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Abstract Purpose To evaluate the influence of the maximum involvement of biopsy core (MIBC) on outcome for prostate cancer patients treated with dose-escalated external beam radiotherapy (EBRT). Methods and materials The outcomes of 590 men with localized prostate cancer treated with EBRT (≥75 Gy) at a single institution were retrospectively analyzed. The influence of MIBC on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS) was compared to other surrogates for biopsy tumor volume, including the percentage of positive biopsy cores (PPC) and the total percentage of cancer volume (PCV). Results MIBC correlated with PSA, T-stage, Gleason score, NCCN risk group, PPC, PCV, and treatment related factors. On univariate analysis, MIBC was prognostic for all endpoints except OS; with greatest impact in those with Gleason scores of 8–10. However, on multivariate analysis, MIBC was only prognostic for FFBF (hazard ratio [HR] 1.9, p = 0.008), but not for FFM (p = 0.19), CSS (p = 0.16), and OS (p = 0.99). Conclusions In patients undergoing dose-escalated EBRT, MIBC had the greatest influence in those with Gleason scores of 8–10 but provided no additional prognostic data as compared to PPC and PCV, which remain the preferable prognostic variables in this patient population.

This feasibility study shows that Spot-scanning Proton Arc therapy (SPArc) is able to significantly reduce the dose to the hippocampus and cochlea compared to both Volumetric Modulated Arc Photon Therapy (VMAT) and the robust optimized Intensity Modulated Proton Therapy (ro-IMPT) plans in whole brain radiotherapy. Furthermore, SPArc not only improves plan robustness but could potentially deliver a treatment as efficient as ro-IMPT when proton system's energy layer switch time is less than 1 s. Purpose: Recently, there have been significant interests towards whole-brain radiotherapy (WBRT) with hippocampal and cochlea sparing. Herein, we present a novel robust, continuous and delivery-efficient spot-scanning proton arc therapy technique (SPArc) to improve such dosimetric outcome. Material and methods: Eight patients were selected for whole brain radiotherapy to evaluate the feasibility of using SPArc for hippocampal and cochlea sparing. Both SPArc and robust optimized Intensity Modulated Proton Therapy(ro-IMPT) plans were generated using the robust optimization of ±3.5% range and 3 mm setup uncertainties and were compared to the Volumetric Modulated Arc Therapy(VMAT). Root-mean-square deviation doses(RMSDs) Volume Histogram, or RVH, was used for proton plan robustness evaluation. Proton plan delivery time was calculated based on a using full gantry rotation with 1 RPM, 2 ms spot switching time, minimum monitor unit per spot = 0.01, and simulate different proton system with energy-layer-switching-time(ELST) from 0.2 to 5 s. Results: SPArc plans showed significant dosimetric improvements in multiple dosimetric parameters. The mean dose to the hippocampus was reduced to 6.20 Gy [RBE] compared to VMAT 10.89 Gy [RBE] (p <.001) and ro-IMPT 9.38 Gy [RBE] (p <.001); D100% to the hippocampus was reduced to 4.50 Gy [RBE] compared to VMAT 9.16 Gy [RBE] (p =.001) and ro-IMPT 7.02 Gy [RBE] (p =.002); cochlear mean dose was reduced to 7.75 Gy [RBE] compared to VMAT 11.52 Gy [RBE] (p =.018) and ro-IMPT 10.15 Gy [RBE] (p =.037); and maximum dose was reduced to 33.84 Gy [RBE] compared to ro-IMPT 36.37 Gy [RBE]. RVH analysis shows SPArc is more robust in Organs-at-risk(OARs) sparing such as hippocampus, cochlea, lens, and eyes. The average total estimated treatment delivery time were 412 s, 627 s, and 1694 s using ELST of 0.2 s, 1 s, and 5 s for SPArc plans, respectively, compared with values of 547 s (p <.001), 626 s (p =.484), and 1025 s (p =.002) for ro-IMPT plans. Conclusion: SPArc could significantly reduce the dose delivered to the hippocampus and cochlea in patients being treated with WBRT. In addition, SPArc plans could potentially achieve similar or faster delivery time in modern proton machine with ELST of less than 1 s. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the role of androgen deprivation therapy (ADT) and duration for high-risk prostate cancer patients treated with dose-escalated radiation therapy (RT). Methods and Materials: A retrospective analysis of high-risk prostate cancer patients treated with dose-escalated RT (minimum 75 Gy) with or without ADT was performed. The relationship between ADT use and duration with biochemical failure (BF), metastatic failure (MF), prostate cancer-specific mortality (PCSM), non-prostate cancer death (NPCD), and overall survival (OS) was assessed as a function of pretreatment characteristics, comorbid medical illness, and treatment using Fine and Gray''s cumulative incidence methodology. Results: The median follow-up time was 64 months. In men with National Comprehensive Cancer Network defined high-risk prostate cancer treated with dose-escalated RT, on univariate analysis, both metastasis (P<.0001; hazard ratio 0.34; 95% confidence interval 0.18-0.67; cumulative incidence at 60 months 13% vs 35%) and PCSM (P=.015; hazard ratio 0.41; 95% confidence interval 0.2-1.0; cumulative incidence at 60 months 6% vs 11%) were improved with the use of ADT. On multivariate analysis for all high-risk patients, Gleason score was the strongest negative prognostic factor, and long-term ADT (LTAD) improved MF (P=.002), PCSM (P=.034), and OS (P=.001). In men with prostate cancer and Gleason scores 8 to 10, on multivariate analysis after adjustment for other risk features, there was a duration-dependent improvement in BF, metastasis, PCSM, and OS, all favoring LTAD in comparison with STAD or RT alone. Conclusion: For men with high-risk prostate cancer treated with dose-escalated EBRT, this retrospective study suggests that the combination of LTAD and RT provided a significant improvement in clinical outcome, which was especially true for those with Gleason scores of 8 to 10. [Copyright &y& Elsevier]

Purpose: To analyze prognostic factors in patients with high-risk prostate cancer treated with dose-escalated external-beam radiation therapy (EBRT) and androgen deprivation (ADT). Methods and Materials: Between 1998 and 2008 at the University of Michigan Medical Center, 718 men were consecutively treated with EBRT to at least 75 Gy. Seven definitions of high-risk prostate cancer, applying to 11–33% of patients, were evaluated. Biochemical failure (BF), salvage ADT use, metastatic progression, and prostate cancer–specific mortality (PCSM) were estimated by the Kaplan-Meier method and Cox proportional hazards regression. Results: Each high-risk definition was associated with increased BF (hazard ratio [HR] 2.8–3.9, p < 0.0001), salvage ADT use (HR 3.9–6.3, p < 0.0001), metastasis (HR 3.7–6.6, p < 0.0001), and PCSM (HR 3.7–16.2, p < 0.0001). Furthermore, an increasing number of high-risk features predicted worse outcome. Adjuvant ADT yielded significant reductions in both metastases (HR 0.19–0.38, p < 0.001) and PCSM (HR 0.38–0.50, p < 0.05) for all high-risk definitions (with the exception of clinical Stage T3–4 disease) but improved BF only for those with elevated Gleason scores (p < 0.03, HR 0.25–0.48). When treated with ADT and dose-escalated EBRT, patients with Gleason scores 8 to 10, without other high-risk features, had 8-year freedom from BF of 74%, freedom from distant metastases of 93%, and cause-specific survival of 92%, with salvage ADT used in 16% of patients. Conclusion: Adjuvant ADT results in a significant improvement in clinical progression and PCSM across multiple definitions of high-risk disease even with dose-escalated EBRT. There is a subset of patients, characterized by multiple high-risk features or the presence of Gleason Pattern 5, who remain at significant risk for metastasis and PCSM despite current treatment. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the prognostic utility of the percentage of cancer volume (PCV) in needle biopsy specimens for prostate cancer patients treated with dose-escalated external beam radiotherapy. Methods and Materials: The outcomes were analyzed for 599 men treated for localized prostate cancer with external beam radiotherapy to a minimal planning target volume dose of 75 Gy (range, 75–79.2). We assessed the effect of PCV and the pretreatment and treatment-related factors on the freedom from biochemical failure, freedom from metastasis, cause-specific survival, and overall survival. Results: The median number of biopsy cores was 7 (interquartile range, 6–12), median PCV was 10% (interquartile range, 2.5–25%), and median follow-up was 62 months. The PCV correlated with the National Comprehensive Cancer Network risk group and individual risk features, including T