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Background: Clinical data suggest that stereotactic body radiation therapy (SBRT) provides similar clinical outcomes as other radiation modalities for prostate cancer. However, data reporting on the safety of SBRT after TURP is limited. Herein, we report our experience using SBRT to deliver hypofractionated radiotherapy in patients with a history of TURP including physician-reported toxicities and patient-reported quality of life. Methods: Forty-seven patients treated with SBRT from 2007 to 2016 at Georgetown University Hospital for localized prostate carcinoma with a history of prior TURP were included in this retrospective analysis. Treatment was delivered using the CyberKnife® (Accuray Incorporated, Sunnyvale, CA) with doses of 35 Gy or 36.25 Gy in 5 fractions without prostatic urethral sparing. Toxicities were recorded and scored using the CTCAE v.4. Cystoscopy findings were retrospectively reviewed. Urinary quality of life data was assessed using the International Prostate Symptom Scoring (IPSS) and Expanded Prostate Cancer Index Composite 26 (EPIC-26). A Wilcoxon signed-rank sum test was used to determine if there was a statistically significant increase or decrease in IPSS or EPIC scores between timepoints. Minimally important differences were calculated by obtaining half the standard deviation at time of start of treatment. Results: Forty-seven patients at a median age of 72 years (range 63–84) received SBRT. The mean follow-up was 4.7 years (range 2–10 years). Late Grade 2 and grade 3 urinary toxicity occurred in 23 (48.9%) and 3 (6.4%) men, respectively. There were no Grade 4 or 5 toxicities. Approximately 51% of patients experienced hematuria following treatment. Mean time to hematuria was 10.5 months. Twenty-five cystoscopies were performed during follow-up and the most common finding was hyperemia, varices of the bladder neck/TURP defect, and/or necrotic tissue in the TURP defect. Baseline urinary QOL composite scores were low, but they did not clinically significantly decline in the first 2 years following treatment. Conclusions: In patients with prior TURP, prostate SBRT was well-tolerated. GU toxicity rates were comparable to similar patients treated with conventionally fractionated radiation therapy. Urinary quality of life was poor at baseline, but did not worsen clinically over time. Stricter dosimetric criteria could potentially improve the rate of high-grade late toxicity, but may increase the risk of peri-urethral recurrence.

Background: Stereotactic body radiation therapy (SBRT) is a safe and effective treatment option for patients with low to intermediate risk prostate cancer (1). SBRT results in very low PSA nadirs secondary to the delivery of high biologically effective doses. Studies reporting on the diagnosis, confirmation, and management of salvageable isolated local failures (ILF) are limited. This study aims to determine the incidence and management approach of ILF after SBRT in a large single institution cohort. Method: All patients with low or intermediate risk localized prostate cancer treated with SBRT at Georgetown University Hospital were eligible for this study. Treatment was delivered using robotic SBRT with doses of 35-36.25 Gy in five fractions. ILF were diagnosed using multiparametric MRI and/or biopsy prompted by rising PSA levels after achieving long-term nadir. Patient's characteristics were extracted from a prospective institutional quality of life trial (IRB 2009-510). Type of salvage therapy and post-salvage PSA were determined on subsequent follow-up and chart review. Results: Between December 2008 to August 2018, 998 men with low to intermediate risk prostate cancer were eligible for inclusion in this analysis. Twenty-four patients (low risk, n = 5; intermediate risk, n = 19) were found to have ILF within the prostate on either MRI (n = 19) and/or biopsy (n = 20). Median pre-treatment PSA was 7.55 ng/ml. Median time to diagnosis of ILF was 72 months (24-110 months) with median PSA at the time of ILF of 2.8 ng/ml (0.7-33 ng/ml). Median PSA doubling time was 17 months (5-47 months). Thirteen patients with biopsy proven ILF proceeded with salvage therapy (cryotherapy n = 12, HIFU n = 1). Of 12 patients who underwent cryotherapy, 7 had a post-treatment PSA of

Background: Patients with a high pretreatment IPSS may have higher rates of late urinary morbidity after radiation therapy for prostate cancer (1). Stereotactic body radiation therapy (SBRT) delivers fewer high-dose fractions of radiation, which may be radiobiologically favorable to the conventional low-dose external beam fractions. The urinary toxicity associated with SBRT, however, remains unclear in patients with a high IPSS (1). We report our experience using SBRT for localized prostate cancer in patients with pretreatment IPSS ≥ 15. Methods: Localized prostate cancer patients with a pre-treatment IPSS ≥ 15 treated with SBRT at Georgetown University Hospital from 2009 to 2016 were included in this retrospective review of prospectively collected data. These patients were treated to 35-36.25 Gy in five fractions delivered via CyberKnife (Accuray Inc., Sunnyvale, CA). Urinary toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4). Urinary quality of life was assessed using validated questionnaires (IPSS and EPIC-26). Results: 53 patients at a median age of 71 years (range 57-89 years) received SBRT with a minimum follow up of 3 years. The median prostate size was 37 cm3 (range 12-100 cm3) and 30.2% patients received ADT. The 3-years incidence rate of Grade 3 urinary toxicity was 7.5% with median time to toxicity of 2.9 years. There were no Grade 4 or 5 toxicities. A mean baseline IPSS score of 19.8 significantly decreased to 12.9 at 3 months post-SBRT (p = 0.002) and remained stable at 36 months (13.7). A mean baseline EPIC-26 obstructive/irritative score of 64.1 significantly improved to 80.2 at 3 months (p = 0.002). This improvement was maintained to 36 months. There was no significant change from the mean baseline EPIC-26 urinary incontinence score at any point during follow up. Conclusions: SBRT for clinically localized prostate cancer was well-tolerated in men with baseline IPSS ≥ 15 (1). Grade 3 toxicities occurred but resolved with time. Our data suggest that poor baseline urinary function does not worsen following SBRT and may even improve. High baseline IPSS score should not be considered a contraindication to SBRT.

Purpose: Retaining quality of life in patients treated with SBRT for prostate cancer remains paramount. As such, balancing the benefits of treatment against the effects of therapy on elderly patients is essential. The EORTC QLQ-ELD14 (ELD-14) is a validated questionnaire with a domain dedicated to burden of illness and treatment in the elderly. The Expanded Prostate Cancer Index Composite (EPIC)-26 is a validated questionnaire which measures urinary, bowel, sexual, and hormonal symptoms. This study reports trends in self-reported burden in patients with prostate cancer treated with SBRT and reveals convergence of self-reported burden with treatment related side effects obtained from the EPIC-26 questionnaire. Methods: All patients ≥70 years old, with localized prostate cancer treated with SBRT ± ADT at Medstar Georgetown University Hospital from 2013 to 2018 and had completed the ELD-14 were eligible for inclusion in this cross-sectional cohort study. Percentage of responses to questions related to disease and treatment burden were counted for each category ("not at all" and "a little" vs. "quite a bit" and "very much"). Additional demographic features were derived from available medical records. A total of 111 patients (median age of 74) responded to the ELD-14 questionnaire at onset of treatment and at the 2-year mark. Responses to EPIC questionnaires at matched follow-ups were scored and correlated with the self-reported burden domain of the ELD-14 using the Spearman correlation coefficient. Results: Number of patients reporting "quite a bit" or "very much" burden from prostate cancer was 6.3% prior to treatment. This was highest at 1-month (10.8%) and decreased to 9.0% at 24 months post-SBRT (X 2 = 3.836, p = 0.6986). By comparison, 3.6 and 5.4% reported "quite a bit" or "very much" burden from treatment at start of treatment and 24 months, respectively (X 2 = 1.046, p = 0.9838). Patient reported treatment burden was found to converge well with individual domains of EPIC-26. Patients undergoing ADT experienced more burden than their non-ADT counterparts. Conclusions: This cross-sectional study suggests a minority of patients reported high burden from their clinically localized prostate cancer or from their SBRT treatment. Self-reported burden converged well with lower EPIC scores in multiple domains.

Patients presenting with prostate cancers undergo clinical staging evaluations to determine the extent of disease to guide therapeutic recommendations. Management options may include watchful waiting, surgery, or radiation therapy. Thus, initial risk stratification of prostate cancer patients is important for achieving optimal therapeutic results or cancer cure and preservation of quality of life. Predictive biomarkers for risks of complications or late effects of treatment are needed to inform clinical decisions for treatment selection. Here, we analyzed pre-treatment plasma metabolites in a cohort of prostate cancer patients (N = 99) treated with Stereotactic Body Radiation Therapy (SBRT) at Medstar-Georgetown University Hospital in a longitudinal, quality-of-life study to determine if individuals experiencing radiation toxicities can be identified by a molecular profile in plasma prior to treatment. We used a multiple reaction mass spectrometry-based molecular phenotyping of clinically annotated plasma samples in a retrospective outcome analysis to identify candidate biomarker panels correlating with adverse clinical outcomes following radiation therapy. We describe the discovery of candidate biomarkers, based on small molecule metabolite panels, showing high correlations (AUCs ≥ 95%) with radiation toxicities, suitable for validation studies in an expanded cohort of patients.

