William C. Jackson

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.

Very Early Salvage Radiotherapy Improves Distant Metastasis-Free Survival

Purpose: Early salvage radiotherapy following radical prostatectomy for prostate cancer is commonly advocated in place of adjuvant radiotherapy. We aimed to determine the optimal definition of early salvage radiotherapy. Materials and Methods: We performed a multi‐institutional retrospective study of 657 men who underwent salvage radiotherapy between 1986 and 2013. Two comparisons were made to determine the optimal definition of early salvage radiotherapy, including 1) the time from radical prostatectomy to salvage radiotherapy (less than 9, 9 to 21, 22 to 47 or greater than 48 months) and 2) the level of detectable pre‐salvage radiotherapy prostate specific antigen (0.01 to 0.2, greater than 0.2 to 0.5 or greater than 0.5 ng/ml). Outcomes included freedom from salvage androgen deprivation therapy, and biochemical relapse‐free, distant metastases‐free and prostate cancer specific survival. Results: Median followup was 9.8 years. Time from radical prostatectomy to salvage radiotherapy did not correlate with 10‐year biochemical relapse‐free survival rates (R2 = 0.18). Increasing pre‐salvage radiotherapy prostate specific antigen strongly correlated with biochemical relapse‐free survival (R2 = 0.91). Increasing detectable pre‐salvage radiotherapy prostate specific antigen (0.01 to 0.2, greater than 0.2 to 0.5 and greater than 0.5 ng/ml) predicted worse 10‐year biochemical relapse‐free survival (62%, 44% and 27%), freedom from salvage androgen deprivation therapy (77%, 66% and 49%), distant metastases‐free survival (86%, 79% and 66%, each p <0.001) and prostate cancer specific survival (93%, 89% and 80%, respectively, p = 0.001). On multivariable analysis early salvage radiotherapy (prostate specific antigen greater than 0.2 to 0.5 ng/ml) was associated with a twofold increase in biochemical failure, use of salvage androgen deprivation therapy and distant metastases compared to very early salvage radiotherapy (prostate specific antigen 0.01 to 0.2 ng/ml). Conclusions: The duration from radical prostatectomy to salvage radiotherapy is not independently prognostic for outcomes after salvage radiotherapy and it should not be used to define early salvage radiotherapy. Grouping all patients with pre‐salvage radiotherapy prostate specific antigen 0.5 ng/ml or less may be inadequate to define early salvage radiotherapy and it has a relevant impact on ongoing and future clinical trials.

Age and Comorbid Illness Are Associated With Late Rectal Toxicity Following Dose-Escalated Radiation Therapy for Prostate Cancer

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.

Independent surgical validation of the new prostate cancer grade-grouping system

To report the independent prognostic impact of the new prostate cancer grade‐grouping system in a large external validation cohort of patients treated with radical prostatectomy (RP).

Characterization of changes in total body composition for patients with head and neck cancer undergoing chemoradiotherapy using dual-energy x-ray absorptiometry.

Patients with head and neck cancer experience significant weight loss secondary to concurrent chemoradiotherapy (CCRT). Using dual‐energy X‐ray absorptiometry (DEXA) scans, we characterize total body composition changes during and after CCRT in order to develop novel clinical care models that will improve the patients quality of life (QOL).

Independent validation of the prognostic capacity of the ISUP prostate cancer grade grouping system for radiation treated patients with long-term follow-up

Background:There has been a recent proposal to change the grading system of prostate cancer into a five-tier grade grouping system. The prognostic impact of this has been demonstrated in regards only to biochemical recurrence-free survival (bRFS) with short follow-up (3 years).Methods:Between 1990 and 2013, 847 consecutive men were treated with definitive external beam radiation therapy at a single academic center. To validate the new grade grouping system, bRFS, distant metastases-free survival (DMFS) and prostate cancer-specific survival (PCSS) were calculated. Adjusted Kaplan–Meier and multivariable Cox regression analyses were performed to assess the independent impact of the new grade grouping system. Discriminatory analyses were performed to compare the commonly used three-tier Gleason score system (6, 7 and 8–10) to the new system.Results:The median follow-up of our cohort was 88 months. The 5-grade groups independently validated differing risks of bRFS (group 1 as reference; adjusted hazard ratio (aHR) 1.35, 2.16, 1.79 and 3.84 for groups 2–5, respectively). Furthermore, a clear stratification was demonstrated for DMFS (aHR 2.03, 3.18, 3.62 and 13.77 for groups 2–5, respectively) and PCSS (aHR 3.00, 5.32, 6.02 and 39.02 for groups 2–5, respectively). The 5-grade group system had improved prognostic discrimination for all end points compared with the commonly used three-tiered system (that is, Gleason score 6, 7 and 8–10).Conclusions:In a large independent radiotherapy cohort with long-term follow-up, we have validated the bRFS benefit of the proposed five-tier grade grouping system. Furthermore, we have demonstrated that the system is highly prognostic for DMFS and PCSS. Grade group 5 had markedly worse outcomes for all end points, and future work is necessary to improve outcomes in these patients.

