Skyler B. Johnson

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.

Dose to the inferior rectum is strongly associated with patient reported bowel quality of life after radiation therapy for prostate cancer.

PURPOSE To evaluate rectal dose and post-treatment patient-reported bowel quality of life (QOL) following radiation therapy for prostate cancer. METHODS Patient-reported QOL was measured at baseline and 2-years via the expanded prostate cancer index composite (EPIC) for 90 patients. Linear regression modeling was performed using the baseline score for the QUANTEC normal tissue complication probability model and dose volume histogram (DVH) parameters for the whole and segmented rectum (superior, middle, and inferior). RESULTS At 2-years the mean summary score declined from a baseline of 96.0-91.8. The median volume of rectum treated to ≥70 Gy (V70) was 11.7% for the whole rectum and 7.0%, 24.4%, and 1.3% for the inferior, middle, and superior rectum, respectively. Mean dose to the whole and inferior rectum correlated with declines in bowel QOL while dose to the mid and superior rectum did not. Low (V25-V40), intermediate (V50-V60) and high (V70-V80) doses to the inferior rectum influenced bleeding, incontinence, urgency, and overall bowel problems. Only the highest dose (V80) to the mid-rectum correlated with rectal bleeding and overall bowel problems. CONCLUSIONS Segmental DVH analysis of the rectum reveals associations between bowel QOL and inferior rectal dose that could significantly influence radiation planning and prognostic models.

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.

Use of alternative medicine for cancer and its impact on survival

There is limited available information on patterns of utilization and efficacy of alternative medicine (AM) for patients with cancer. We identified 281 patients with nonmetastatic breast, prostate, lung, or colorectal cancer who chose AM, administered as sole anticancer treatment among patients who did not receive conventional cancer treatment (CCT), defined as chemotherapy, radiotherapy, surgery, and/or hormone therapy. Independent covariates on multivariable logistic regression associated with increased likelihood of AM use included breast or lung cancer, higher socioeconomic status, Intermountain West or Pacific location, stage II or III disease, and low comorbidity score. Following 2:1 matching (CCT = 560 patients and AM = 280 patients) on Cox proportional hazards regression, AM use was independently associated with greater risk of death compared with CCT overall (hazard ratio [HR] = 2.50, 95% confidence interval [CI] = 1.88 to 3.27) and in subgroups with breast (HR = 5.68, 95% CI = 3.22 to 10.04), lung (HR = 2.17, 95% CI = 1.42 to 3.32), and colorectal cancer (HR = 4.57, 95% CI = 1.66 to 12.61). Although rare, AM utilization for curable cancer without any CCT is associated with greater risk of death.

Overactive Bladder and Mental Health Symptoms in Recently Deployed Female Veterans

PURPOSE We estimate the prevalence of current overactive bladder symptoms in recently deployed female veterans, and determine if overactive bladder symptoms are associated with problems commonly reported after deployment including mental health symptoms and prior sexual assault. MATERIALS AND METHODS Baseline data were analyzed from a nationwide cohort study of urogenital symptoms in female veterans. Women returning from deployment to Iraq or Afghanistan in the prior 2 years and ending military service were eligible. Self-reported data were collected by computer assisted telephone interview. Overactive bladder and mental health conditions were identified using standardized definitions as well as validated urinary and mental health instruments. Associations between overactive bladder and depression, post-traumatic stress disorder, anxiety and sexual assault were assessed in separate logistic regression models using propensity scores to adjust for confounding. RESULTS The 1,702 participants had a mean (SD) age of 31.1 (8.4) years and were racially/ethnically diverse. Overall 375 participants (22%; 95% CI 20.1, 24.1) reported overactive bladder. Mental health outcomes included post-traumatic stress disorder (19%), anxiety (21%), depression (10%) and prior sexual assault (27%). All outcomes were associated with overactive bladder (adjusted OR 2.7, 95% CI [2.0, 3.6], 2.7 [2.0, 3.5], 2.5 [1.5, 4.3] and 1.4 [1.1, 1.9], respectively). CONCLUSIONS Overactive bladder symptoms occurred in 22% of recently deployed female veterans, and were associated with self-reported mental health symptoms and traumatic events including prior sexual assault. Screening and evaluation for bothersome urinary symptoms and mental health problems appear warranted in female veterans presenting for primary and urological care after deployment.