Background Recent data suggest that intensity-modulated radiation therapy (IMRT) plus brachytherapy boost for unfavorable prostate cancer provides improved biochemical relapse-free survival over IMRT alone. Stereotactic body radiation therapy (SBRT) may be a less invasive alternative to brachytherapy boost. Here, we report the 3-year gastrointestinal (GI) and genitourinary (GU) toxicities of IMRT plus SBRT boost. Materials and methods Between March 2008 and September 2012, patients with prostate cancer were treated with robotic SBRT (19.5 Gy in three fractions) followed by fiducial-guided IMRT (45–50.4 Gy) on an institutional protocol. Toxicity was prospectively graded using the common terminology criteria for adverse events version 4.0 (CTCAEv.4) at the start of and at 1- to 6-month intervals after therapy. Rectal telangiectasias were graded using the Vienna Rectoscopy Score (VRS). Results At a median follow-up of 4.2 years (2.4–7.5), 108 patients (4 low-, 45 intermediate-, and 59 high-risk) with a median age of 74 years (55–92) were treated with SBRT plus IMRT, with 8% on anticoagulation and an additional 48% on antiplatelet therapy at the start of therapy. The cumulative incidence of late ≥grade 2 GI toxicity was 12%. Of these, 7% were due to late rectal bleeding, with six patients requiring up to two coagulation procedures. One patient with rectal telangiectasias was treated with hyperbaric oxygen (grade 3 toxicity). No rectal fistulas or stenoses were observed. Ten patients had multiple non-confluent telangiectasias (VRS grade 2), and three patients had multiple confluent telangiectasias (VRS grade 3). The cumulative incidence of late grade 3 GU toxicity was 6%. Most late toxicities were due to hematuria requiring bladder fulguration. There were no late ≥grade 4 GU toxicities. Conclusion Rates of clinically significant GI and GU toxicities are modest following IMRT plus SBRT boost. Future studies should compare cancer control, quality of life, and toxicity with other treatment modalities for patients with high-risk prostate cancer.

Predictors of acute urinary symptom flare following stereotactic body radiation therapy (SBRT) in the definitive treatment of localized prostate cancer

// Lymor Ringer 1,* , Paul Sirajuddin 1,* , Lucas Tricoli 1,* , Sarah Waye 1 , Muhammad Umer Choudhry 1 , Erika Parasido 1 , Angiela Sivakumar 1 , Mary Heckler 1 , Aisha Naeem 1 , Iman Abdelgawad 1,6 , Xuefeng Liu 2 , Adam S. Feldman 3 , Richard J. Lee 3 , Chin-Lee Wu 3 , Venkata Yenugonda 1 , Bhaskar Kallakury 2 , Anatoly Dritschilo 4 , John Lynch 4 , Richard Schlegel 1,2 , Olga Rodriguez 1 , Richard G. Pestell 5 , Maria Laura Avantaggiati 1,* and Chris Albanese 1,2,* 1 Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA 2 Department of Pathology, Georgetown University Medical Center, Washington, DC, USA 3 Massachusetts General Hospital, Boston, USA 4 Georgetown University Hospital, Washington, DC, USA 5 Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 6 National Cancer Institute of Egypt, Cairo, Egypt * These authors contributed equally to this work Correspondence: Chris Albanese, email: // Keywords : p53, apoptosis, autophagy, primary cells, prostate Received : July 14, 2014 Accepted : September 25, 2014 Published : September 26, 2014 Abstract The p53 tumor suppressor protein plays a crucial role in influencing cell fate decisions in response to cellular stress. As p53 elicits cell cycle arrest, senescence or apoptosis, the integrity of the p53 pathway is considered a key determinant of anti-tumor responses. p53 can also promote autophagy, however the role of p53-dependent autophagy in chemosensitivity is poorly understood. VMY-1-103 (VMY), a dansylated analog of purvalanol B, displays rapid and potent anti-tumor activities, however the pathways by which VMY works are not fully defined. Using established prostate cancer cell lines and novel conditionally reprogrammed cells (CRCs) derived from prostate cancer patients; we have defined the mechanisms of VMY-induced prostate cancer cell death. Herein, we show that the cytotoxic effects of VMY required a p53-dependent induction of autophagy, and that inhibition of autophagy abrogated VMY-induced cell death. Cancer cell lines harboring p53 missense mutations evaded VMY toxicity and treatment with a small molecule compound that restores p53 activity re-established VMY-induced cell death. The elucidation of the molecular mechanisms governing VMY-dependent cell death in cell lines, and importantly in CRCs, provides the rationale for clinical studies of VMY, alone or in combination with p53 reactivating compounds, in human prostate cancer.

ObjectiveActive surveillance (AS) is an increasingly utilized strategy for monitoring men with low-risk prostate cancer (PCa) that allows them to defer active treatment (AT) in the absence of cancer progression. Studies have explored reasons for selecting AS and for then switching to AT, but less is known about men's experiences being on AS. We interviewed men to determine the clinical and psychological factors associated with selecting and adhering to AS protocols.MethodsWe conducted semi-structured interviews with men with a low-risk PCa at two academic medical centers. Subjects had either been on AS for ≥ 1 year or had opted for AT after a period of AS. We used an iterative, content-driven approach to analyze the interviews and to identify themes.ResultsWe enrolled 21 subjects, mean age 70.4 years, 3 racial/ethnic minorities, and 16 still on AS. Men recognized the favorable prognosis of their cancer (some had sought second opinions when initially offered AT), valued avoiding treatment complications, were reassured that close monitoring would identify progression early enough to be successfully treated, and trusted their urologists. Although men reported feeling anxious around the time of surveillance testing, those who switched to AT did so based only on evidence of cancer progression.ConclusionsOur selected sample was comfortable being on AS because they understood and valued the rationale for this approach. However, this highlights the importance of ensuring that men newly diagnosed with a low-risk PCa are provided sufficient information about prognosis and treatment options to make informed decisions.

BACKGROUND Routine symptom and health-related quality of life (HRQOL) assessments can engage patients, give provider feedback, and improve doctor/patient communication. OBJECTIVE We compared the impact of a technology-assisted symptom monitoring system versus usual care on HRQOL and doctor/patient communication in early-stage prostate cancer (PCa) survivors. METHODS Men (N = 94) were on average 62-years old, mostly African American (AA; 61.7%), and 10-19 months post-treatment. They were randomized to symptom monitoring plus feedback (SM + F; n = 49) or usual care (UC; n = 45). SM+F participants completed a 12-item telephoneassisted monitoring intervention. All participants completed a baseline and 2 follow-up interviews. RESULTS Among the SM+F participants, perceptions of the monitoring system were positive: 97.1% endorsed it as easy/very easy to use and 85% felt all patients could benefit from it. At baseline, men reported favorable general and cancer-specific HRQOL and doctor/patient communication, but poorer urinary and sexual function. Although there was no overall impact of the intervention, post hoc exploratory analyses indicated that among AA men, those who received SM+F improved relative to UC on doctor/patient communication (P < .05), general HRQOL (P < .06), and sexual function (P < .05). LIMITATIONS Variability in survivor follow-up care, limited access to eligible participants, and minimal physician training in the use of reports likely decreased physician investment. CONCLUSION Overall, PCa survivors were receptive to this monitoring system. Exploratory analyses suggest that this technology-assisted monitoring system may be of particular benefit to African American men. Additional studies with larger samples, more intervention time-points, and increased physician training are needed to strengthen the intervention's impact.

