable modeling of distant metastasis using competing risks hazards regression, adjusting for age, prostate-specific antigen, Gleason score, T stage, and treatment. RESULTS: Modeling identified four biomarkers (Ki-67, MDM2, p16 and Cox-2) that were jointly associated with distant metastasis. The c-index was 0.77 for the full model and 0.70 for the model without the biomarkers; a relative improvement of about 10% (likelihood ratio P < 0.001). Subdivision of the patients into quartiles based on predicted distant metastasis risk identified a high-risk group with 10-year distant metastasis risk of 52.5% after EBRT + STADT and 31% with EBRT + LTADT; associated 10-year prostate cancer-specific mortality (PCSM) risks were 45.9% and 14.5% with STADT and LTADT. CONCLUSION: Four biomarkers were found to contribute significantly to a model that predicted distant metastasis and identified a subgroup of patients at a particularly high risk of both distant metastasis and PCSM when EBRT + STADT was used. LTADT resulted in significant reductions in distant metastasis and improvements in PCSM, and there was a suggestion of greater importance in the very high risk subgroup.

Radiotherapy doses of 80 Gy and higher are associated with lower mortality in men with Gleason score 8 to 10 prostate cancer.

PURPOSE: Men with Gleason score (GS) 8-10 prostate cancer (PCa) are assumed to have a high risk of micrometastatic disease at presentation. However, local failure is also a major problem. We sought to establish the importance of more aggressive local radiotherapy (RT) to ≥80 Gy. METHODS AND MATERIALS: There were 226 men treated consecutively with RT ± ADT from 1988 to 2002 for GS 8-10 PCa. Conventional, three-dimensional conformal or intensity-modulated (IM) RT was used. Radiation dose was divided into three groups: (1) <75 Gy (n = 50); (2) 75-79.9 Gy (n = 60); or (3) ≥80 Gy (n = 116). The endpoints examined included biochemical failure (BF; nadir + 2 definition), distant metastasis (DM), cause-specific mortality, and overall mortality (OM). RESULTS: Median follow-up was 66, 71, and 58 months for Groups 1, 2, and 3. On Fine and Gray's competing risk regression analysis, significant predictors of reduced BF were RT dose ≥80 Gy (p = 0.011) and androgen deprivation therapy duration ≥24 months (p = 0.033). In a similar model of DM, only RT dose ≥80 Gy was significant (p = 0.007). On Cox regression analysis, significant predictors of reduced OM were RT dose ≥80 Gy (p = 0.035) and T category (T3/4 vs. T1, p = 0.041). Dose was not a significant determinant of cause-specific mortality. Results for RT dose were similar in a model with RT dose and ADT duration as continuous variables. CONCLUSION: The results indicate that RT dose escalation to ≥80 Gy is associated with lower risks of BF, DM, and OM in men with GS 8-10 PCa, independently of androgen deprivation therapy.

Older age predicts decreased metastasis and prostate cancer-specific death for men treated with radiation therapy: meta-analysis of radiation therapy oncology group trials.

PURPOSE: The impact of age on prostate cancer (PCa) outcome has been controversial; therefore, we analyzed the effect of age on overall survival (OS), distant metastasis, prostate cancer-specific death (PCSD), and nonprostate cancer death (NPCD) on patients with locally advanced PCa. METHODS AND MATERIALS: Patients who participated in four Radiation Therapy Oncology Group (RTOG) phase III trials, 8531, 8610, 9202, and 9413, were studied. Cox proportional hazards regression was used for OS analysis, and cumulative events analysis with Fine and Gray's regression was used for analyses of metastasis, PCSD, and NPCD. RESULTS: Median follow-up of 4,128 patients with median age of 70 (range, 43-88 years) was 7.3 years. Most patients had high-risk disease: cT3 to cT4 (54%) and Gleason scores (GS) of 7 (45%) and 8 to 10 (27%). Older age (≤70 vs. >70 years) predicted for decreased OS (10-year rate, 55% vs. 41%, respectively; p<0.0001) and increased NPCD (10-year rate, 28% vs. 46%, respectively; p<0.0001) but decreased metastasis (10-year rate, 27% vs. 20%, respectively; p<0.0001) and PCSD (10-year rate, 18% vs. 14%, respectively; p<0.0001). To account for competing risks, outcomes were analyzed in 2-year intervals, and age-dependent differences in metastasis and PCSD persisted, even in the earliest time periods. When adjusted for other covariates, an age of >70 years remained associated with decreased OS (hazard ratio [HR], 1.56 [95% confidence interval [CI], 1.43-1.70] p<0.0001) but with decreased metastasis (HR, 0.72 [95% CI, 0.63-0.83] p<0.0001) and PCSD (HR, 0.78 [95% CI, 0.66-0.92] p<0.0001). Finally, the impact of the duration of androgen deprivation therapy as a function of age was evaluated. CONCLUSIONS: These data support less aggressive PCa in older men, independent of other clinical features. While the biological underpinning of this finding remains unknown, stratification by age in future trials appears to be warranted.