stage, prostate-specific antigen level, Gleason score, and percentage of positive biopsy cores. On log–rank analysis, the PCV stratified by quartile was prognostic for all endpoints, including overall survival. In addition, the PCV was a stronger prognostic factor than the percentage of positive biopsy cores when the two metrics were analyzed together. On multivariate analysis, the PCV predicted a worse outcome for all endpoints, including freedom from biochemical failure, (hazard ratio, 1.9; p = .0035), freedom from metastasis (hazard ratio, 1.7, p = .09), cause-specific survival (hazard ratio, 3.9, p = .014), and overall survival (hazard ratio, 1.8, p = .02). Conclusions: For patients treated with dose-escalated external beam radiotherapy, the volume of cancer in the biopsy specimen adds prognostic value for clinically relevant endpoints, particularly in intermediate- and high-risk patients. Although the PCV determination is more arduous than the percentage of positive biopsy cores, it provides superior risk stratification. [ABSTRACT FROM AUTHOR]

Purpose: To assess the impacts of patient age and comorbid illness on rectal toxicity following external beam radiation therapy (EBRT) for prostate cancer and to assess the Qualitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) normal tissue complication probability (NTCP) model in this context. Methods and Materials: Rectal toxicity was analyzed in 718 men previously treated for prostate cancer with EBRT (≥75 Gy). Comorbid illness was scored using the Charlson Comorbidity Index (CCMI), and the NTCP was evaluated with the QUANTEC model. The influence of clinical and treatment-related parameters on rectal toxicity was assessed by Kaplan-Meier and Cox proportional hazards models. Results: The cumulative incidence of rectal toxicity grade ≥2 was 9.5% and 11.6% at 3 and 5 years and 3.3% and 3.9% at 3 and 5 years for grade ≥3 toxicity, respectively. Each year of age predicted an increasing relative risk of grade ≥2 (P<.03; hazard ratio [HR], 1.04 [95% confidence interval {CI}, 1.01-1.06]) and ≥3 rectal toxicity (P<.0001; HR, 1.14 [95% CI,1.07-1.22]). Increasing CCMI predicted rectal toxicity where a history of either myocardial infarction (MI) (P<.0001; HR, 5.1 [95% CI, 1.9-13.7]) or congestive heart failure (CHF) (P<.0006; HR, 5.4 [95% CI, 0.6-47.5]) predicted grade ≥3 rectal toxicity, with lesser correlation with grade ≥2 toxicity (P<.02 for MI, and P<.09 for CHF). An age comorbidity model to predict rectal toxicity was developed and confirmed in a validation cohort. The use of anticoagulants increased toxicity independent of age and comorbidity. NTCP was prognostic for grade ≥3 (P=.015) but not grade ≥2 (P=.49) toxicity. On multivariate analysis, age, MI, CHF, and an NTCP >20% all correlated with late rectal toxicity. Conclusions: Patient age and a history of MI or CHF significantly impact rectal toxicity following EBRT for the treatment of prostate cancer, even after controlling for NTCP. [Copyright &y& Elsevier]

Purpose: To assess the prognostic value of perineural invasion (PNI) for patients treated with dose-escalated external-beam radiation therapy for prostate cancer. Methods and Materials: Outcomes were analyzed for 651 men treated for prostate cancer with EBRT to a minimum dose ≥75 Gy. We assessed the impact of PNI as well as pretreatment and treatment-related factors on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival. Results: PNI was present in 34% of specimens at biopsy and was significantly associated with higher Gleason score (GS), T stage, and prostate-specific antigen level. On univariate and multivariate analysis, the presence of PNI was associated with worse FFBF (hazard ratio = 1.7, p <0.006), FFM (hazard ratio = 1.8, p <0.03), and CSS (HR = 1.4, p <0.05) compared with absence of PNI; there was no difference in overall survival. Seven-year rates of FFBF, FFM, and CCS were 64% vs. 80%, 84% vs. 92%, and 91% vs. 95% for those patients with and without PNI, respectively. On recursive partitioning analysis, PNI predicted for worse FFM and CSS in patients with GS 8–10, with FFM of 67% vs. 89% (p <0.02), and CSS of 69% vs. 91%, (p <0.04) at 7 years for those with and without PNI, respectively. Conclusions: The presence of PNI in the prostate biopsy predicts worse clinical outcome for patients treated with dose-escalated external-beam radiation therapy. Particularly in patients with GS 8–10 disease, the presence of PNI suggests an increased risk of metastasis and prostate cancer death. [ABSTRACT FROM AUTHOR]