Background: Proctitis following prostate cancer radiation therapy is a primary determinant of quality of life (QOL). While previous studies have assessed acute rectal morbidity at 1 month after stereotactic body radiotherapy (SBRT), little data exist on the prevalence and severity of rectal morbidity within the first week following treatment. This study reports the acute bowel morbidity one week following prostate SBRT. Materials and methods: Between May 2013 and August 2014, 103 patients with clinically localized prostate cancer were treated with 35 to 36.25 Gy in five fractions using robotic SBRT delivered on a prospective clinical trial. Bowel toxicity was graded using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv.4). Bowel QOL was assessed using EPIC-26 questionnaire bowel domain at baseline, one week, one month, and three months. Time-dependent changes in bowel symptoms were statistically compared using the Wilcoxon signed-rank test. Clinically significant change was assessed by the minimally important difference (MID) in EPIC score. This was defined as a change of one-half standard deviation (SD) from the baseline score. Results: One hundred and three patients with a minimum of three months of follow-up were analyzed. The cumulative incidence of acute grade 2 GI toxicity was 23%. There were no acute ≥ grade 3 bowel toxicities. EPIC bowel summary scores maximally declined at 1 week after SBRT (-13.9, p

Purpose/objective(s) Stereotactic body radiation therapy (SBRT) is emerging as a minimally invasive alternative to brachytherapy to deliver highly conformal, dose-­escalated radiation therapy (RT) to the prostate. SBRT alone may not adequately cover the tumor extensions outside the prostate commonly seen in unfavorable prostate cancer. External beam radiation therapy (EBRT) with high dose rate brachytherapy boost is a proven effective therapy for unfavorable prostate cancer. This study reports on early prostate-specific antigen and prostate cancer-specific quality of life (QOL) outcomes in a cohort of unfavorable patients treated with intensity-modulated radiation therapy (IMRT) and SBRT boost. Materials/methods Prostate cancer patients treated with SBRT (19.5 Gy in three fractions) followed by fiducial-guided IMRT (45–50.4 Gy) from March 2008 to September 2012 were included in this retrospective review of prospectively collected data. Biochemical failure was assessed using the Phoenix definition. Patients completed the expanded prostate cancer index composite (EPIC)-26 at baseline, 1 month after the completion of RT, every 3 months for the first year, then every 6 months for a minimum of 2 years. Results One hundred eight patients (4 low-, 45 intermediate-, and 59 high-risk) with median age of 74 years completed treatment, with median follow-up of 4.4 years. Sixty-four percent of the patients received androgen deprivation therapy prior to the initiation of RT. The 3-year actuarial biochemical control rates were 100 and 89.8% for intermediate- and high-risk patients, respectively. At the initiation of RT, 9 and 5% of men felt their urinary and bowel function was a moderate to big problem, respectively. Mean EPIC urinary and bowel function and bother scores exhibited transient declines, with subsequent return to near baseline. At 2 years posttreatment, 13.7 and 5% of men felt their urinary and bowel function was a moderate to big problem, respectively. Conclusion At 3-year follow-up, biochemical control was favorable. Acute urinary and bowel symptoms were comparable to conventionally fractionated IMRT and brachytherapy. Patients recovered to near their baseline urinary and bowel function by 2 years posttreatment. A combination of IMRT with SBRT boost is well tolerated with minimal impact on prostate cancer-specific QOL.

Background Stereotactic body radiation therapy (SBRT) delivers high doses of radiation to the prostate while minimizing radiation to the adjacent critical organs. Large fraction sizes may increase urinary morbidity due to unavoidable treatment of the prostatic urethra. This study reports rates of acute urinary morbidity following SBRT for localized prostate cancer with prophylactic alpha-adrenergic antagonist utilization and urethral dose reduction (UDR). Methods From April 2013 to September 2014, 102 patients with clinically localized prostate cancer were treated with robotic SBRT to a total dose of 35–36.25 Gy in five fractions. UDR was employed to limit the maximum point dose of the prostatic urethra to 40 Gy. Prophylactic alpha-adrenergic antagonists were initiated 5 days prior to SBRT and continued until resolution of urinary symptoms. Quality of life (QoL) was assessed before and after treatment using the American Urological Association Symptom Score (AUA) and the Expanded Prostate Cancer Index Composite-26 (EPIC-26). Clinical significance was assessed using a minimally important difference (MID) of one half SD change from baseline. Results One hundred two patients underwent definitive prostate SBRT with UDR and were followed for 3 months. No patient experienced acute urinary retention requiring catheterization. A mean baseline AUA symptom score of 9.06 significantly increased to 11.83 1-week post-SBRT (p = 0.0024) and 11.84 1-month post-SBRT (p = 0.0023) but returned to baseline by 3 months. A mean baseline EPIC-26 irritative/obstructive score of 87.7 decreased to 74.1 1-week post-SBRT (p

The capacity of an individual to process DNA damage is considered a crucial factor in carcinogenesis. The comet assay is a phenotypic measure of the combined effects of sensitivity to a mutagen exposure and repair capacity. In this paper, we evaluate the association of the DNA repair kinetics, as measured by the comet assay, with prostate cancer risk. In a pilot study of 55 men with prostate cancer, 53 men without the disease, and 71 men free of cancer at biopsy, we investigated the association of DNA damage with prostate cancer risk at early (0–15 min) and later (15–45 min) stages following gamma-radiation exposure. Although residual damage within 45 min was the same for all groups (65% of DNA in comet tail disappeared), prostate cancer cases had a slower first phase (38% vs. 41%) and faster second phase (27% vs. 22%) of the repair response compared to controls. When subjects were categorized into quartiles, according to efficiency of repairing DNA damage, high repair-efficiency within the first 15 min after exposure was not associated with prostate cancer risk while higher at the 15–45 min period was associated with increased risk (OR for highest-to-lowest quartiles = 3.24, 95% CI = 0.98–10.66, p-trend = 0.04). Despite limited sample size, our data suggest that DNA repair kinetics marginally differ between prostate cancer cases and controls. This small difference could be associated with differential responses to DNA damage among susceptible individuals.

Clinical data suggest that large radiation fractions are biologically superior to smaller fraction sizes in prostate cancer radiotherapy. The CyberKnife is an appealing delivery system for hypofractionated radiosurgery due to its ability to deliver highly conformal radiation and to track and adjust for prostate motion in real-time. We report our early experience using the CyberKnife to deliver a hypofractionated stereotactic body radiation therapy (SBRT) boost to patients with intermediate- to high-risk prostate cancer. Twenty-four patients were treated with hypofractionated SBRT and supplemental external radiation therapy plus or minus androgen deprivation therapy (ADT). Patients were treated with SBRT to a dose of 19.5 Gy in 3 fractions followed by intensity modulated radiation therapy (IMRT) to a dose of 50.4 Gy in 28 fractions. Quality of life data were collected with American Urological Association (AUA) symptom score and Expanded Prostate Cancer Index Composite (EPIC) questionnaires before and after treatment. PSA responses were monitored; acute urinary and rectal toxicities were assessed using Common Toxicity Criteria (CTC) v3. All 24 patients completed the planned treatment with an average follow-up of 9.3 months. For patients who did not receive ADT, the median pre-treatment PSA was 10.6 ng/ml and decreased in all patients to a median of 1.5 ng/ml by 6 months post-treatment. Acute effects associated with treatment included Grade 2 urinary and gastrointestinal toxicity but no patient experienced acute Grade 3 or greater toxicity. AUA and EPIC scores returned to baseline by six months post-treatment. Hypofractionated SBRT combined with IMRT offers radiobiological benefits of a large fraction boost for dose escalation and is a well tolerated treatment option for men with intermediate- to high-risk prostate cancer. Early results are encouraging with biochemical response and acceptable toxicity. These data provide a basis for the design of a phase II clinical trial.

BACKGROUND The high incidence of and few identified risk factors for prostate cancer underscore the need to further evaluate markers of prostate carcinogenesis. The aim of this pilot study was to evaluate urinary estrogen metabolites as a biomarker of prostate cancer risk. METHODS Using a liquid chromatography–tandem mass spectrometry method, urinary concentrations of 15 estrogen metabolites were determined in 77 prostate cancer cases, 77 healthy controls, and 37 subjects who had no evidence of prostate cancer after a prostate biopsy. RESULTS We observed an inverse association between the urinary 16-ketoestradiol (16-KE2) and 17-epiestriol (17-epiE3)—metabolites with high estrogenic activity—and prostate cancer risk. Men in the lowest quartile of 16-KE2, had a 4.6-fold risk of prostate cancer (OR = 4.62, 95% CI = 1.34–15.99), compared with those in the highest quartile. CONCLUSIONS We observed modest differences in estrogen metabolite concentrations between prostate cancer patients and subjects without cancer. Larger studies with both androgen and estrogen measurements are needed to confirm these results to clarify further whether estrogen metabolites are independent biomarkers for prostate cancer risk and whether androgen/estrogen imbalance influences prostate cancer risk. Prostate 77:507–516, 2011. © 2010 Wiley-Liss, Inc.

