External Beam Radiation Therapy With or Without Brachytherapy Boost in Men With Very-High-Risk Prostate Cancer: A Large Multicenter International Consortium Analysis.

PURPOSE: Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear. METHODS AND MATERIALS: This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression. RESULTS: Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P = .42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P = .42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P = .38). CONCLUSIONS: In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

IMPORTANCE: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain. OBJECTIVE: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). DESIGN, SETTINGS, AND PARTICIPANTS: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021. EXPOSURES: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs). MAIN OUTCOMES AND MEASURES: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months). RESULTS: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01). CONCLUSIONS AND RELEVANCE: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.

The risk of death from prostate cancer in men with Gleason score 3+4 prostate cancer treated using brachytherapy with or without a short course of androgen deprivation therapy.

OBJECTIVE: We evaluated whether intermediate-risk factors, in addition to age, were associated with risk of prostate cancer-specific mortality (PCSM) among men with Gleason 3+4 prostate cancer. MATERIALS AND METHODS: We conducted a prospective cohort study of 1,920 men with Gleason 3+4 adenocarcinoma of the prostate who received brachytherapy (BT) or BT and a median of 4 months of androgen deprivation therapy (ADT). Separate multivariable Fine and Gray competing risks regression models among men treated with BT or BT and ADT were used to assess whether percentage of positive biopsies (PPB), cT2b-T2c stage, prostate-specific antigen (PSA) of 10.1-20.0 ng/ml, and age >70 years (median) were associated with risk of PCSM after adjustment for comorbidity. RESULTS: After median follow-up of 7.8 years, 284 men (14.8%) had died (31 from prostate cancer). For BT alone, increasing PPB, PSA of 10.1-20.0 vs. 4.0-10.0 ng/mL, and age >70 vs. ≤70 were significantly associated with increased risk of PCSM (adjusted hazard ratio 1.015, 95% confidence interval 1.000-1.031, P = 0.048; 5.55, 2.01-15.29, P<0.001; and 3.66, 1.16-11.56, P = 0.03, respectively). The respective results for BT and ADT were 1.009, 0.987-1.031, P = 0.44; 4.17, 1.29-13.50, P = 0.02; and 3.74, 0.87-16.05, P = 0.08. CONCLUSION: Among men with Gleason score 3+4 prostate cancer treated with BT, the risk of PCSM was elevated in those with PSA of 10.1-20.0 ng/mL and possibly age >70 years, despite the addition of ADT. Should these findings be validated in future studies, then advanced imaging and targeted biopsy of suspicious areas should be investigated in an effort to personalize treatment and minimize the risk of PCSM in these men.

Performance of a Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Derived Risk-Stratification Tool for High-risk and Very High-risk Prostate Cancer.