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.

The Impact of Numeracy on Verbatim Knowledge of the Longitudinal Risk for Prostate Cancer Recurrence following Radiation Therapy

Objective. Given the long natural history of prostate cancer, we assessed differing graphical formats for imparting knowledge about the longitudinal risks of prostate cancer recurrence with or without ‘hormone’ or ‘androgen deprivation’ therapy. Methods. Male volunteers without a history of prostate cancer were randomized to 1 of 8 risk communication instruments that depicted the likelihood of prostate cancer returning or spreading over 1, 2, and 3 years. The tools differed in format (line, pie, bar, or pictograph) and whether the graph also included no numbers, 1 number (indicating the number of affected individuals), or 2 numbers (indicting both the number affected and the number unaffected). The main outcome variables evaluated were graphical preference and knowledge. Results. A total of 420 men were recruited; respondents were least familiar and experienced with pictographs (P < 0.0001), and only 10% preferred this particular format. Overall accuracy ranged from 79% to 92%, and when assessed across all graphical subtypes, the addition of numerical information did not improve verbatim knowledge (P = 0.1). Self-reported numeracy was a strong predictor of accuracy of responses (odds ratio [OR] = 2.6, P = 0.008), and the impact of high numeracy varied across graphical type, having a greater impact on line (OR = 5.1; 95% confidence interval [CI] = 1.6–16; P = 0.04) and pie charts (OR = 7.1; 95% CI = 2.6–19; P =0.01), without an impact on pictographs (OR = 0.4; 95% CI = 0.1–1.7; P = 0.17) or bar charts (OR = 0.5; 95% CI = 0.1–1.8; P = 0.24). Conclusion. For longitudinal presentation of risk, baseline numeracy was strongly prognostic for outcome. However, the addition of numbers to risk graphs improved only the delivery of verbatim knowledge for subjects with lower numeracy. Although subjects reported the least familiarity with pictographs, they were one of the most effective means of transferring information regardless of numeracy.

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.

Patient-reported quality of life after stereotactic body radiation therapy versus moderate hypofractionation for clinically localized prostate cancer

BACKGROUND AND PURPOSE Evaluate changes in bowel, urinary and sexual patient-reported quality of life following treatment with moderately hypofractionated radiotherapy (<5Gray/fraction) or stereotactic body radiation therapy (SBRT;5-10Gray/fraction) for prostate cancer. MATERIALS AND METHODS In a pooled multi-institutional analysis of men treated with moderate hypofractionation or SBRT, we compared minimally detectable difference in bowel, urinary and sexual quality of life at 1 and 2years using chi-squared analysis and logistic regression. RESULTS 378 men received moderate hypofractionation compared to 534 men who received SBRT. After 1year, patients receiving moderate hypofractionation were more likely to experience worsening in bowel symptoms (39.5%) compared to SBRT (32.5%; p=.06), with a larger difference at 2years (37.4% versus 25.3%, p=.002). Similarly, patients receiving moderate fractionation had worsening urinary symptom score compared to patients who underwent SBRT at 1 and 2years (34.7% versus 23.1%, p<.001; and 32.8% versus 14.0%, p<.001). There was no difference in sexual symptom score at 1 or 2years. After adjusting for age and cancer characteristics, patients receiving SBRT were less likely to experience worsening urinary symptom scores at 2years (odds ratio: 0.24[95%CI: 0.07-0.79]). CONCLUSIONS Patients who received SBRT or moderate hypofractionation have similar patient-reported change in bowel and sexual symptoms, although there was worse change in urinary symptoms for patients receiving moderate hypofractionation.

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.