52 Background: Anxiety is a common aliment among elderly men. It may be negatively impacted by the diagnosis of cancer. Effective cancer treatment may alleviate anxiety. The EORTC QLQ-ELD14 (ELD14) is a validated questionnaire, which evaluates patient reported anxiety. Using the ELD14 questionnaire, this study assesses the trends in prostate cancer patient’s anxiety before and after treatment with SBRT. Methods: All patients with localized prostate cancer who received SBRT at Georgetown University Hospital from 2007 to 2016 were eligible for inclusion in this cross-sectional cohort. The ELD14 questionnaire was used to assess quality of life before and following treatment. Initially, approximately 267 patients (median age of 70) responded to the ELD14 questionnaire. This study is focused on questions related to patient’s anxiety regarding their families, future, health and end of life. The responses to these questions were grouped into three clinically relevant categories (not at all, a little and quite a bit to very much). Results: Prior to treatment, 19% of patients felt quite a bit or very much worried about their families coping with their illness. This decreased to 9% at 24 months post-SBRT (p = 0.007). Initially, 27% of patients reported concerns for the future of their families, which subsequently decreased to 20% at 24 months (p = 0.15). At initial consult, 32% of patients reported being worried about their future health. This decreased to 13% at 24 months (p < 0.001). Twenty percent of patient reported concern about their future at initial consult; this declined to 11% at 24 months (p = 0.03). And finally, self reported anxiety about end of life was 18% at the initial consult and 12% at 24 months (p = 0.16). Conclusions: Self-reported anxiety surrounding family, health and future is prevalent amongst prostate cancer patients at initial evaluation. Significant reduction in anxiety is observed in our cohort post-SBRT. Further investigations in the causes of pre and post-treatment anxiety may offer valuable insight into preventable root causes and improvement in patient’s quality of life.

51 Background: Retaining quality of life in patients treated with SBRT for prostate cancer remains paramount. As such, balancing the benefits of treatment against the effects of therapy on patients is essential. The quality of life is influenced by the disease and treatment related burden. The EORTC QLQ-ELD14 (ELD14) is a validated questionnaire that can assess burden. This study reports burden trends in patients with prostate cancer treated with SBRT. Methods: All patients with localized prostate cancer treated with SBRT at Georgetown University Hospital from 2007 to 2016 were eligible for inclusion in this cross-sectional cohort. The ELD14 questionnaire was used to assess self-reported patient quality of life at time points before and following treatment. Initially, 267 patients (Median age of 70) responded to the ELD14 questionnaire. Approximately 30% received ADT. The specific questions reviewed for this study were focused on burden of disease and treatment. The responses to these questions were grouped into three clinically relevant categories (not at all, a little and quite a bit to very much). Results: Number of patients reporting quite a bit or very much burden from prostate cancer declined over time from 13% prior to treatment to 8% at 36 months post-SBRT. This was highest at one month post-SBRT (15%) and resolved to baseline by 6 months. Treatment burden similarly decreased over time from 10% to 3%. Patients treated with androgen deprivation therapy (ADT) experienced greater burden than others. At initial consult, 19% of patients on ADT reported quite a bit or very much burden from their illness. At one month post-SBRT, this had increased to 27% and subsequently decreased to 16% at 36 months. Of those not receiving ADT, 12% reported having quite a bit or very much burden from illness initially, 9% at one month and 6% at 36 months. Conclusions: This cross-sectional study suggests that the burden of clinically localized prostate and its treatment with SBRT improves over time. Increased burden was noted in patients receiving ADT. These findings can inform decision making in improving quality of life for patients with prostate cancer treated with SBRT.

Purpose: Magnetic resonance imaging (MRI)-directed stereotactic body radiation therapy (SBRT) has been established as a safe and effective treatment for prostate cancer. For patients with contraindications to MRI, CT-urethrogram is an alternative imaging approach to identify the location of the prostatic apex to guide treatment. This study sought to evaluate the safety of urethrogram-directed SBRT for prostate cancer.Methods: Between February 2009 and January 2014, 31 men with clinically localized prostate cancer were treated definitively with urethrogram-directed SBRT with or without supplemental intensity modulated radiation therapy (IMRT) at Georgetown University Hospital. SBRT was delivered either as a primary treatment of 35-36.25 Gray (Gy) in 5 fractions or as a boost of 19.5 Gy in 3 fractions followed by supplemental conventionally fractionated intensity modulated radiation therapy (45-50.4 Gy). Toxicities were recorded and scored using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v.4.0).Results: The median patient age was 70 years with a median prostate volume of 38 cc. The median follow-up was 3.7 years. The patients were elderly (Median age = 70), and comorbidities were common (Carlson Comorbidity Index > 2 in 36%). 71% of patients utilized alpha agonists prior to treatment, and 9.7% had prior procedures for benign prostatic hyperplasia (BPH). The 3-year actuarial incidence rates of > Grade 3 GU toxicity and > Grade 2 GI toxicity were 3.2% and 9.7%, respectively. There were no Grade 4 or 5 toxicities.Conclusions: MRI is the preferred imaging modality to guide prostate SBRT treatment. However, urethrogram-directed SBRT is a safe alternative for the treatment of patients with prostate cancer who are unable to undergo MRI.

Background Dysuria following prostate radiation therapy is a common toxicity that adversely affects patients’ quality of life and may be difficult to manage. Methods Two hundred four patients treated with stereotactic body radiation therapy (SBRT) from 2007 to 2010 for localized prostate carcinoma with a minimum follow-up of 3 years were included in this retrospective review of prospectively collected data. All patients were treated to 35–36.25 Gy in five fractions delivered with robotic SBRT with real time fiducial tracking. Dysuria and other lower urinary tract symptoms were assessed via Question 4b (Pain or burning on urination) of the expanded prostate index composite-26 and the American Urological Association (AUA) Symptom Score at baseline and at routine follow-up. Results Two hundred four patients (82 low-, 105 intermediate-, and 17 high-risk according to the D’Amico classification) at a median age of 69 years (range 48–91) received SBRT for their localized prostate cancer with a median follow-up of 47 months. Bother associated with dysuria significantly increased from a baseline of 12% to a maximum of 43% at 1 month (p

Purpose: Stereotactic body radiation therapy (SBRT) is increasingly utilized as primary treatment for clinically localized prostate cancer. Consensus regarding the appropriate patient-reported outcome (PRO) endpoints for clinical trials evaluating radiation modalities for early stage prostate cancer is lacking. To aid in clinical trial design, this study presents PROs over a 36-month period following SBRT for clinically localized prostate cancer. Methods: Between February 2008 and September 2010, 174 hormone-naïve patients with clinically localized prostate cancer were treated with 35–36.25 Gy SBRT (CyberKnife, Accuray) delivered in 5 fractions. Patients completed the validated Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaire at baseline and all follow-ups. The proportion of patients developing a clinically significant decline in each EPIC domain score was determined. The minimally important difference (MID) was defined as a change of one-half the standard deviation from the baseline. Per Radiation Therapy Oncology Group (RTOG) 0938, we also examined the patients who experienced a decline in EPIC urinary domain summary score of >2 points (unacceptable toxicity defined as ≥60% of all patients reporting this degree of decline) and EPIC bowel domain summary score of >5 points (unacceptable toxicity defined as >55% of all patients reporting this degree of decline) from baseline to 1 year. Results: A total of 174 patients at a median age of 69 years received SBRT with a minimum follow-up of 36 months. The proportion of patients reporting a clinically significant decline (MID for urinary/bowel are 5.5/4.4) in EPIC urinary/bowel domain scores was 34%/30% at 6 months, 40%/32.2% at 12 months, and 32.8%/21.5% at 36 months. The patients reporting a decrease in the EPIC urinary domain summary score of >2 points was 43.2% (CI: 33.7%, 54.6%) at 6 months, 51.6% (CI: 43.4%, 59.7%) at 12 months, and 41.8% (CI: 33.3%, 50.6%) at 36 months. The patients reporting a decrease in the EPIC bowel domain summary score of >5 points was 29.6% (CI: 21.9%, 39.3%) at 6 months, 29% (CI: 22%, 36.8%) at 12 months, and 22.4% (CI: 15.7%, 30.4%) at 36 months. Conclusion: Following prostate SBRT, clinically significant urinary symptoms are more common than bowel symptoms. Our prostate SBRT treatment protocol meets the RTOG 0938 criteria for moving forward to a Phase III trial comparing it to conventionally fractionated radiation therapy. Notably, between 12 and 36 months, the proportion of patients reporting a significant decrease in both EPIC urinary and bowel domain scores declined, suggesting a late improvement in these symptom domains. Further investigation is needed to elucidate (1) which EPIC domains bear the greatest influence on post-treatment quality of life and (2) at what time point PRO endpoint(s) should be assessed.