Purpose: The division of Gleason score (GS) into three categories (2–6, 7, 8–10) may not fully use its prognostic power, as revealed by recent reports demonstrating the presence of Gleason Pattern 5 (GP5) as a strong predictor for biochemical recurrence. Therefore, we analyzed the clinical outcomes in patients treated with dose-escalated radiation therapy (RT) based on the presence or absence of GP5. Methods and Materials: Outcomes were analyzed for 718 men treated for localized prostate cancer with external-beam RT to a minimum planning target volume dose of at least 75 Gy. We assessed the impact of GP5 and that of pretreatment- and treatment-related factors on freedom from biochemical failure, freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS). Results: At biopsy, 89% of patients had no GP5, and 11% (76/718) had GP5. There were no differences in age, comorbid illness, T stage, prostate-specific antigen, or the use or duration of androgen deprivation therapy between GS8 without GP5 and GS8–10 with GP5. The presence of GP5 predicted lower FFM (p < 0.002; hazard ratio [HR] 3.4 [1.7–7.1]); CSS (p < 0.0001; HR 12.9 [5.4-31]); and OS (p < 0.0001; HR 3.6 [2.0-6.5]) in comparison with GS8 (without GP5). The 8-year FFM, CSS, and OS were 89%, 98%, and 57%, respectively, for those with Gleason 8 prostate cancer without GP5 in comparison with 61%, 55%, and 31%, respectively, for those with GP5. In addition, both FFM and CSS were strongly influenced by androgen deprivation therapy given concurrently with RT. On multivariate analysis, GP5 was the strongest prognostic factor for all clinical endpoints, including OS. Conclusion: The presence of GP5 predicts for worse clinical behavior, which therefore needs to be accounted for by risk stratification schemes. Further intensification of local and/or systemic therapy may be appropriate for such patients. [ABSTRACT FROM AUTHOR]

Purpose: To examine the prognostic utility of the percentage of positive cores (PPC) at the time of prostate biopsy for patients treated with dose-escalated external beam radiation therapy. Methods and Materials: We performed a retrospective analysis of patients treated at the University of Michigan Medical Center to at least 75 Gy. Patients were stratified according to PPC by quartile, and freedom from biochemical failure (nadir + 2 ng/mL), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS) were assessed by log-rank test. Receiver operator characteristic (ROC) curve analysis was used to determine the optimal cut point for PPC stratification. Finally, Cox proportional hazards multivariate regression was used to assess the impact of PPC on clinical outcome when adjusting for National Comprehensive Cancer Network (NCCN) risk group and androgen deprivation therapy. Results: PPC information was available for 651 patients. Increasing-risk features including T stage, prostate-specific antigen, Gleason score, and NCCN risk group were all directly correlated with increasing PPC. On log-rank evaluation, all clinical endpoints, except for OS, were associated with PPC by quartile, with worse clinical outcomes as PPC increased, with the greatest impact seen in the highest quartile (>66.7% of cores positive). ROC curve analysis confirmed that a cut point using two-thirds positive cores was most closely associated with CSS (p = 0.002; area under ROC curve, 0.71). On univariate analysis, stratifying patients according to PPC less than or equal to 66.7% vs. PPC greater than 66.7% was prognostic for freedom from biochemical failure (p = 0.0001), FFM (p = 0.0002), and CSS (p = 0.0003) and marginally prognostic for OS (p = 0.055). On multivariate analysis, after adjustment for NCCN risk group and androgen deprivation therapy use, PPC greater than 66.7% increased the risk for biochemical failure (p = 0.0001; hazard ratio [HR], 2.1 [95% confidence interval (CI), 1.4–3.0]) and FFM (p = 0.05; HR, 1.7 [95% CI, 1.1–2.9]) and marginally increased the risk for CSS (p = 0.057; HR, 2.1 [95% CI, 1.0–4.6]). Conclusion: PPC at the time of biopsy adds prognostic value for clinically meaningful endpoints for patients treated with dose-escalated radiation therapy. This was particularly true for NCCN-defined intermediate- and high-risk patients. [Copyright &y& Elsevier]