Impact of ultrahigh baseline PSA levels on biochemical and clinical outcomes in two Radiation Therapy Oncology Group prostate clinical trials.

PURPOSE: To assess ultrahigh (UH; prostate-specific antigen [PSA] levels ≥50 ng/ml) patient outcomes by comparison to other high-risk patient outcomes and to identify outcome predictors. METHODS AND MATERIALS: Prostate cancer patients (PCP) from two Phase III Radiation Therapy Oncology Group clinical trials (studies 9202 and 9413) were divided into two groups: high-risk patients with and without UH baseline PSA levels. Predictive variables included age, Gleason score, clinical T stage, Karnofsky performance score, and treatment arm. Outcomes included overall survival (OS), distant metastasis (DM), and biochemical failure (BF). Unadjusted and adjusted hazard ratios (HRs) were calculated using either the Cox or Fine and Gray's regression model with associated 95% confidence intervals (CI) and p values. RESULTS: There were 401 patients in the UH PSA group and 1,792 patients in the non-UH PSA PCP group of a total of 2,193 high-risk PCP. PCP with UH PSA were found to have inferior OS (HR, 1.19; 95% CI, 1.02-1.39, p = 0.02), DM (HR, 1.51; 95% CI, 1.19-1.92; p = 0.0006), and BF (HR, 1.50; 95% CI, 1.29-1.73; p < 0.0001) compared to other high-risk PCP. In the UH cohort, PSA level was found to be a significant factor for the risk of DM (HR, 1.01; 95% CI, 1.001-1.02) but not OS and BF. Gleason grades of 8 to 10 were found to consistently predict for poor OS, DM, and BF outcomes (with HR estimates ranging from 1.41-2.36) in both the high-risk cohort and the UH cohort multivariable analyses. CONCLUSIONS: UH PSA levels at diagnosis are related to detrimental changes in OS, DM, and BF. All three outcomes can be modeled by various combinations of all predictive variables tested.

Baseline serum testosterone in men treated with androgen deprivation therapy and radiotherapy for localized prostate cancer.

INTRODUCTION: It is believed that men diagnosed with prostate cancer and a low baseline serum testosterone (BST) may have more aggressive disease, and it is frequently recommended they forego testosterone replacement therapy. We used two large Phase III trials involving androgen deprivation therapy and external beam radiation therapy to assess the significance of a BST. METHODS AND MATERIALS: All patients with a BST and complete data (n = 2,478) were included in this analysis and divided into four categories: "Very Low BST" (VLBST) ≤16.5th percentile of BST (≤248 ng/dL; n = 408); "Low BST" (LBST) >16.5th percentile and ≤33rd percentile (>248 ng/dL but ≤314 ng/dL; n = 415); "Average BST" (ABST) >33rd percentile and ≤67th percentile (314-437 ng/dL; n = 845); and "High BST" (HBST) >67th percentile (>437 ng/dL; n = 810). Outcomes included overall survival, distant metastasis, biochemical failure, and cause-specific survival. All outcomes were adjusted for the following covariates: treatment arm, BST, age (<70 vs. ≥70), prostate-specific antigen (PSA; <10 vs. 10 ≤ PSA <20 vs. 20 ≤), Gleason score (2-6 vs. 7 vs. 8-10); T stage (T1-T2 vs. T3-T4), and Karnofsky Performance Status (60-90 vs. 100). RESULTS: On multivariable analysis age, Gleason score, and PSA were independently associated with an increased risk of biochemical failure, distant metastasis and a reduced cause-specific and overall survival (p < 0.05), but BST was not. CONCLUSIONS: BST does not affect outcomes in men treated with external beam radiation therapy and androgen deprivation therapy for prostate cancer.

MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer: RTOG 92-02.

PURPOSE MDM2 regulates p53, which controls cell cycle arrest and apoptosis. Both proteins, along with Ki-67, which is an established strong determinant of metastasis, have shown promise in predicting the outcome of men treated with radiation therapy (RT) with or without short-term androgen deprivation (STAD). This report compares the utility of abnormal expression of these biomarkers in estimating progression in a cohort of men treated on RTOG 92-02. PATIENTS AND METHODS Adequate tissue for immunohistochemistry was available for p53, Ki-67, and MDM2 analyses in 478 patient cases. The percentage of tumor nuclei staining positive (PSP) was quantified manually or by image analysis, and the per-sample mean intensity score (MIS) was quantified by image analysis. Cox regression models were used to estimate overall mortality (OM), and Fine and Gray's regressions were applied to the end points of distant metastasis (DM) and cause-specific mortality (CSM). Results In multivariate analyses that adjusted for all markers and treatment covariates, MDM2 overexpression was significantly related to DM (P = .02) and OM (P = .003), and Ki-67 overexpression was significantly related to DM (P < .0001), CSM (P = .0007), and OM (P = .01). P53 overexpression was significantly related to OM (P = .02). When considered in combination, the overexpression of both Ki-67 and MDM2 at high levels was associated with significantly increased failure rates for all end points (P < .001 for DM, CSM, and OM). CONCLUSION Combined MDM2 and Ki-67 expression levels were independently related to distant metastasis and mortality and, if validated, could be considered for risk stratification of patients with prostate cancer in clinical trials.

Potential surrogate endpoints for prostate cancer survival: analysis of a phase III randomized trial.

BACKGROUND: The identification of surrogate endpoints for prostate cancer-specific survival may shorten the length of clinical trials for prostate cancer. We evaluated distant metastasis and general clinical treatment failure as potential surrogates for prostate cancer-specific survival by use of data from the Radiation Therapy and Oncology Group 92-02 randomized trial. METHODS: Patients (n = 1554 randomly assigned and 1521 evaluable for this analysis) with locally advanced prostate cancer had been treated with 4 months of neoadjuvant and concurrent androgen deprivation therapy with external beam radiation therapy and then randomly assigned to no additional therapy (control arm) or 24 additional months of androgen deprivation therapy (experimental arm). Data from landmark analyses at 3 and 5 years for general clinical treatment failure (defined as documented local disease progression, regional or distant metastasis, initiation of androgen deprivation therapy, or a prostate-specific antigen level of 25 ng/mL or higher after radiation therapy) and/or distant metastasis were tested as surrogate endpoints for prostate cancer-specific survival at 10 years by use of Prentice's four criteria. All statistical tests were two-sided. RESULTS: At 3 years, 1364 patients were alive and contributed data for analysis. Both distant metastasis and general clinical treatment failure at 3 years were consistent with all four of Prentice's criteria for being surrogate endpoints for prostate cancer-specific survival at 10 years. At 5 years, 1178 patients were alive and contributed data for analysis. Although prostate cancer-specific survival was not statistically significantly different between treatment arms at 5 years (P = .08), both endpoints were consistent with Prentice's remaining criteria. CONCLUSIONS: Distant metastasis and general clinical treatment failure at 3 years may be candidate surrogate endpoints for prostate cancer-specific survival at 10 years. These endpoints, however, must be validated in other datasets.

Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31.