Background Hematuria following prostate radiotherapy is a known toxicity that may adversely affect a patient’s quality of life. Given the higher dose of radiation per fraction using stereotactic body radiation therapy (SBRT) there is concern that post-SBRT hematuria would be more common than with alternative radiation therapy approaches. Herein, we describe the incidence and severity of hematuria following stereotactic body radiation therapy (SBRT) for prostate cancer at our institution. Methods Two hundred and eight consecutive patients with prostate cancer treated with SBRT monotherapy with at least three years of follow-up were included in this retrospective analysis. Treatment was delivered using the CyberKnife® (Accuray) to doses of 35–36.25 Gy in 5 fractions. Toxicities were scored using the CTCAE v.4. Hematuria was counted at the highest grade it occurred in the acute and late setting for each patient. Cystoscopy findings were retrospectively reviewed. Univariate and multivariate analyses were performed. Hematuria-associated bother was assessed via the Expanded Prostate Index Composite (EPIC)-26. Results The median age was 69 years with a median prostate volume of 39 cc. With a median follow-up of 48 months, 38 patients (18.3%) experienced at least one episode of hematuria. Median time to hematuria was 13.5 months. In the late period, there were three grade 3 events and five grade 2 events. There were no grade 4 or 5 events. The 3-year actuarial incidence of late hematuria ≥ grade 2 was 2.4%. On univariate analysis, prostate volume (p = 0.022) and history of prior procedure(s) for benign prostatic hypertrophy (BPH) (p = 0.002) were significantly associated with hematuria. On multivariate analysis, history of prior procedure(s) for BPH (p

123 Background: Our previous work on early PSA kinetics following prostate SBRT showed that an initial rapid and then slow PSA decline may result in very low PSA nadirs. This retrospective study sought to evaluate the PSA nadir 5 years following SBRT for low and intermediate risk prostate cancer (PCa). Methods: 65 low and 80 intermediate risk PCa patients were treated definitively with SBRT at Georgetown University Hospital between January 2008 and October 2011. All patients were treated to 35-37.5 Gy in 5 fractions delivered via the CyberKnife Radiosurgical System. Patients who received androgen deprivation therapy were excluded from this study. Pre- and post-treatment PSA and total testosterone levels were obtained during routine follow up visits. Biochemical relapse was defined as a PSA rise > 2 ng/mL above the nadir and analyzed using the Kaplan Meier method. The PSA nadir was defined as the lowest PSA value prior to biochemical relapse or as the lowest value recorded during follow up. Prostate ablation was defined as a PSA nadir < 0.2 ng/mL. Univariate logistic regression analysis was used to evaluate relevant variables on the likelihood of achieving a PSA nadir < 0.2 ng/mL. Results: The median age at the start of SBRT was 72 years. These patients had a median prostate volume of 36 cc with a median 25% of total cores involved. At a median follow up of 5.8 years, 84% and 37% of patients achieved a PSA nadir ≤ 0.5 ng/mL and < 0.2 ng/mL, respectively. Five low and 8 intermediate risk patients experienced a biochemical relapse; those who did not experience a biochemical relapse, achieved a median PSA nadir of 0.2 ng/mL. There was no difference between the 5-year bRFS rate for low (96.6%) and intermediate risk (97.4%) patients and the median time to PSA nadir was 36 months. Initial PSA (p = 0.024) and a lower testosterone at the time of the PSA nadir (p = 0.049) were found to be significant predictors of achieving a PSA nadir < 0.2 ng/mL. Conclusions: SBRT for low and intermediate risk PCa is a convenient treatment option with low PSA nadirs and a high rate of early bRFS. Less than 40% of patients achieved an ablative PSA nadir. Thus, the role of further dose escalation is an area of active investigation.

Background: Irritative voiding symptoms are common in elderly men and following prostate radiotherapy. There is limited clinical data on the impact of hypofractionated treatment on irritative voiding symptoms. This study sought to evaluate urgency, frequency, and nocturia following stereotactic body radiation therapy (SBRT) for prostate cancer. Methods: Patients treated with SBRT monotherapy for localized prostate cancer from August 2007 to July 2011 at Georgetown University Hospital were included in this study. Treatment was delivered using the CyberKnife® with doses of 35–36.25 Gy in five fractions. Patient-reported urinary symptoms were assessed using the International Prostate Symptom Score (IPSS) before treatment and at 1, 3, 6, 9, and 12 months post-treatment and every 6 months thereafter. Results: Two hundred four patients at a median age of 69 years received SBRT with a median follow-up of 4.8 years. Prior to treatment, 50.0% of patients reported moderate to severe lower urinary tract symptoms (LUTS) and 17.7% felt that urinary frequency was a moderate to big problem. The mean prostate volume was 39 cc and 8% had prior procedures for benign prostatic hyperplasia. A mean baseline IPSS-irritative (IPSS-I) score of 4.8 significantly increased to 6.5 at 1 month (p

Background Obstructive voiding symptoms (OVS) are common following prostate cancer treatment with radiation therapy. The risk of urinary retention (UR) following hypofractionated radiotherapy has yet to be fully elucidated. This study sought to evaluate OVS and UR requiring catheterization following SBRT for prostate cancer. Methods Patients treated with SBRT for localized prostate cancer from February 2008 to July 2011 at Georgetown University were included in this study. Treatment was delivered using the CyberKnife® with doses of 35 Gy-36.25 Gy in 5 fractions. UR was prospectively scored using the CTCAE v.3. Patient-reported OVS were assessed using the IPSS-obstructive subdomain at baseline and at 1, 3, 6, 9, 12, 18 and 24 months. Associated bother was evaluated via the EPIC-26. Results 269 patients at a median age of 69 years received SBRT with a median follow-up of 3 years. The mean prostate volume was 39 cc. Prior to treatment, 50.6% of patients reported moderate to severe lower urinary track symptoms per the IPSS and 6.7% felt that weak urine stream and/or incomplete emptying were a moderate to big problem. The 2-year actuarial incidence rates of acute and late UR ≥ grade 2 were 39.5% and 41.4%. Alpha-antagonist utilization rose at one month (58%) and 18 months (48%) post-treatment. However, Grade 3 UR was low with only 4 men (1.5%) requiring catheterization and/or TURP. A mean baseline IPSS-obstructive score of 3.6 significantly increased to 5.0 at 1 month (p < 0.0001); however, it returned to baseline in 92.6% within a median time of 3 months. Late increases in OVS were common, but transient. Only 7.1% of patients felt that weak urine stream and/or incomplete emptying was a moderate to big problem at two years post-SBRT (p = 0.6854). Conclusions SBRT treatment caused an acute increase in OVS which peaked within the first month post-treatment, though acute UR requiring catheterization was rare. OVS returned to baseline in > 90% of patients within a median time of three months. Transient Late increases in OVS were common. However, less than 10% of patients felt that OVS were a moderate to big problem at two years post-SBRT.

Background Proctitis after radiation therapy for prostate cancer remains an ongoing clinical challenge and critical quality of life issue. SBRT could minimize rectal toxicity by reducing the volume of rectum receiving high radiation doses and offers the potential radiobiologic benefits of hypofractionation. This study sought to evaluate the incidence and severity of proctitis following SBRT for prostate cancer. Methods Between February 2008 and July 2011, 269 men with clinically localized prostate cancer were treated definitively with SBRT monotherapy at Georgetown University Hospital. All patients were treated to 35-36.25Gy in 5 fractions delivered with the CyberKnife Radiosurgical System (Accuray). Rectal bleeding was recorded and scored using the CTCAE v.4. Telangiectasias were graded using the Vienna Rectoscopy Score (VRS). Proctitis was assessed via the Bowel domain of the Expanded Prostate Index Composite (EPIC)-26 at baseline and at 1, 3, 6, 9, 12, 18 and 24 months post-SBRT. Results The median age was 69 years with a median prostate volume of 39 cc. The median follow-up was 3.9 years with a minimum follow-up of two years. The 2-year actuarial incidence of late rectal bleeding ≥ grade 2 was 1.5%. Endoscopy revealed VRS Grade 2 rectal telangiectasias in 11% of patients. All proctitis symptoms increased at one month post-SBRT but returned to near-baseline with longer follow-up. The most bothersome symptoms were bowel urgency and frequency. At one month post-SBRT, 11.2% and 8.5% of patients reported a moderate to big problem with bowel urgency and frequency, respectively. The EPIC bowel summary scores declined transiently at 1 month and experienced a second, more protracted decline between 6 months and 18 months before returning to near-baseline at two years post-SBRT. Prior to treatment, 4.1% of men felt their bowel function was a moderate to big problem which increased to 11.5% one month post-SBRT but returned to near-baseline at two years post-SBRT. Conclusions In this single institution cohort, the rate and severity of proctitis observed following SBRT is low. QOL decreased on follow-up; however, our results compare favorably to those reported for patients treated with alternative radiation modalities. Future prospective randomized studies are needed to confirm these observations.