Importance: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect low-volume, nonlocalized (ie, regional or metastatic) prostate cancer that was occult on conventional imaging. However, the long-term clinical implications of PSMA PET/CT upstaging remain unclear. Objectives: To evaluate the prognostic significance of a nomogram that models an individual's risk of nonlocalized upstaging on PSMA PET/CT and to compare its performance with existing risk-stratification tools. Design, Setting, and Participants: This cohort study included patients diagnosed with high-risk or very high-risk prostate cancer (ie, prostate-specific antigen [PSA] level >20 ng/mL, Gleason score 8-10, and/or clinical stage T3-T4, without evidence of nodal or metastatic disease by conventional workup) from April 1995 to August 2018. This multinational study was conducted at 15 centers. Data were analyzed from December 2020 to March 2021. Exposures: Curative-intent radical prostatectomy (RP), external beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT), with or without androgen deprivation therapy. Main Outcomes and Measures: PSMA upstage probability was calculated from a nomogram using the biopsy Gleason score, percentage positive systematic biopsy cores, clinical T category, and PSA level. Biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) were analyzed using Fine-Gray and Cox regressions. Model performance was quantified with the concordance (C) index. Results: Of 5275 patients, the median (IQR) age was 66 (60-72) years; 2883 (55%) were treated with RP, 1669 (32%) with EBRT, and 723 (14%) with EBRT plus BT; median (IQR) PSA level was 10.5 (5.9-23.2) ng/mL; 3987 (76%) had Gleason grade 8 to 10 disease; and 750 (14%) had stage T3 to T4 disease. Median (IQR) follow-up was 5.1 (3.1-7.9) years; 1221 (23%) were followed up for at least 8 years. Overall, 1895 (36%) had BCR, 851 (16%) developed DM, and 242 (5%) died of prostate cancer. PSMA upstage probability was significantly prognostic of all clinical end points, with 8-year C indices of 0.63 (95% CI, 0.61-0.65) for BCR, 0.69 (95% CI, 0.66-0.71) for DM, 0.71 (95% CI, 0.67-0.75) for PCSM, and 0.60 (95% CI, 0.57-0.62) for PCSM (P < .001). The PSMA nomogram outperformed existing risk-stratification tools, except for similar performance to Staging Collaboration for Cancer of the Prostate (STAR-CAP) for PCSM (eg, DM: PSMA, 0.69 [95% CI, 0.66-0.71] vs STAR-CAP, 0.65 [95% CI, 0.62-0.68]; P < .001; Memorial Sloan Kettering Cancer Center nomogram, 0.57 [95% CI, 0.54-0.60]; P < .001; Cancer of the Prostate Risk Assessment groups, 0.53 [95% CI, 0.51-0.56]; P < .001). Results were validated in secondary cohorts from the Surveillance, Epidemiology, and End Results database and the National Cancer Database. Conclusions and Relevance: These findings suggest that PSMA upstage probability is associated with long-term, clinically meaningful end points. Furthermore, PSMA upstaging had superior risk discrimination compared with existing tools. Formerly occult, PSMA PET/CT-detectable nonlocalized disease may be the main driver of outcomes in high-risk patients.

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown. Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment. Design, Setting, and Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT). Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models. Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001). Conclusions and Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.

Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer.

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa. PATIENT SUMMARY: High-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.

Long-term outcomes of a prospective randomized trial of 131Cs/125I permanent prostate brachytherapy.

PURPOSE: Iodine-125 (125I) is the most commonly used isotope for prostate brachytherapy (BT). Cesium-131 (131Cs) has a higher dose rate and shorter dose delivery time resulting in decreased duration of acute urinary morbidity. Long-term data suggest excellent oncologic outcomes; it is not known how outcomes compare. A prospective randomized trial comparing the two isotopes was initiated. MATERIALS AND METHODS: Patients with low- or intermediate-risk disease were treated with a BT in a single outpatient facility. Prescription dose was 144 Gy for 125I and 115 Gy for 131Cs. Androgen deprivation or supplemental EBRT was not allowed. The primary study objective was comparison of the mean EPIC Urinary Domain Score. Secondary objective was biochemical relapse-free survival (BRFS) comparison. Time-to-event for all outcomes of interest was measured from implant date. RESULTS: One hundred forty men were enrolled; 81.4% were low-risk and 18.6% were intermediate-risk. The median followup was 97 months. Urinary and sexual health-related quality of life did not differ between isotopes at any recorded time point. At 2 months after implantation, bowel health-related quality of life was worse with 125I; however, this difference was lost at subsequent time points. The 9-year BRFS was 87.2% and 84.0% for the 125I and 131Cs group, respectively (p = 0.897). There was no statistically significant difference in BRFS based on initial T stage, PSA, or Gleason score. CONCLUSIONS: Short- and long-term urinary, sexual, and bowel quality of life, as well as long-term biochemical control were comparable between 125I and 131Cs. This report therefore supports the continued use of 131Cs as an effective and comparable alternative isotope.

Long-term biochemical outcomes using cesium-131 in prostate brachytherapy.

