Corey Foster

Gleason pattern 5 is the strongest pathologic predictor of recurrence, metastasis, and prostate cancer–specific death in patients receiving salvage radiation therapy following radical prostatectomy

The presence of Gleason pattern 5 (GP5) at radical prostatectomy (RP) has been associated with worse clinical outcome; however, this pathologic variable has not been assessed in patients receiving salvage radiation therapy (SRT) after a rising prostate‐specific antigen level.

A prostate-specific antigen doubling time of <6 months is prognostic for metastasis and prostate cancer-specific death for patients receiving salvage radiation therapy post radical prostatectomy

BackgroundThe ideal prostate-specific antigen (PSA) doubling time (PSADT) threshold for identifying patients at high-risk for poor clinical outcome following salvage radiation therapy (SRT) has not been well established. We sought to assess what PSADT threshold is most clinically prognostic in this setting.Methods575 patients who received SRT at a single institution for biochemical recurrence after radical prostatectomy were retrospectively reviewed. We assessed the impact of pre-SRT PSADT on biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall mortality (OM). Kaplan-Meier methods, hazard ratio (HR) assessment, and Cox Proportional Hazard models were used to assess the discriminatory ability of various PSADT thresholds.ResultsSufficient data to calculate PSADTs were available for 277 patients. PSADT was prognostic for BF, DM, PCSM, and OM on univariate analysis regardless of threshold. HR assessment identified 6 months as a strong threshold. No statistically significant difference was observed in BF, DM, PCSM, or OM between patients with PSADT <3 (n=40) and 3–6 months (n=61) or between 6–10 (n=62) and >10 months (n=114). However significant differences were seen in BF (HR:2.2, [95%CI: 1.4-3.5], p<0.01) and DM (HR:2.2, [95%CI: 1.2-4.3], p=0.02) between a PSADT of 3–6 and 6–10 months. On multivariate analysis a PSADT <6 months predicted BF (HR:2.0, [95%CI: 1.4-2.9], p=0.0001), DM (HR:2.0, [95%CI: 1.2-3.4], p=0.01), and PCSM (HR:2.6, [95%CI: 1.1-5.9], p=0.02).ConclusionsA pre-SRT PSADT <6 months was a strong predictor of outcomes in our data set, including PCSM. The most common nomogram for SRT uses a 10-month PSADT threshold for assigning points used to assess BF following SRT. If validated, our findings suggest that a PSADT threshold of <6 months should be considered for stratification of patients in future clinical trials in this setting.

Combining prostate-specific antigen nadir and time to nadir allows for early identification of patients at highest risk for development of metastasis and death following salvage radiation therapy.

PURPOSE Little is known regarding the prognostic capability of prostate-specific antigen (PSA) nadir (nPSA) and time to nPSA (TnPSA) following salvage radiation therapy (SRT) for biochemical failure (BF) postradical prostatectomy (RP). We sought to assess their prognostic significance in this setting. METHODS AND MATERIALS A total of 448 patients who received SRT without androgen deprivation therapy at a single academic institution were included in this retrospective analysis. Univariate analysis and multivariate Cox proportional hazards models were used to assess BF, distant metastasis (DM), prostate cancer-specific death (PCSD), and overall survival (OS). A prognostic nomogram incorporating nPSA and TnPSA was developed and validated in randomly allocated training and validation cohorts. RESULTS Median follow-up post-SRT was 64 months. Median nPSA and TnPSA were undetectable and 6.7 months, respectively. On univariate analysis, a detectable nPSA (P < .01) and TnPSA <6 months (P < .01) were predictive of all outcomes. In a training cohort, a 14-point nomogram incorporating detectable nPSA, TnPSA, Gleason score, pre-radiation therapy PSA, and seminal vesicle invasion predicted BF (hazard ratio[HR], 1.4; P < .0001), DM (HR, 1.3; P < .0001), PCSD (HR, 1.3; P < .0001), and decreased OS (HR, 1.2; P < .0001). Adding nPSA and TnPSA improved the prognostic value of the nomogram compared to using clinical predictors only. The nomogram was evaluated in a validation cohort where it was predictive of BF (c-index = 0.77), DM (0.73), and PCSD (0.69). CONCLUSIONS Patients with a detectable nPSA also having a TnPSA <6 months post-SRT are at high-risk for DM, PCSD, and decreased OS. These patients are unlikely to have clinically localized disease and should be considered for initiation of systemic therapies.