BACKGROUND Molecular markers that can discriminate indolent cancers from aggressive ones may improve the management of prostate cancer and minimize unnecessary treatment. Aberrant DNA methylation is a common epigenetic event in cancers and HOXD3 promoter hypermethylation (H3PH) has been found in prostate cancer. Our objective was to evaluate the relationship between H3PH and clinicopathologic features in screening prostate biopsies. METHODS Ninety-two patients who underwent a prostate biopsy at our institution between October 2011 and May 2012 were included in this study. The core with the greatest percentage of the highest grade disease was analyzed for H3PH by methylation-specific PCR. Correlational analysis was used to analyze the relationship between H3PH and various clinical parameters. Chi-square analysis was used to compare H3PH status between benign and malignant disease. RESULTS Of the 80 biopsies with HOXD3 methylation status assessable, 66 sets were confirmed to have cancer. In the 14 biopsies with benign disease there was minimal H3PH with the mean percentage of methylation reference (PMR) of 0.7%. In contrast, the HOXD3 promoter was hypermethylated in 16.7% of all cancers and in 50% of high risk tumors with an average PMR of 4.3% (P = 0.008). H3PH was significantly correlated with age (P = 0.013), Gleason score (P = 0.031) and the maximum involvement of the biopsy core (P = 0.035). CONCLUSIONS H3PH is associated with clinicopathologic features. The data indicate that H3PH is more common in older higher risk patients. More research is needed to determine the role of this marker in optimizing management strategies in men with newly diagnosed prostate cancer. Prostate 74:714–721, 2014. © 2014 The Authors. The Prostate published by Wiley Periodicals, Inc.

In order to define technical limitations of conventional external beam irradiation for clinically localized prostate cancer, we evaluated the impact of several reduced-field treatment factors, such as reduced-field (RF) irradiated volume, RF technique, photon energy of treatment, and dose on survival endpoints and local control in a retrospective series. Several survival endpoints, such as disease-specific survival, freedom from relapse survival, biochemical no-evidence of disease (bNED) survival, and local control were associated with several treatment variables using univariate and multivariate analyses in 329 patients. Reduced-field technique appeared to predict survival outcome, with patients treated by bilateral 120° arcs faring less well than those treated by full 360° rotational fields. The irradiated volume of the reduced-field was also significantly associated with survival outcome, with patients treated with smaller volumes faring less well. Local failure rates also appeared increased, although not statistically, in patients treated with smaller RF sizes. In an attempt to explain these detected deficiencies, dose-volume histograms for prostate coverage were created for a small sample of patients. The deficiencies related to small reduced-field volume appeared to be largely attributable to poor dosimetric coverage of the prostate. These results underscore the limitations of conventional external beam treatment for prostate carcinoma when conventional techniques are employed, particularly if small reduced fields are used, and further supports the development of improved treatment techniques, such as conformal irradiation, as alternatives. Int. J. Cancer (Radiat. Oncol. Invest.) 90:265–274, 2000. © 2000 Wiley-Liss, Inc.

Background: The low-affinity nerve growth factor receptor (LNGFR) exhibits an inverse association of epithelial expression with the degree of differentiation of prostate adenocarcinoma tissue. However, the stage at which loss of LNGFR expression is first manifested in the malignant prostate has not been determined. Methods: In order to characterize loss of LNGFR expression in the clinically localized malignant prostate of untreated patients, the pattern of expression of the LNGFR was examined in nonmalignant tissues, consisting of normal and prostatic intraepithelial neoplastic tissues, and in malignant tissues that had been graded by Gleason's scores and categorized into well, moderately, and poorly differentiated adenocarcinomas. In order to determine whether there was an inverse correlation between LNGFR expression and prostate-specific antigen (PSA) secretion, preoperative concentrations of PSA in the serum were also analyzed in relation to the differentiative state of the adenocarcinomas. Results: Premalignant prostate tissues exhibited expression of the LNGFR on all epithelia, whereas in malignant prostate tissues a proportion of epithelia exhibited loss of expression of the LNGFR. An increase in Gleason score of the adenocarcinoma tissue was associated with an increase in the proportion of epithelia that exhibited loss of expression of the LNGFR. Moreover, the proportion of epithelia expressing the LNGFR was inversely correlated with an increase in the concentration of serum PSA. The loss of LNGFR expression was first manifested in epithelia that occurred toward the center of adenocarcinoma tissue. Furthermore, extensive loss of expression of the LNGFR of approximately 63% occurred in well-differentiated adenocarcinomas. Conclusions: These observations demonstrate that loss of LNGFR expression is first observed in well-differentiated malignant epithelia. Hence, loss of the LNGFR may be indicative of the initial stages of malignant transformation of prostate epithelia, as well as all subsequent stages of prostate adenocarcinomas.

Background Stereotactic body radiation therapy (SBRT) delivers high doses of radiation to the prostate while minimizing radiation to adjacent normal tissues. Large fraction sizes may increase the risk of functional decrements. Treatment-related bother may be more important to a patient than treatment-related dysfunction. This study reports on patient-reported outcomes following SBRT for clinically localized prostate cancer. Methods Between August 2007 and July 2011, 228 consecutive hormone-naïve patients with clinically localized prostate cancer were treated with 35–36.25 Gy SBRT delivered using the CyberKnife Radiosurgical System (Accuray) in 5 fractions. Quality of life was assessed using the American Urological Association Symptom Score (AUA) and the Expanded Prostate Cancer Index Composite (EPIC)-26. Urinary symptom flare was defined as an AUA score 15 or more with an increase of 5 or more points above baseline 6 months after treatment. Results 228 patients (88 low-, 126 intermediate- and 14 high-risk) at a median age of 69 (44–90) years received SBRT with a minimum follow-up of 24 months. EPIC urinary and bowel summary scores declined transiently at 1 month and experienced a second, more protracted decline between 9 months and 18 months before returning to near baseline 2 years post-SBRT. 14.5% of patients experienced late urinary symptom flare following treatment. Patients who experienced urinary symptom flare had poorer bowel quality of life following SBRT. EPIC scores for urinary bother declined transiently, first at 1 month and again at 12 months, before approaching pre-treatment scores by 2 years. Bowel bother showed a similar pattern, but the second decline was smaller and lasted 9 months to 18 months. EPIC sexual summary and bother scores progressively declined over the 2 years following SBRT without recovery. Conclusions In the first 2 years, the impact of SBRT on urination and defecation was minimal. Transient late increases in urinary and bowel dysfunction and bother were observed. However, urinary and bowel function and bother recovered to near baseline by 2 years post-SBRT. Sexual dysfunction and bother steadily increased following treatment without recovery. SBRT for clinically localized prostate cancer was well tolerated with treatment-related dysfunction and bother comparable to conventionally fractionated radiation therapy or brachytherapy.

Despite advances in treatment for metastatic prostate cancer, patients eventually progress to castrate-resistant disease and ultimately succumb to their cancer. Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer and has been shown to improve median time to progression and median survival time. Research suggests that castrate-resistant clones may be present early in the disease process prior to the initiation of ADT. These clones are not susceptible to ADT and may even flourish when androgen-responsive clones are depleted. Stereotactic body radiation therapy (SBRT) is a safe and efficacious method of treating clinically localized prostate cancer and metastases. In patients with a limited number of metastatic sites, SBRT may have a role in eliminating castrate-resistant clones and possibly delaying progression to castrate-resistant disease.