PURPOSE: Long-term outcomes reveal equivalent biochemical outcomes with low-dose-rate (LDR) brachytherapy (BT) compared with radical prostatectomy and external-beam radiotherapy for the management of prostate cancer. Iodine-125, the most commonly used isotope, may be associated with long-term urinary consequences. Cesium-131 (131Cs) has a higher dose rate and shorter dose delivery time, predicting a shorter duration of urinary morbidity. We report our institution's high-volume experience and the most mature data to date on outcomes with 131Cs prostate BT. METHODS AND MATERIALS: 571 men (median age: 65.38 years) with low (55%)-, intermediate (36%)-, and high-risk disease (9%) received monobrachytherapy, dual-modality, or trimodality using 131Cs at a single institution. Risk groups were defined according to the National Comprehensive Cancer Network definition. Median prescription dose for definitive LDR-BT and LDR-BT boost was 115 Gy and 70 Gy, respectively. Median initial PSA was 6.1 ng/mL (IQR: 4.6-8.7). RESULTS: Median followup time was 5 years. 5/7-year overall survival for low-, intermediate-, and high-risk patients was 96.9%/96/9%, 92.8%/89.7%, and 95.8%/87.1%, respectively (p = 0.02). 5/7-year freedom from biochemical failure for low-, intermediate-, and high-risk patients was 98.5%/96.3%, 94.1%/86.4%, and 93.2%/74.5%, respectively (p < 0.01). 5/7-year prostate cancer -specific survival was 100%/100%, 99.3%/99.3%, and 98.0%/98.0% for low-, intermediate-, and high-risk patients, respectively (p < 0.01). CONCLUSIONS: 131Cs is a viable alternative isotope for prostate brachytherapy for organ-confined disease. Long-term biochemical control and survival outcomes are excellent and on par with those attained with the use of 125I or 103Pd. This report therefore supports the continued use of 131Cs as an effective and comparable alternative isotope.

Surgery vs Radiotherapy in the Management of Biopsy Gleason Score 9-10 Prostate Cancer and the Risk of Mortality.

Importance: It is unknown how treatment with radical prostatectomy (RP) and adjuvant external beam radiotherapy (EBRT), androgen deprivation therapy (ADT), or both (termed MaxRP) compares with treatment with EBRT, brachytherapy, and ADT (termed MaxRT). Objective: To investigate whether treatment of Gleason score 9-10 prostate cancer with MaxRP vs MaxRT was associated with prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) risk. Design, Setting, and Participants: The study cohort comprised 639 men with clinical T1-4,N0M0 biopsy Gleason score 9-10 prostate cancer. Between February 6, 1992, and April 26, 2013, a total of 80 men were consecutively treated with MaxRT at the Chicago Prostate Cancer Center, and 559 men were consecutively treated with RP and pelvic lymph node dissection at the Martini-Klinik Prostate Cancer Center. Follow-up started on the day of prostate EBRT or RP and concluded on October 27, 2017. Exposures: Of the 559 men managed with RP and pelvic lymph node dissection, 88 (15.7%) received adjuvant EBRT, 49 (8.8%) received ADT, and 50 (8.9%) received both. Main Outcomes and Measures: Treatment propensity score-adjusted risk of PCSM and ACM and the likelihood of equivalence of these risks between treatments using a plausibility index. Results: The cohort included 639 men, with a mean (SD) age of 65.83 (6.52) years. After median follow-ups of 5.51 years (interquartile range, 2.19-6.95 years) among 80 men treated with MaxRT and 4.78 years (interquartile range, 4.01-6.05 years) among 559 men treated with RP-containing treatments, 161 men had died, 106 (65.8%) from prostate cancer. There was no significant difference in the risk of PCSM (adjusted hazard ratio, 1.33; 95% CI, 0.49-3.64; P = .58) and ACM (adjusted hazard ratio, 0.80; 95% CI, 0.36-1.81; P = .60) when comparing men who underwent MaxRP vs MaxRT, with plausibility indexes for equivalence of 76.75% for the end point of the risk of PCSM and 77.97% for the end point of the risk of ACM. Plausibility indexes for all other treatment comparisons were less than 63%. Conclusions and Relevance: Results of this study suggest that it is plausible that treatment with MaxRP or MaxRT for men with biopsy Gleason score 9-10 prostate cancer can lead to equivalent risk of PCSM and ACM.

Long-term outcomes analysis of low-dose-rate brachytherapy in clinically T3 high-risk prostate cancer.