PURPOSE: Gonadotropin-releasing hormone (GnRH) agonists are associated with greater risk of coronary heart disease and myocardial infarction in men with prostate cancer, but little is known about potential impact on cardiovascular mortality. We assessed the relationship between GnRH agonists and cardiovascular mortality in a large randomized phase III trial of men treated with or without adjuvant goserelin after radiation therapy (RT) for locally advanced prostate cancer. PATIENTS AND METHODS: Between 1987 and 1992, 945 men with locally advanced prostate cancer were randomly assigned to RT and adjuvant goserelin or RT alone. Fine and Gray's regression was used to evaluate treatment effect on cardiovascular mortality. Covariates included age, prevalent cardiovascular disease (CVD), hypertension, diabetes mellitus (DM), body mass index, race, Gleason score, stage, acid phosphatase level, prostatectomy history, and nodal involvement. RESULTS: After a median follow-up of 8.1 years, there were 117 cardiovascular-related deaths but no treatment-related increase in cardiovascular mortality. At 9 years, cardiovascular mortality for men receiving adjuvant goserelin was 8.4% v 11.4% for men treated without adjuvant goserelin (Gray's P = .17). In multiple regression analyses, treatment arm was not significantly associated with increased risk of cardiovascular mortality (adjusted hazard ratio [HR] = 0.73; 95% CI, 0.47 to 1.15; P = .16; when censoring at time of salvage goserelin therapy, HR = 0.99; 95% CI, 0.58 to 1.69; P = .97). Traditional cardiac risk factors, including prevalent CVD and DM, were significantly associated with greater cardiovascular mortality. CONCLUSION: GnRH agonists do not seem to increase cardiovascular mortality in men with locally advanced prostate cancer. Further studies are warranted to evaluate adverse effects of GnRH agonists in men with lower cancer-specific mortality.

Diabetes and mortality in men with locally advanced prostate cancer: RTOG 92-02.

PURPOSE: Diabetes is associated with lower risk of prostate cancer. Most men with diabetes are obese, and obesity is associated with greater prostate cancer mortality. Whether diabetes influences outcomes after prostate cancer diagnosis is unknown. PATIENTS AND METHODS: We assessed the relationship between prevalent diabetes and mortality using data from Radiation Therapy Oncology Group Protocol 92-02, a large randomized trial of men (N = 1,554) treated with radiation therapy and short-term versus long-term adjuvant goserelin for locally advanced prostate cancer. Regression and proportional hazard models were performed to evaluate relationships between prevalent diabetes and all-cause mortality, prostate cancer mortality, and non-prostate cancer mortality. Covariates included age, race, tumor stage, Gleason score, prostate-specific antigen, weight, and treatment arm. RESULTS: There were a total of 765 deaths; 210 (27%) were attributed to prostate cancer. In univariate analyses, prevalent diabetes was associated with greater all-cause mortality and non-prostate cancer mortality but not prostate cancer mortality. After controlling for other covariates, prevalent diabetes remained significantly associated with greater all-cause mortality and non-prostate cancer mortality (hazard ratio [HR] = 2.12; 95% CI, 1.69 to 2.66; P < .0001) but not prostate cancer mortality (HR = 0.80; 95% CI, 0.51 to 1.25; P = .34). In contrast, weight was associated with greater prostate cancer mortality (HR = 1.77; 95% CI, 1.22 to 2.55; P = .002) but not all-cause or non-prostate cancer mortality. CONCLUSION: Weight but not prevalent diabetes is associated with greater prostate cancer mortality in men receiving combined modality treatment for locally advanced disease. These observations suggest that the association between obesity and greater prostate cancer mortality is mediated by mechanism(s) other than the characteristic metabolic alterations of diabetes.

Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer.