Background Erectile dysfunction after prostate radiation therapy remains an ongoing challenge and critical quality of life issue. Given the higher dose of radiation per fraction using stereotactic body radiation therapy (SBRT) there is concern that post-SBRT impotency would be higher than conventional radiation therapy approaches. This study sought to evaluate potency preservation and sexual function following SBRT for prostate cancer. Methods Between February 2008 and March 2011, 216 men with clinically localized prostate cancer were treated definitively with SBRT monotherapy at Georgetown University Hospital. Potency was defined as the ability to have an erection firm enough for intercourse with or without sexual aids while sexual activity was defined as the ability to have an erection firm enough for masturbation and foreplay. Patients who received androgen deprivation therapy (ADT) were excluded from this study. Ninety-seven hormone-naïve men were identified as being potent at the initiation of therapy and were included in this review. All patients were treated to 35–36.25 Gy in 5 fractions delivered with the CyberKnife Radiosurgical System (Accuray). Prostate specific antigen (PSA) and total testosterone levels were obtained pre-treatment, every 3 months for the first year and every 6 months for the subsequent year. Sexual function was assessed with the Sexual Health Inventory for Men (SHIM), the Expanded Prostate Index Composite (EPIC)-26 and Utilization of Sexual Medication/Device questionnaires at baseline and all follow-up visits. Results Ninety-seven men (43 low-, 50 intermediate- and 4 high-risk) at a median age of 68 years (range, 48–82 years) received SBRT. The median pre-treatment PSA was 5.9 ng/ml and the minimum follow-up was 24 months. The median pre-treatment total serum testosterone level was 11.4 nmol/L (range, 4.4-27.9 nmol/L). The median baseline SHIM was 22 and 36% of patients utilized sexual aids prior to treatment. Although potency rates declined following treatment: 100% (baseline); 68% (6 months); 62% (12 months); 57% (18 months) and 54.4% (24 months), 78% of previously potent patients had erections sufficient for sexual activity at 24 months post-treatment. Overall sexual aid utilization increased from 36% at baseline to 49% at 24 months. Average EPIC sexual scores showed a slow decline over the first two years following treatment: 77.6 (baseline); 68.7 (6 months); 63.2 (12 months); 61.9 (18 months); 59.3 (24 months). All sexual functions including orgasm declined with time. Prior to treatment, 13.4% of men felt their sexual function was a moderate to big problem which increased to 26.7% two years post treatment. Post-treatment testosterone levels gradually decreased with a median value at two year follow-up of 10.7 nmol/L. However, the average EPIC hormonal scores did not illustrate a statistically significant difference two years post-treatment. Review of the radiation doses to the penile bulb in this study, a potential marker of post-treatment sexual function, revealed that the dose was relatively low and at these low doses the percentage of the penile bulb receiving 29.5 Gy did not correlate with the development of ED. Conclusions Men undergoing SBRT monotherapy for prostate cancer report sexual outcomes comparable to those reported for conventional radiation modalities within the first 24 months after treatment. Longer follow-up is required to confirm the durability of these findings.

Objectives Although post–radical prostatectomy (RP) adjuvant radiation therapy (ART) benefits disease that is staged as pT3 or higher, the optimal ART timing remains unknown. Our objective is to characterize the outcomes and optimal timing of early vs. delayed ART. Materials and methods From the Surveillance, Epidemiology and End Results-Medicare data from 1995 to 2007, we identified 963 men with pT3N0 disease receiving early ( n = 419) vs. delayed (4–12 mo after RP, n = 544) ART after RP. Utilizing propensity score methods, we compared overall mortality, prostate cancer–specific mortality (PCSM), bone-related events (BRE), salvage hormonal therapy utilization, and intervention for urethral stricture. We then used the maximal statistic approach to determine at what time post-RP ART had the most significant effect on outcomes of interest in men with pT3N0 disease. Results When compared with delayed ART in men with pT3 disease, early ART was associated with improved PCSM (0.47 vs. 1.02 events per 100 person-years; P = 0.038) and less salvage hormonal therapy (2.88 vs. 4.59 events per 100 person-years; P = 0.001). Delaying ART beyond 5 months is associated with worse PCSM (hazard ratio [HR] 2.3; P = 0.020), beyond 3 months is associated with more BRE (HR 1.6; P = 0.025), and beyond 4 months is associated higher rates of salvage hormonal therapy (HR 1.6; P = 0.002). ART performed after 9 months was associated with fewer urethral strictures (HR 0.6; P = 0.042). Conclusion Initiating ART less than 5 months after RP for pT3 is associated with improved PCSM. Early ART is also associated with fewer BRE and less use of salvage hormonal therapy if administered earlier than 3 and 4 months after RP, respectively. However, ART administered later than 9 months after RP is associated with fewer urethral strictures. Our population-based findings complement randomized trials designed with fixed ART timing.

Objective To compare the efficacy of intermittent androgen deprivation therapy (IADT) vs continuous androgen deprivation therapy (CADT) for the treatment of advanced prostate cancer; we performed a meta-analysis of randomized controlled trials (RCTs), assessing the risks of disease progression, all-cause, and disease-specific mortality. Materials and Methods We conducted a systematic search of several bibliographic systems to identify all RCTs of IADT in men with newly diagnosed metastatic or biochemical only prostate cancer. We abstracted outcome data, study characteristics, and participant demographics. We performed heterogeneity tests and calculated the summarized risk differences (RD) and risk ratios at 95% confidence intervals (CI), using inverse variance methods in random-effects approaches. Results We identified 8 RCTs (N = 4664) comparing mortality between IADT and CADT. For all men combined, we observed small but nonsignificant differences in all-cause mortality (RD = 0.02, 95% CI = −0.02, 0.06), disease-specific mortality (RD = 0.04, 95% CI = −0.01, 0.08), and disease progression (RD = −0.03, 95% CI = −0.09, 0.04). Among the prespecified subgroup with histologically confirmed, newly diagnosed metastatic disease, we found no difference in overall survival (RD = 0.00, 95% CI = −0.09, 0.09). Conclusion We found no difference in overall survival, but a small increased risk in disease-specific survival for men treated with IADT relative to CADT was observed. IADT could be considered as an alternative to CADT because of better quality of life outcome. Patients should be informed of the possible risks and benefits of both therapies. More research confirming the benefits of IADT vs CADT is needed to inform treatment decisions.

Optimal treatment of prostate cancer patients is ­provided by a multidisciplinary team comprised of urologists, radiation oncologists, and medical oncologists, working together to stratify patients based upon their life expectancy, extent of disease, acceptance of risks and benefits, and consideration of potential changes in quality of life. Available treatment options range from radical prostatectomy to various forms of radiation therapy including ­intensity-modulated radiation therapy (IMRT), low dose rate (LDR) brachytherapy, high dose rate (HDR) brachytherapy, proton beam therapy, and robotic radiosurgery. Robotic radiosurgery is the most recent addition to the treatment arsenal for clinically localized prostate cancer that builds upon developments in enhanced precision of radiation delivery and the use of imaging guidance throughout treatment. Given the variety of available treatment options, the clinical considerations and patient selection criteria for each of these treatment options will be reviewed with a focus on applications of robotic radiosurgery for patients with disease confined to the prostate and adjacent tissues.

Background The CyberKnife is an appealing delivery system for hypofractionated stereotactic body radiation therapy (SBRT) because of its ability to deliver highly conformal radiation therapy to moving targets. This conformity is achieved via 100s of non-coplanar radiation beams, which could potentially increase transitory testicular irradiation and result in post-therapy hypogonadism. We report on our early experience with CyberKnife SBRT for low- to intermediate-risk prostate cancer patients and assess the rate of inducing biochemical and clinical hypogonadism. Methods Twenty-six patients were treated with hypofractionated SBRT to a dose of 36.25 Gy in 5 fractions. All patients had histologically confirmed low- to intermediate-risk prostate adenocarcinoma (clinical stage ≤ T2b, Gleason score ≤ 7, PSA ≤ 20 ng/ml). PSA and total testosterone levels were obtained pre-treatment, 1 month post-treatment and every 3 months thereafter, for 1 year. Biochemical hypogonadism was defined as a total serum testosterone level below 8 nmol/L. Urinary and gastrointestinal toxicity was assessed using Common Toxicity Criteria v3; quality of life was assessed using the American Urological Association Symptom Score, Sexual Health Inventory for Men and Expanded Prostate Cancer Index Composite questionnaires. Results All 26 patients completed the treatment with a median 15 months (range, 13-19 months) follow-up. Median pre-treatment PSA was 5.75 ng/ml (range, 2.3-10.3 ng/ml), and a decrease to a median of 0.7 ng/ml (range, 0.2-1.8 ng/ml) was observed by one year post-treatment. The median pre-treatment total serum testosterone level was 13.81 nmol/L (range, 5.55 - 39.87 nmol/L). Post-treatment testosterone levels slowly decreased with the median value at one year follow-up of 10.53 nmol/L, significantly lower than the pre-treatment value (p < 0.013). The median absolute fall was 3.28 nmol/L and the median percent fall was 23.75%. There was no increase in biochemical hypogonadism at one year post-treatment. Average EPIC sexual and hormonal scores were not significantly changed by one year post-treatment. Conclusions Hypofractionated SBRT offers the radiobiological benefit of a large fraction size and is well-tolerated by men with low- to intermediate-risk prostate cancer. Early results are encouraging with an excellent biochemical response. The rate of new biochemical and clinical hypogonadism was low one year after treatment.