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.

MDM2 Inhibition Sensitizes Prostate Cancer Cells to Androgen Ablation and Radiotherapy in a p53-Dependent Manner

PURPOSE: Increased murine double minute 2 (MDM2) expression, independent of p53 status, is associated with increased cancer-specific mortality for men with prostate cancer treated with radiotherapy. We assessed MI-219, a small molecule inhibitor of MDM2 with improved pharmacokinetics over nutlin-3, for sensitization of prostate cancer cells to radiotherapy and androgen deprivation therapy, a standard treatment option for men with high-risk prostate cancer. EXPERIMENTAL DESIGN: The effect of MDM2 inhibition by MI-219 was assessed in vitro and in vivo with mouse xenograft models across multiple prostate cancer cell lines containing varying p53 functional status. RESULTS: MDM2 inhibition by MI-219 resulted in dose- and time-dependent p53 activation and decreased clonogenic cell survival after radiation in a p53-dependent manner. Mechanistically, radiosensitization following inhibition of MDM2 was largely the result of p53-dependent increases in apoptosis and DNA damage as evidenced by Annexin V flow cytometry and γ-H2AX foci immunofluorescence. Similarly, treatment with MI-219 enhanced response to antiandrogen therapy via a p53-dependent increase in apoptotic cell death. Lastly, triple therapy with radiation, androgen deprivation therapy, and MI-219 decreased xenograft tumor growth compared with any single- or double-agent treatment. CONCLUSION: MDM2 inhibition with MI-219 results in p53-dependent sensitization of prostate cancer cells to radiation, antiandrogen therapy, and the combination. These findings support MDM2 small molecule inhibitor therapy as a therapy intensification strategy to improve clinical outcomes in high-risk localized prostate cancer. TRANSLATIONAL RELEVANCE: The combination of radiotherapy and androgen deprivation therapy is a standard treatment option for men with high-risk prostate cancer. Despite improvements in outcomes when androgen deprivation therapy is added to radiation, men with high-risk prostate cancer have significant risk for disease recurrence, progression, and even death within the first 10 years following treatment. We demonstrate that treatment with MI-219 (an inhibitor of MDM2) results in prostate cancer cell sensitization to radiation and androgen deprivation therapy in vitro and in vivo. Triple therapy with MI-219, radiation, and androgen deprivation therapy dramatically decreased tumor growth compared with any single- or double-agent therapy. These findings provide evidence that inhibition of MDM2 is a viable means by which to enhance the efficacy of both radiation and androgen deprivation therapy and thereby improve outcomes in the treatment of prostate cancer. As such, further investigation is warranted to translate these findings to the clinical setting.

A comprehensive assessment of the prognostic utility of the Stephenson nomogram for salvage radiation therapy postprostatectomy

PURPOSE To investigate the prognostic utility of the Stephenson nomogram for clinically relevant endpoints, freedom from metastasis (FFM), and prostate cancer-specific survival (PCSS) in patients treated with salvage external beam radiation therapy (SRT) following a rising prostate-specific antigen (PSA) after radical prostatectomy (RP). METHODS AND MATERIALS From an institutional cohort of 575 patients treated with SRT between 1986 and 2010, the Stephenson nomogram variables were retrospectively collected and available for 179 patients. The prognostic impact of the Stephenson nomogram on 6-year freedom from biochemical failure (FFBF), FFM, and PCSS was assessed on univariate and multivariate analysis using Kaplan-Meier and Cox proportional hazards models. The prognostic utility of the Stephenson nomogram was compared with individual pretreatment, treatment, and clinical characteristics using concordance indices. RESULTS In the 179 patients with all available nomogram variables, median follow-up was 85.0 months (interquartile range [IQR], 53-113) and 6-year FFBF, FFM, and PCSS were 38% (95% confidence interval [CI], 30-46), 79% (95% CI, 73-85), and 96% (95% CI, 92-100), respectively. Univariate analysis, demonstrated that the Stephenson nomogram, as a continuous variable and as a risk stratified group, was prognostic of FFBF (both, P < .0001), FFM (both, P < .0001), and PCSS (both, P ≤ .0005). When analyzing individual Stephenson nomogram variables, multivariate analysis revealed that positive surgical margins (P = .02; hazard ratio [HR], 0.4; 95% CI, 0.2-0.8) and pre-RT PSA (P = .0001; HR, 1.6; 95% CI, 1.3-2.0) were prognostic for FFM, while pre-RT PSA (P = .03; HR, 1.2; 95% CI, 1.0-1.4) was the only prognostic variable for PCSS. Concordance indices revealed the Stephenson nomogram to have superior prognostic capability for biochemical failure (0.71), distant metastasis (0.75), and prostate cancer-specific mortality (0.75) when compared with individual variables (BF all ≤ 0.65, DM all ≤ 0.67, PCSM all ≤ 0.71). CONCLUSIONS For patients treated with SRT for a rising PSA postprostatectomy, the Stephenson nomogram is an appropriate prognostic tool for estimating the response to treatment; however, there remains a need for improvement in current and future nomograms.

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.