Larger Maximum Tumor Diameter at Radical Prostatectomy Is Associated With Increased Biochemical Failure, Metastasis, and Death From Prostate Cancer After Salvage Radiation for Prostate Cancer

PURPOSE To investigate the maximum tumor diameter (MTD) of the dominant prostate cancer nodule in the radical prostatectomy specimen as a prognostic factor for outcome in patients treated with salvage external beam radiation therapy (SRT) for a rising prostate-specific antigen (PSA) value after radical prostatectomy. METHODS AND MATERIALS From an institutional cohort of 575 patients treated with SRT, data on MTD were retrospectively collected. The impact of MTD on biochemical failure (BF), metastasis, and prostate cancer-specific mortality (PCSM) was assessed on univariate and multivariate analysis using Kaplan-Meier and Cox proportional hazards models. RESULTS In the 173 patients with MTD data available, median follow-up was 77 months (interquartile range, 47-104 months) after SRT, and median MTD was 18 mm (interquartile range, 13-22 mm). Increasing MTD correlated with increasing pT stage, Gleason score, presence of seminal vesicle invasion, and lymph node invasion. Receiver operating characteristic curve analysis identified MTD of >14 mm to be the optimal cut-point. On univariate analysis, MTD >14 mm was associated with an increased risk of BF (P=.02, hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2-2.8), metastasis (P=.002, HR 4.0, 95% CI 2.1-7.5), and PCSM (P=.02, HR 8.0, 95% CI 2.9-21.8). On multivariate analysis MTD >14 mm remained associated with increased BF (P=.02, HR 1.9, 95% CI 1.1-3.2), metastasis (P=.02, HR 3.4, 95% CI 1.2-9.2), and PCSM (P=.05, HR 9.7, 95% CI 1.0-92.4), independent of extracapsular extension, seminal vesicle invasion, positive surgical margins, pre-RT PSA value, Gleason score, and pre-RT PSA doubling time. CONCLUSIONS For patients treated with SRT for a rising PSA value after prostatectomy, MTD at time of radical prostatectomy is independently associated with BF, metastasis, and PCSM. Maximum tumor diameter should be incorporated into clinical decision making and future clinical risk assessment tools for those patients receiving SRT.

Maximum tumor diameter as a predictor for outcome following salvage radiation for prostate cancer.

78 Background: While maximum tumor diameter (MTD), as identified on radical prostatectomy (RP) specimens, has been associated with prostate cancer recurrence, the prognostic significance of this variable is unknown in the context of salvage external beam radiation therapy (EBRT) following a rising PSA after RP. Here, we investigate associations between MTD and outcomes in this setting. METHODS From an IRB approved retrospective single-institutional cohort, 575 patients treated with salvage radiation therapy (SRT) were identified, with MTD data available on 173. ANOVA and chi-square were utilized to compare prognostic variables with MTD. The impact of MTD on biochemical failure (BF), metastasis (Mets), prostate cancer-specific mortality (PCSM) and overall survival (OS) was assessed on univariate and multivariate analysis using Kaplan-Meier and Cox-proportional hazards regression. RESULTS Median follow up was 76.5 months (IQR, 46.5-104.0) and median MTD was 18 mm (IQR, 13-22). Median RT dose was 68.4 Gy (IQR, 64.8-68.4). MTD size correlated with pT-stage, Gleason score, and presence of seminal vesicle invasion or lymph node invasion. Receiver operator characteristic (ROC) curve analysis was used to correlate MTD with clinical end-points and identified 14 mm as the most prognostic cut-point. A MTD >14 mm was associated with a 1.8, 4.0 and 8-fold increase in the risk of BF (p<0.02), Mets (p<0.002), and PCSM (p<0.02), respectively. As a continuous variable, on multivariate analysis, MTD was shown to be a marginally significant predictor of OS (p=0.056, HR [95%] 1.6 [1.0-2.5]), and a significant predictor of PCSM (p<0.03, HR [95%] 2.0 [1.1-3.8]) and Mets (p=0.01, HR [95%] 1.7 [1.1-2.6) but not BF. In this model, for every 10 mm increase in MTD, there is a 1.7, 2.0, and 1.6 fold risk of metastasis, prostate cancer death and overall death, respectively. CONCLUSIONS As a categorical and continuous variable, MTD is a significant predictor of prostate cancer outcomes following SRT and should be used in clinical decision making in this population and in future clinical risk assessment tools.

PSA doubling time of ≤6 months as the optimal cutoff for predicting clinically relevant outcomes for men receiving salvage radiation therapy post radical prostatectomy.