PURPOSE: The available data demonstrating that superiority of LDR brachytherapy (LDR-BT) boost in high-risk prostate cancer patients under represents patients with extracapsular extension (T3a) and/or seminal vesicle invasion (T3b) have been limited. We report long-term clinical outcomes data for patients with cT3a/b disease receiving LDR-BT. METHODS AND MATERIALS: Ninety-nine men (median age: 69.4 years) with cT3a/bN0M0 high-risk prostate adenocarcinoma received definitive LDR-BT or LDR-BT boost after external beam radiation therapy (EBRT) at a single institution between 1998 and 2007. About 86% of patients received androgen deprivation therapy. Freedom from biochemical failure (FFBF), prostate cancer-specific survival (PCSS), and overall survival (OS) was calculated using the Kaplan-Meier method with the Phoenix definition used as definition of failure. Cox regression analysis was used to compare outcomes between clinical stage, initial PSA, Gleason Score, and percent core positive rate. RESULTS: With a median followup of 7 years, 7-year rate of FFBF, PCSS, and OS for the entire cohort was 65.2% (±5.6%), 90.1% (±3.6%), and 77.9% (±4.7%), respectively. LDR-BT boost patients achieved a 7-year FFBF rate of 73.5 (±6.5%). No significant difference in outcomes was present between T3a or T3b disease, Gleason score, iPSA stratification and percent core positive rates. CONCLUSIONS: LDR-BT, primarily as a boost in conjunction with ADT and EBRT, is not only feasible, but also highly effective in men with cT3a and cT3b high-risk prostate cancer resulting in excellent biochemical control and survival outcomes. LDR-BT boost implantation of patients should be strongly considered for cT3 patients given the merits of trimodality care.

Comorbidity and the Receipt of Curative Therapy for Favorable-risk Prostate Cancer Prior to and Following the Publication of PIVOT.

The publication of the randomized Prostate Cancer Intervention Versus Observation Trial (PIVOT) in July 2012, in which men with favorable-risk prostate cancer (PCa) were not found to benefit from radical prostatectomy, had the potential to shift PCa practice patterns. Using a prospectively assembled database of 5398 men with low-risk or favorable intermediate-risk PCa selected for curative treatment with brachytherapy in the years preceding and the year following the publication of PIVOT, we evaluated the odds of receiving curative treatment after adjusting for risk group (favorable intermediate vs low), race (black, Hispanic, or other), number of cardiometabolic comorbidities, and age. Following publication, the receipt of curative treatment was significantly lower (adjusted odds ratio [AOR]: 0.40; 95% confidence interval [CI], 0.16-0.99; p=0.05) among men with at least two cardiometabolic comorbidities, in contrast to the increasing trend (p=0.02) noted prior to PIVOT. Among black men, a subgroup at risk for occult high-grade disease, the odds of receiving curative treatment increased after PIVOT (AOR: 1.55; 95% CI, 1.06-2.26; p=0.02). These observations suggest that PIVOT's publication appropriately contributed to decreasing the use of curative treatment in men unlikely to benefit. PATIENT SUMMARY: The Prostate Intervention Versus Observation Trial (PIVOT) showed that radical prostatectomy did not benefit men with favorable-risk prostate cancer. Following the publication of PIVOT, the selection of men with multiple medical issues for curative treatment declined, whereas treatment of men at high risk of having aggressive prostate cancer increased.

Brachytherapy monotherapy may be sufficient for a subset of patients with unfavorable intermediate risk prostate cancer.