PURPOSE: To determine whether adding 2 years of androgen-deprivation therapy (ADT) improved outcome for patients electively treated with ADT before and during radiation therapy (RT). PATIENTS AND METHODS: Prostate cancer patients with T2c-T4 prostate cancer with no extra pelvic lymph node involvement and prostate-specific antigen (PSA) less than 150 ng/mL were included. All patients received 4 months of goserelin and flutamide before and during RT. They were randomized to no further ADT (short-term ADT [STAD] + RT) or 24 months of goserelin (long-term ADT [LTAD] + RT). A total of 1,554 patients were entered. RT was 45 Gy to the pelvic nodes and 65 to 70 Gy to the prostate. Median follow-up of all survival patients is 11.31 and 11.27 years for the two arms. RESULTS: At 10 years, the LTAD + RT group showed significant improvement over the STAD + RT group for all end points except overall survival: disease-free survival (13.2% v 22.5%; P < .0001), disease-specific survival (83.9% v 88.7%; P = .0042), local progression (22.2% v 12.3%; P < .0001), distant metastasis (22.8% v 14.8%; P < .0001), biochemical failure (68.1% v 51.9%; P

Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: analysis of RTOG 92-02.

OBJECTIVES: Gonadotropin-releasing hormone agonists (GnRHa) are associated with greater risk of coronary heart disease and myocardial infarction in men with prostate cancer, but little is known about their potential effects on cardiovascular mortality. We assessed the relationship between duration of GnRHa therapy and cardiovascular mortality in a large randomized trial of men treated with short-term versus longer-term adjuvant goserelin and radiation therapy (RT) for locally advanced prostate cancer. METHODS: From 1992 to 1995, 1554 men with locally advanced prostate cancer (T2c-4, prostate-specific antigen [PSA] <150 ng/ml) received RT and 4 mo of goserelin and then were randomized to no additional therapy (arm 1) or 24 mo adjuvant goserelin (arm 2) in a phase 3 trial (Radiation Therapy Oncology Group [RTOG] 92-02). Cox regression analyses were performed to evaluate the relationship between treatment arm and cardiovascular mortality. Covariates included age, prevalent cardiovascular disease (CVD), hypertension, diabetes (DM), race, PSA, Gleason score, and stage. RESULTS: After median follow-up of 8.1 yr, 185 cardiovascular-related deaths had occurred. No increase in cardiovascular mortality occurred for men receiving a longer duration of goserelin. At 5 yr, cardiovascular mortality for men receiving longer-term adjuvant goserelin was 5.9% versus 4.8% with short-term goserelin (Gray's p=0.16). In multivariate analyses, treatment arm was not significantly associated with increased risk of cardiovascular mortality (adjusted hazard ratio [HR]=1.09; 95% confidence interval [CI], 0.81-1.47; p=0.58; when censoring at time of salvage goserelin, HR=1.02, 95%CI, 0.73-1.43; p=0.9). Traditional cardiac risk factors, including age, prevalent CVD, and DM, were significantly associated with greater cardiovascular mortality. CONCLUSIONS: Longer duration of adjuvant GnRHa therapy does not appear to increase cardiovascular mortality in men with locally advanced prostate cancer.

Long-term treatment sequelae after external beam irradiation with or without hormonal manipulation for adenocarcinoma of the prostate: analysis of radiation therapy oncology group studies 85-31, 86-10, and 92-02.

PURPOSE: Late gastrointestinal (GI) and genitourinary (GU) morbidity from external beam irradiation used to treat adenocarcinoma of the prostate continue to be a concern of physicians and patients alike. In addition, for locally advanced/high-risk cancer, the appropriate use of hormonal manipulation in addition to radiation therapy (RT) may increase toxicity. We analyzed three large Radiation Therapy Oncology Group (RTOG) studies (85-31, 86-10, and 92-02) to try to address these issues. METHODS AND MATERIALS: A total of 2,922 patients were accrued with a median follow-up of 10.3 years for surviving patients. The RTOG scoring scheme was used to assess GI, GU, and other toxicities. Toxicity reported was Grade 3 or higher late toxicity. Patient toxicity level was assessed by study and by treatment type combining RT only vs. RT + short-course hormone therapy (STH) vs. RT + long-term hormone therapy (LTH). RESULTS: Multivariate analysis reveals that age >70 was statistically significantly associated with a decrease in late any Grade 3+ toxicity (hazard ratio [HR] = 0.78, p = 0.0476) adjusted for treatment type. Comparing treatment type, patients treated with RT+STH had a statistically significant lower probability of Grade 3+ GI, GU, and other toxicity compared with RT alone (p = .00006; p = 0.0037; p = 0.0127, respectively). Patients treated with RT+LTH had a statistically significant lower probability of Grade 3+ GU toxicity compared with RT alone (p = 0.023). CONCLUSIONS: These data show that external beam radiation therapy remains a safe option for locally advanced/high-risk prostate cancer, and the use of hormonal manipulation does appear to be protective for GU and GI toxicity depending upon length of treatment.