167 Background: Short PSA doubling time (PSADT) after biochemical recurrence (BR) post radical prostatectomy (RP) is known to predict worse outcomes following salvage external beam radiation therapy (SRT). The ideal PSADT cut-off, however, in this context remains uncertain. In this study, we sought to identify the best PSADT cut-off for predicting clinical outcomes following SRT for BR after RP. METHODS 575 patients who received SRT at a single institution for BR after RP were retrospectively reviewed in an IRB approved analysis. The impact of PSADT on biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) was assessed using Kaplan-Meier and Cox Proportional Hazards models. RESULTS Median follow up was 56.7 months post SRT. PSADTs could be calculated for 277 patients. PSADT strongly predicted BF, DM, PCSM, and OS on univariate analysis regardless of cut-off point. There was no statistical difference in BF, DM, PCSM, or OS between patients with PSADT <3 (n=40) and 3-6 months (n=61) or between 6-10 (n=62) and >10 months (n=114). A difference existed in BF (p<0.01 HR: 2.2 [95%CI: 1.4-3.5]) and DM (p=0.02 HR: 2.2 [95%CI: 1.2-4.3]) between PSADT of 3-6 and 6-10 months. PSADT ≤6 had the largest positive predictive value (PPV) for BF (70%), DM (36%), and PCSM (13%) at 5 years. There was no difference in negative predictive value between a PSADT >10 vs. >6 months for BF, DM, PCSM, and OS with 5 year rates of (60% vs. 60%, 86% vs. 86%, 99% vs. 98%, and 95 vs. 94% respectively). On multivariate analysis PSADT ≤6 was a strong predictor of BF (p<0.01 HR: 2.1 [95%CI: 1.5-3.0]), DM (p=0.01 HR: 2.0 [95%CI: 1.2-3.4]), and PCSM (p=0.04 HR: 2.3 [95%CI: 1.1-5.2]), with a trend towards predicting OS (p=0.12 HR: 1.5 [95%CI: 0.9-2.6]). CONCLUSIONS A PSADT ≤6 months was the best predictor of outcomes in our data set, particularly for DM and PCSM. Currently, the most common predictive nomogram for SRT uses PSADT <10 months as the cut-off point for BF. These results suggest that using a PSADT of ≤6 months may improve the ability to predict clinically significant outcomes and hence identify men who may benefit from additional therapy.

Gleason pattern 5 as a pathologic predictor of recurrence, development of metastasis, and prostate cancer-specific death for patients receiving salvage radiation therapy following radical prostatectomy.

151 Background: The presence of primary, secondary, and tertiary Gleason pattern 5 (GP5) in prostate cancer has been shown to predict outcomes and improve risk stratification following radical prostatectomy (RP) and external beam radiation therapy (EBRT). However, the predictive value of GP5 has not been assessed in salvage EBRT (SRT) for a rising PSA after RP. We sought to assess the prognostic capability of the presence of GP5 in this setting. METHODS 575 patients who received SRT at a single institution for biochemical recurrence after RP were retrospectively reviewed in an IRB approved analysis. We assessed the impact of GP5 on biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) using Kaplan-Meier and Cox Proportional Hazards models. RESULTS Median follow up was 56.7 months post SRT. On pathologic evaluation, 563 patients had a documented Gleason score (GS). 60 patients (10.7%) had primary, secondary, or tertiary GP5. GP5 was the strongest pathologic predictor of DM (p<0.01 HR: 1.9 [95%CI: 1.3-2.9]) and PCSM (p<0.01 HR: 4.0 [95%CI: 2.1-7.7]) on univariate analysis. The presence of GP5 was a better predictor of BF, DM, PCSM, and OS than stratification by GS8-10. Patients with GP5 had clinically worse outcomes than GS8 patients without GP5. There was no difference in outcome between primary, secondary, and tertiary GP5. On multivariate analysis, GP5 was the strongest pathologic predictor of BF (p<0.01 HR: 2.7 [95%CI: 1.6-4.5]), DM (p<0.01 HR: 11.2 [95%CI: 3.9-32.2]), and PCSM (p<0.01 HR: 6.0 [95%CI: 1.8-19.6]). CONCLUSIONS In SRT, where pathologic factors including extra-capsular extension, seminal vesicle invasion, and margin status are known, the presence of GP5 is the strongest pathologic predictor of BF, DM, and PCSM. Traditional GS risk stratification fails to fully utilize the prognostic capabilities of individual GPs for SRT patients following RP. Intensification of treatment regimens, such as early use of androgen deprivation therapy or adjuvant radiation, may be appropriate for patients with GP5 in this setting.