PURPOSE/OBJECTIVE(S): Brachytherapy (BT) monotherapy is a well-established treatment modality for favorable intermediate risk (FIR) prostate cancer. However, patients with unfavorable intermediate risk (UIR) disease are often recommended trimodality therapy involving BT, androgen deprivation therapy (ADT), and external beam radiation therapy (EBRT). We sought to investigate the relative benefit of supplemental therapies (ADT and/or EBRT) for FIR and UIR prostate cancer in a large dataset. MATERIALS/METHODS: We identified 3,723 patients with intermediate risk prostate cancer treated with BT between 1997 and 2013, including 1,989 and 1,734 patients with FIR and UIR disease, respectively. For the FIR cohort, Fine and Gray's competing risks regression model was used to evaluate whether there was a difference in prostate cancer specific mortality (PCSM) between BT vs. BT + supplemental therapy (ADT, EBRT, or both). For the UIR cohort, this regression model was used to evaluate whether supplemental ADT, EBRT, or both decreased PCSM beyond BT alone. Both regression models were adjusted for clinical and treatment-related factors. RESULTS: The median follow-up periods were 7.7 years (interquartile range: 5.4-10.5) for the FIR cohort and 7.8 years (interquartile range: 5.3-10.6) for the UIR cohort. For the FIR cohort, there was no difference in PCSM between BT monotherapy vs. BT + supplemental therapy (adjusted hazard ratio [AHR] = 1.70; 95% CI: 0.46-6.29; P = 0.43). For the UIR cohort, supplemental EBRT (AHR = 2.66; 95% CI: 1.12-6.34; P = 0.03), ADT (AHR = 0.96; 95% CI: 0.38-2.43; P = 0.93), or both (AHR = 1.46; 95% CI: 0.42-5.01; P = 0.55) were not associated with improved PCSM compared with BT alone. CONCLUSION: In our analysis, supplemental therapies did not offer an improvement in PCSM compared with BT alone for FIR or UIR prostate cancers. Further prospective clinical trials are required to determine whether BT monotherapy may be sufficient for a subset of patients with UIR disease.

Androgen Deprivation Therapy Use in the Setting of High-dose Radiation Therapy and the Risk of Prostate Cancer-Specific Mortality Stratified by the Extent of Competing Mortality.

PURPOSE: The addition of androgen deprivation therapy (ADT) to radiation therapy (RT) is the standard of care for men with intermediate- and high-risk prostate cancer (PC). However, whether competing mortality (CM) affects the ability of ADT to improve, survival remains unanswered. METHODS AND MATERIALS: We calculated a CM risk score using a Fine-Gray semiparametric model that included age and cardiometabolic comorbidities from a cohort of 17,669 men treated with high-dose RT with or without supplemental ADT for nonmetastatic PC. Fine and Gray competing risk regression analysis was used to assess whether ADT reduced the risk of PC-specific mortality for men with a low versus a high risk of CM among the 4550 patients within the intermediate- and high-risk cohort after adjustment for established PC prognostic factors, year of treatment, site, and ADT propensity score. RESULTS: After a median follow-up of 8.4 years, 1065 men had died, 89 (8.36%) of PC. Among the men with a low CM score, ADT use was associated with a significant reduction in the risk of PC-specific mortality (adjusted hazard ratio 0.35, 95% confidence interval 0.14-0.87, P=.02) but was not for men with high CM (adjusted hazard ratio 1.33, 95% confidence interval 0.77-2.30, P=.30). CONCLUSIONS: Adding ADT to high-dose RT appears to be associated with decreased PC-specific mortality risk in men with a low but not a high CM score. These data should serve to heighten awareness about the importance of considering competing risks when determining whether to add ADT to RT for older men with intermediate- or high-risk PC.

Race and mortality risk after radiation therapy in men treated with or without androgen-suppression therapy for favorable-risk prostate cancer.

BACKGROUND: African American (AA) men are more likely than non-AA men to have a comorbid illness that could interact with androgen-deprivation therapy (ADT) and shorten survival. This study assessed the impact that race had on the risk of all-cause mortality (ACM) and other-cause mortality (OCM) among men definitively treated for favorable-risk prostate cancer (PC). METHODS: Between 1997 and 2013, 7252 men with low-risk or favorable intermediate-risk PC were treated with brachytherapy with neoadjuvant ADT (n = 1501) or without neoadjuvant ADT (n = 5751) for a 4-month median duration. Cox and Fine-Gray multivariate regressions were used to analyze whether the risk of ACM and OCM increased among AA men versus non-AA men receiving ADT; adjustments were made for the age at brachytherapy, year of brachytherapy, cardiometabolic comorbidity status, risk group, and ADT treatment propensity score. RESULTS: After a median follow-up of 8.04 years, 869 men (12.0%) died: 48 (5.52%) of PC and 821 (94.48%) of other causes. There was a significant association between AA race and an increased risk of both ACM (adjusted hazard ratio [AHR], 1.77; 95% confidence interval [CI], 1.06-2.94; P = .028) and OCM (AHR, 1.86; 95% CI, 1.08-3.19; P = .024) among AA men versus non-AA men who received ADT but not among those who did not receive ADT (AHR for ACM, 1.33; 95% CI, 0.93-1.91; P = .12; AHR for OCM, 1.39; 95% CI, 0.96-2.02; P = .08). CONCLUSIONS: ADT use may shorten survival in AA men with favorable-risk PC; therefore, its reservation for the treatment of higher risk PC, for which level 1 evidence supports its use, should be considered. Cancer 2016;122:3608-14. © 2016 American Cancer Society.