Obesity and mortality in men with locally advanced prostate cancer: analysis of RTOG 85-31.

BACKGROUND: Greater body mass index (BMI) is associated with shorter time to prostate-specific antigen (PSA) failure following radical prostatectomy and radiation therapy (RT). Whether BMI is associated with prostate cancer-specific mortality (PCSM) was investigated in a large randomized trial of men treated with RT and androgen deprivation therapy (ADT) for locally advanced prostate cancer. METHODS: Between 1987 and 1992, 945 eligible men with locally advanced prostate cancer were enrolled in a phase 3 trial (RTOG 85-31) and randomized to RT and immediate goserelin or RT alone followed by goserelin at recurrence. Height and weight data were available at baseline for 788 (83%) subjects. Cox regression analyses were performed to evaluate the relations between BMI and all-cause mortality, PCSM, and nonprostate cancer mortality. Covariates included age, race, treatment arm, history of prostatectomy, nodal involvement, Gleason score, clinical stage, and BMI. RESULTS: The 5-year PCSM rate for men with BMI <25 kg/m(2) was 6.5%, compared with 13.1% and 12.2% in men with BMI > or =25 to <30 and BMI > or =30, respectively (Gray's P = .005). In multivariate analyses, greater BMI was significantly associated with higher PCSM (for BMI > or =25 to <30, hazard ratio [HR] 1.52, 95% confidence interval [CI], 1.02-2.27, P = .04; for BMI > or =30, HR 1.64, 95% CI, 1.01-2.66, P = .04). BMI was not associated with nonprostate cancer or all-cause mortality. CONCLUSIONS: Greater baseline BMI is independently associated with higher PCSM in men with locally advanced prostate cancer. Further studies are warranted to evaluate the mechanism(s) for increased cancer-specific mortality and to assess whether weight loss after prostate cancer diagnosis alters disease course.

Prostate cancer risk assessment program: a 10-year update of cancer detection.

PURPOSE: Guidelines for screening men at high risk for prostate cancer remain under investigation. We report our 10-year cancer detection data from the Prostate Cancer Risk Assessment Program, a longitudinal screening program for men at high risk. MATERIALS AND METHODS: Men between ages 35 and 69 years with a family history of prostate cancer, any black man regardless of family history or any patient with a known mutation in the BRCA 1 gene are eligible for the Prostate Cancer Risk Assessment Program and undergo longitudinal followup. Cancer detection, prostate cancer features and the predictive value of screening parameters were determined based on Prostate Cancer Risk Assessment Program biopsy criteria. RESULTS: A total of 609 men were accrued to the Prostate Cancer Risk Assessment Program as of the end of June 2006, of whom 61.2% were black. Of all participants 19% underwent prostate biopsies. The prostate cancer incidence was 9.0%, more than 90% of prostate cancers were Gleason score 6 or higher and 22% were Gleason score 7 or higher. The majority were organ confined. Of men diagnosed with prostate cancer 20% had a prostate specific antigen of less than 2.5 ng/ml and a free prostate specific antigen of less than 25% with a normal digital rectal examination. CONCLUSIONS: Our results support aggressive screening measures for men at high risk for prostate cancer. The majority of cancers detected were at a prostate specific antigen of less than 4.0 ng/ml with a fifth diagnosed at a prostate specific antigen of below 2.5 ng/ml. These cancers were intermediate to high grade and organ confined, indicating a greater likelihood of cure following local therapy in these men.