We describe the first histopathologic analysis of prostatic tissue following hypofractionated robotic radiation therapy. A 66 year-old man presented with stage II, low risk adenocarcinoma of the prostate and underwent elective conformal hypofractionated radiation therapy. His pretreatment evaluation revealed T1c adenocarcinoma, Gleason's grade 3 + 3 = 6 and a prostate specific antigen (PSA) level of 4.87 ng/ml. Hypofractionated radiation therapy (37.5 Gy in five daily fractions of 7.5 Gy) was completed on an Internal Review Board approved protocol. One year later, he developed progressive urinary retention. Transurethral prostatic resection was performed to alleviate obstructive symptoms. Bilobar hypertrophy was observed without evidence of stricture. Histolopathologic analyses of resected prostate tissues revealed changes consistent with radiation treatment, including cellular changes, inflammation, glandular atrophy and hyperplasia. There was no evidence of residual cancer, fibrosis or necrosis. The patient's postoperative course was uneventful with post-treatment PSA of 0.5 ng/ml and residual grade 1 stress incontinence.

Prostate cancer (PCa) and colorectal cancer (CRC) are the second and third leading causes of cancer death, respectively.1 Although substantial evidence suggests that CRC screening is effective in reducing disease-related mortality,2-7 the effectiveness of PCa screening remains uncertain.8,9 As a result, CRC screening is widely recommended by all major medical organizations.4,6,10 However, for PCa screening, the US Preventive Services Task Force has stated that there is not enough evidence to make a recommendation for or against PCa screening for men younger than 75 years, and that physicians and patients should make a shared decision.11 Despite these differences in evidence and in recommendations, adherence rates are very similar, with about ½ of age-eligible US men adherent to PCa screening1 and to CRC screening.12-15 The 2006 Behavioral Risk Factors Surveillance System reported that 61.5% of men aged 50 years or older in the United States were adherent to CRC screening,13 and 55.4% of men aged 50 year and older had had a prostate-specific antigen (PSA) blood test in the past year.4 Several studies have assessed the predictors of CRC screening, reporting that higher education,16-27 a usual source of care,12,16,19-26 a physician recommendation,17,23,28,29 being insured,12,16,19,22-24,26-28,30 a higher income,16,18,19,22,24,27,30 exercise and other positive health behaviors,16,19,26,27 older age,16,19,21,23,25-27 and a recent PSA test12,21,23,25,31 are all positively associated with CRC screening. There have been conflicting results regarding CRC screening adherence and self-reported health status,12,17,19,20 as well as among former smokers,18,23,26 although current smoking has consistently predicted lower CRC screening adherence.16,26,30 There have also been conflicting findings regarding race differences for CRC screening, with some studies showing no race differences,16,25,27 others showing lower adherence among African Americans,20,32 and 1 study showing higher adherence among African American men.12 Possible explanations for these conflicting findings include demographic differences in the samples studied, such as different ages20 or socioeconomic status (SES) levels. Given the racial disparities in incidence and mortality of CRC,33,34 it is particularly important to understand the impact of race and related factors on CRC screening behaviors. Among a sample of men who had registered to undergo free PCa screening, we assessed the rates and sociodemographic correlates of prior CRC screening. The primary goal of this study was to determine whether free PCa screening programs, at which over 100,000 US men are screened each year,35 might provide access to a large and easily accessible group of men who are aware of cancer early detection, but who are perhaps unaware of or nonadherent to CRC screening recommendations. Given the differences in cost, invasiveness, and preparation for screening of these 2 cancers, we evaluated whether a portion of men attending free PCa screening were eligible for but nonadherent to CRC screening, suggesting that PCa screening sites could serve as a teachable moment12,36 for CRC screening education.

A review of numerous clinical series dealing with the treatment of patients with clinical stage C prostate cancer failed to find the treatment or a combination of treatments that is superior to any other. Accurate staging, which was difficult in older studies, and stage migration, which complicates the comparison of recent to older studies, may contribute to this lack of identification. The majority of patients ultimately experience disease progression and are therefore treated with hormonal therapy, the use of which obscures survival data for initial modes of treatment. These observations point to the need for control of randomised clinical trials to identify effective treatments in the future.

Increased long-term survival rates have led to a greater focus on the health-related quality of life (HRQL) of prostate cancer survivors. This study assessed the motivations of prostate cancer survivors for disclosing their diagnosis and treatment to close others, and their perceptions of their own and others' responses to the disclosure.Prostate cancer survivors (N=35) who were 24-36 months post-treatment for localized disease completed a semi-structured telephone interview. Open-ended questions concerning disclosure of men's diagnosis and treatment and their perceptions of their own and others' reactions to the disclosure were included.Regarding men's motivations for disclosing their diagnosis and treatment, men reported that they were seeking social support (SS) and that others had a 'right to know.' Further, the receipt of emotional support and feeling a sense of positive emotions were common following disclosure about their diagnosis and treatment. Participants reported continuing to discuss their treatment side effects 2-3 years post-treatment.Prostate cancer survivors reported an overall positive and supportive response following the disclosure of their diagnosis and treatment. Further examination of the relationship between SS and HRQL will be necessary to identify interventions to enhance the well-being of this growing population of survivors.Providers need to be aware of the extent and long-term nature of the side effects following treatment for prostate cancer. If providers encourage men to talk about their diagnosis, treatment, and side effects, providers may better understand men's experience with the disease, and men may be more likely to accept these commonly experienced changes, as well as seek treatment for them. These efforts may result in improved quality of life for survivors of prostate cancer.

High-intensity focused ultrasound (HIFU) has emerged in the past decade as a new addition to the armamentarium of treatment options for prostate cancer. Clinical studies have investigated its use as a treatment for clinically localized disease and as salvage therapy in the setting of failure after external beam radiotherapy. Additional studies with long-term follow-up are needed to further evaluate the cancer control and quality of life outcomes of this new therapeutic modality.

BACKGROUND. Dose escalation has resulted in improved biochemical control in patients with clinically localized prostate cancer treated with conformal external beam radiation (EBRT). Conformal dose distributions may also be achieved with brachytherapy. Therefore, biochemical control was evaluated for patients treated with combined external radiation therapy and low dose rate brachytherapy (EBRT + LDR). METHODS. A matched pair analysis was performed to compare biochemical control of patients treated with EBRT + LDR to patients treated with EBRT alone. The study endpoints were biochemical control and late toxicities. RESULTS. The 5-year biochemical failure free survival (BFFS) was 86% for patients treated with EBRT + LDR and 72% for patients treated with EBRT (P = 0.03). Both treatments were associated with comparable incidences of late genitourinary (GU) side effects (18-19%). Late rectal toxicity was decreased by 15% in patients treated with EBRT + LDR (P = 0.0003). CONCLUSIONS. These results support EBRT followed by brachytherapy boost as a safe and effective method for dose escalation in the treatment of prostate cancer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to reduce inflammation and as analgesics by inhibition of cyclooxygenase-2. At higher concentrations, some NSAIDs inhibit proliferation and induce apoptosis of cancer cells. Although several molecular mechanisms have been postulated to explain the anticancer effects of NSAIDs, they do not involve merely the inhibition of cyclooxygenase-2, and a more proximate initiator molecule may be regulated by NSAIDs to inhibit growth. The p75 neurotrophin receptor (p75NTR) is a proximate cell membrane receptor glycoprotein that has been identified as a tumor and metastasis suppressor. We observed that NSAID treatment of cell lines from bladder and other organs induced expression of the p75NTR protein. Of the different types of NSAIDs examined, ibuprofen was more efficacious than aspirin and acetaminophen and comparable with (R)-flurbiprofen and indomethacin in induction of p75NTR protein expression. This rank order NSAID induction of the p75NTR protein correlated with the ability of these NSAIDs to reduce cancer cell survival. To examine a mechanistic relationship between ibuprofen induction of p75NTR protein and inhibition of survival, bladder cancer cells were transfected with ponasterone A-inducible vectors that expressed a death domain-deleted (ΔDD) or intracellular domain-deleted (ΔICD) p75NTR product that acts as a dominant negative antagonist of the intact p75NTR protein. Expression of ΔDD and ΔICD rescued cells from ibuprofen inhibition of growth. These observations suggest that p75NTR is an important upstream modulator of the anticancer effects of NSAIDs and that ibuprofen induction of the p75NTR protein establishes an alternate mechanism by which ibuprofen may exert an anticancer effect.