Influence of Comorbidity on the Risk of Mortality in Men With Unfavorable-Risk Prostate Cancer Undergoing High-Dose Radiation Therapy Alone.

PURPOSE: To explore whether a subgroup of men with unfavorable-risk prostate cancer (PC) exists in whom high-dose radiation therapy (RT) alone is sufficient to avoid excess PC death due to competing risk from cardiometabolic comorbidity. METHODS AND MATERIALS: This was a cohort study of 7399 men in whom comorbidity (including congestive heart failure, diabetes mellitus, or myocardial infarction) was assessed and recorded with T1-3NxM0 PC treated with brachytherapy with or without neoadjuvant RT, October 1997 to May 2013 at a single providing institution. Cox and competing risks regression analyses were used to assess whether men with unfavorable-intermediate/high-risk versus favorable-intermediate/low-risk PC were at increased risk of PC-specific, all-cause, or other-cause mortality (PCSM, ACM, OCM), adjusting for number of comorbidities, age at and year of brachytherapy, RT use, and an RT treatment propensity score. RESULTS: After a median follow-up of 7.7 years, 935 men died: 80 of PC and 855 of other causes. Among men with no comorbidity, PCSM risk (adjusted hazard ratio [AHR] 2.74 [95% confidence interval (CI) 1.49-5.06], P=.001) and ACM risk (AHR 1.30 [95% CI 1.07-1.58], P=.007) were significantly increased in men with unfavorable-intermediate/high-risk PC versus favorable-intermediate/low-risk PC, with no difference in OCM (P=.07). Although PCSM risk was increased in men with 1 comorbidity (AHR 2.87 [95% CI 1.11-7.40], P=.029), ACM risk was not (AHR 1.03 [95% CI 0.78-1.36], P=.84). Neither PCSM risk (AHR 4.39 [95% CI 0.37-51.98], P=.24) or ACM risk (AHR 1.43 [95% CI 0.83-2.45], P=.20) was increased in men with 2 comorbidities. CONCLUSIONS: To minimize death from PC, high-dose RT alone may be sufficient treatment in men with 2 or more cardiometabolic comorbidities and unfavorable-intermediate- and high-risk PC.

Gleason Score 3 + 5 or 5 + 3 versus 4 + 4 Prostate Cancer: The Risk of Death.

UNLABELLED: The International Society of Urological Pathology recommends that Gleason score (GS) 8 prostate cancer (PC) is one prognostic category, yet heterogeneity in cancer control potentially exists amongst men with GS 3+5/5+3 versus GS 4+4 PC. We compared PC-specific mortality (PCSM) and all-cause mortality (ACM) risk among men with GS 3+5/5+3 versus GS 4+4 PC using competing-risks and Cox regression analyses, adjusting for age, known PC prognostic factors, treatment, and a treatment propensity score. Between 1998 and 2012, 462 men with GS 8 PC were treated using brachytherapy with supplemental external-beam radiation therapy and/or androgen deprivation therapy at the Chicago Prostate Cancer Center. After a median follow-up of 7.6 yr, 118 men died, 26 of PC. PCSM (adjusted hazard ratio [AHR] 2.77, 95% confidence interval [CI] 1.13-6.80; p=0.026) and ACM (AHR 1.75, 95% CI 1.06-2.87; p=0.028) were significantly higher for men with GS 3+5/5+3 PC than for men with GS 4+4 PC. Subcategorizing GS 8 into PC with or without grade 5 should be considered as a stratification factor in randomized trials. PATIENT SUMMARY: Long-term success rates for men with Gleason score 8 prostate cancer vary depending on whether the most aggressive type of cancer (grade 5) is present at biopsy.

Definition and Validation of "Favorable High-Risk Prostate Cancer": Implications for Personalizing Treatment of Radiation-Managed Patients.

PURPOSE: To define and validate a classification of favorable high-risk prostate cancer that could be used to personalize therapy, given that consensus guidelines recommend similar treatments for all radiation-managed patients with high-risk disease. METHODS AND MATERIALS: We studied 3618 patients with cT1-T3aN0M0 high-risk or unfavorable intermediate-risk prostate adenocarcinoma treated with radiation at a single institution between 1997 and 2013. Favorable high-risk was defined as T1c disease with either Gleason 4 + 4 = 8 and prostate-specific antigen <10 ng/mL or Gleason 6 and prostate-specific antigen >20 ng/mL. Competing risks regression was used to determine differences in the risk of prostate cancer-specific mortality (PCSM) after controlling for baseline factors and treatment. Our results were validated in a cohort of 13,275 patients using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. RESULTS: Patients with favorable high-risk disease had significantly better PCSM than other men with high-risk disease (adjusted hazard ratio [AHR] 0.42, 95% confidence interval [CI] 0.18-0.996, P=.049) and similar PCSM as men with unfavorable intermediate-risk disease (AHR 1.17, 95% CI 0.50-2.75, P=.710). We observed very similar results within the SEER-Medicare cohort (favorable high-risk vs other high-risk: AHR 0.21, 95% CI 0.11-0.41, P<.001; favorable high-risk vs unfavorable intermediate-risk: AHR 0.67, 95% CI 0.33-1.36, P=.268). CONCLUSIONS: Patients with favorable high-risk prostate cancer have significantly better PCSM than other patients with high-risk disease and similar PCSM as those with unfavorable intermediate-risk disease, who are typically treated with shorter-course androgen deprivation therapy. This new classification system may allow for personalization of treatment within high-risk disease, such as consideration of shorter-course androgen deprivation therapy for favorable high-risk disease.

Short-course androgen deprivation therapy and the risk of death from high-risk prostate cancer in men undergoing external beam radiation therapy and brachytherapy.

PURPOSE: We estimated the risks of prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) in men with high-risk prostate cancer (PC) undergoing external beam radiation therapy and brachytherapy with short-course androgen deprivation therapy (ADT) (median 4 months) as compared with men with more favorable-risk PC undergoing standard of care as per the National Comprehensive Cancer Network guidelines. METHODS AND MATERIALS: The prospective study cohort comprised 6595 consecutively treated men with T1-4 N0M0 PC whose treatment included brachytherapy between October 16, 1997, and May 28, 2013. Fine and Gray competing risk regression and Cox regression analyses were used to assess the risks of PCSM and ACM in men with high, unfavorable intermediate, and favorable intermediate risk as compared with low-risk PC. RESULTS: After median followup of 7.76 years, 820 men died (12.43%): 72 of PC (8.78%). Men with favorable intermediate-risk PC did not have significantly increased PCSM risk as compared with men with low-risk PC (adjusted hazard ratio [AHR], 1.26; 95% confidence interval [CI] 0.56, 2.88; p-Value 0.58), whereas men with high-risk PC (AHR, 3.74; 95% CI 1.12, 12.53; p-Value 0.032) and unfavorable intermediate-risk PC (AHR, 3.10; 95% CI 1.43, 6.72; p-Value 0.004) did. Based on 10-year adjusted point estimates of PCSM and ACM for men with high-risk PC being 6.01% (95% CI 3.79%, 8.94%) and 21.30% (95% CI 17.45%, 25.42%), respectively, PCSM comprised 28% of ACM. CONCLUSIONS: In the setting of external beam radiation therapy and brachytherapy, men with high-risk PC have low absolute adjusted estimates of PCSM (~6%) during the first decade after treatment despite receiving only short-course ADT. Whether long-term ADT can lower PCSM and improve survival in these men requires additional study.

Risk Group and Death From Prostate Cancer: Implications for Active Surveillance in Men With Favorable Intermediate-Risk Prostate Cancer.

IMPORTANCE: Active surveillance (AS), per the National Comprehensive Cancer Network (NCCN) guidelines, is considered for patients with low-risk prostate cancer (PC) and a life expectancy of at least 10 years. However, given the grade migration following the 2005 International Society of Urologic Pathology consensus conference, AS may be appropriate for men presenting with favorable intermediate-risk PC. OBJECTIVE: To estimate and compare the risk of PC-specific mortality (PCSM) and all-cause mortality (ACM) following brachytherapy among men with low and favorable intermediate-risk PC. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 5580 consecutively treated men (median age, 68 years) with localized adenocarcinoma of the prostate treated with brachytherapy at the Prostate Cancer Foundation of Chicago between October 16, 1997, and May 28, 2013. INTERVENTION: Standard of practice per the NCCN guidelines. MAIN OUTCOMES AND MEASURES: Fine and Gray competing risks regression and Cox regression analyses were used to assess whether the risks of PCSM and ACM, respectively, were increased in men with favorable intermediate-risk vs low-risk PC. Analyses were adjusted for age at brachytherapy, year of treatment, and known PC prognostic factors. RESULTS: After median follow-up of 7.69 years, 605 men had died (10.84% of total cohort), 34 of PC (5.62% of total deaths). Men with favorable intermediate-risk PC did not have significantly increased risk of PCSM and ACM compared with men with low-risk PC (adjusted hazard ratio [HR], 1.64; 95% CI, 0.76-3.53; P = .21 for PCSM; adjusted HR, 1.11; 95% CI, 0.88-1.39; P = .38 for ACM). Eight-year adjusted point estimates for PCSM were low: 0.48% (95% CI, 0.23%-0.93%) and 0.33% (95% CI, 0.19%-0.56%) for men with favorable intermediate-risk PC and low-risk PC, respectively. The respective estimates for ACM were 10.45% (95% CI, 8.91%-12.12%) and 8.68% (95% CI, 7.80%-9.61%). CONCLUSIONS AND RELEVANCE: Men with low-risk PC and favorable intermediate-risk PC have similarly low estimates of PCSM and ACM during the first decade following brachytherapy. While awaiting the results of ProtecT, the randomized trial of AS vs treatment, our results provide evidence to support AS as an initial approach for men with favorable intermediate-risk PC.

Androgen deprivation therapy and the risk of death from prostate cancer among men with favorable or unfavorable intermediate-risk disease.

BACKGROUND: Radiotherapy (RT), short-course androgen deprivation therapy (ADT), and brachytherapy in various combinations are treatment options for patients with intermediate-risk prostate cancer (PC), but the question of which combination if any is necessary to minimize PC-specific mortality (PCSM) risk in patients with favorable or unfavorable intermediate-risk PC is unknown. The authors assessed PCSM risk after commonly used treatments. METHODS: The cohort consisted of 2510 men with favorable (1902 men; 75.78%) or unfavorable (608 men; 24.22%) intermediate-risk PC who were treated from 1997 to 2013. Treatment included brachytherapy with or without neoadjuvant ADT among men with favorable disease and brachytherapy with neoadjuvant RT or ADT among men with unfavorable disease. Fine and Gray's competing-risks regression model was used to assess whether ADT among men with favorable disease or RT or ADT among men with unfavorable disease decreased PCSM risk after adjusting for treatment propensity score, year of brachytherapy, and PC prognostic factors. RESULTS: After a median follow-up of 7.78 years, 366 deaths (14.58%) were observed, 29 of which (7.92%) were from PC. There was a significant reduction in PCSM risk in men with unfavorable disease who were treated with ADT versus RT (adjusted hazard ratio, 0.34; 95% confidence interval, 0.13-0.91 [P = .03]), but no significant difference in PCSM risk in men with favorable disease who received ADT and brachytherapy versus brachytherapy (adjusted hazard ratio, 0.67; 95% confidence interval, 0.18-2.57 [P =.56]). CONCLUSIONS: Neoadjuvant ADT does not appear to reduce PCSM risk in men undergoing brachytherapy for favorable intermediate-risk PC and should not be considered a standard; however, it appears superior to neoadjuvant RT in men with unfavorable intermediate-risk PC undergoing brachytherapy, making neoadjuvant ADT and brachytherapy a preferred option in these men.