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Gleason score from biopsy specimens is important for prostate cancer (PCa) risk stratification and influences treatment decisions. Gleason score upgrading (GSU) between biopsy and surgical pathology specimens has been reported as high as 50 % and presents a challenge in counseling low-risk patients. While recent studies have investigated predictors of GSU, populations in these studies have been largely Caucasian. We report our analysis of predictors of GSU in a large urban African-American population. A total of 959 patients with D’Amico low-risk prostate cancer underwent radical prostatectomy at Georgetown University or Washington Hospital Center between January 2005 and July 2012. Race, age, PSA, body mass index (BMI), cancer of the prostate risk assessment (CAPRA) score, and transrectal ultrasound (TRUS) biopsy characteristics (percent of biopsy cores showing adenocarcinoma, highest percent of biopsy core involved with cancer, and measured TRUS prostate volume) were analyzed with both univariate and multivariate analyses to identify significant predictors of GSU while controlling for clinical parameters. Of the 959 cases, 288 (30.0 %) were upgraded on final pathologic specimen with approximately 38 % (133/355) of African-American patients experiencing GSU. BMI (P = 0.02), percent positive biopsy cores (P

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 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.

G207, a replication-competent herpes simplex virus type 1 (HSV-1) virus, has been previously shown to be effective against human prostate cancer xenografts in mice. This study assesses its safety in the prostate of two animal models known for their sensitivity to HSV-1. BALB/c mice were injected intraprostatically with either HSV-1 G207 or strain F and observed for 5 months. None of the G207-injected animals exhibited any clinical signs of disease or died. However, 50% of strain F-injected mice displayed sluggish, hunched behavior and died by day 13. Histopathologically, the G207-injected prostates were normal whereas strain F-injected prostates showed epithelial flattening, sloughing, and stromal edema. Four Aotus nancymae monkeys were also injected with G207 intraprostatically and observed short term (up to 21 days) and long term (56 days). Safety was assessed on the basis of clinical observations, viral biodistribution, virus shedding, and histopathology. None of the injected monkeys displayed evidence of clinical disease, shedding of infectious virus, or spread of the virus into other organs. Except for minor histological changes unrelated to the study, no significant abnormalities were observed. These results demonstrate that G207 can be safely inoculated into the prostate and should be considered for human trials for the treatment of prostate cancer.

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.

INTRODUCTION AND OBJECTIVES: Gleason score from biopsy specimens is important for prostate cancer risk stratification and influences treatment decisions. Gleason score upgrading (GSU) between biopsy and surgical pathology specimens has been reported as high as 50% and presents a challenge in counseling low-risk patients. While recent studies have investigated predictors of GSU, populations in these studies have been largely Caucasian. We report our analysis of predictors of GSU in a large urban African-American population across two institutions. METHODS: A total of 959 patients with DAEAmico low risk prostate cancer underwent radical prostatectomy at our institution between January 2005 and July 2012. Race, age, PSA, body mass index, CAPRA score and TRUS biopsy characteristics (number of reported biopsy cores showing adenocarcinoma, highest percent of biopsy core positive for adenocarcinoma, and measured TRUS prostate volume) were analyzed with both univariate and multivariate analysis to identify significant predictors of GSU while controlling for clinical parameters. RESULTS: Of the 959 cases, 288 (30.0%) were upgraded on final pathologic specimen, while the remaining 671 had the same Gleason sum as the preoperative biopsy. (Table 1) Our patient population consisted of 40.0% African-Americans and 42.0 of the AfricanAmerican population showed GSU. Mean Gleason score for those who were upgraded was 7.24. Upon univariate and multivariate analysis, BMI, total positive biopsy cores, percent of core involved with cancer, CAPRA score, and smaller prostate volume were statistically significant in the upgraded cohort. Patients who upgraded tended to be of higher BMI and of African-American descent in our analysis. Transrectal biopsies of these patients showed smaller prostate volumes but higher cores positive with high % disease per core. CONCLUSIONS: More than a quarter of low-risk prostate cancer patients were upgraded on final pathology in our series. Higher BMI and CAPRA score, smaller prostate volume and total number of cores and percent of cores involved were independent predictors of GSU. Individuals, especially African-Americans, with those clinical parameters may harbor occult high-grade disease and should be carefully counseled on 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.

Background Stereotactic body radiation therapy (SBRT) delivers fewer high-dose fractions of radiation which may be radiobiologically favorable to conventional low-dose fractions commonly used for prostate cancer radiotherapy. We report our early experience using SBRT for localized prostate cancer. Methods Patients treated with SBRT from June 2008 to May 2010 at Georgetown University Hospital for localized prostate carcinoma, with or without the use of androgen deprivation therapy (ADT), were included in this retrospective review of data that was prospectively collected in an institutional database. Treatment was delivered using the CyberKnife® with doses of 35 Gy or 36.25 Gy in 5 fractions. Biochemical control was assessed using the Phoenix definition. Toxicities were recorded and scored using the CTCAE v.3. Quality of life was assessed before and after treatment using the Short Form-12 Health Survey (SF-12), the American Urological Association Symptom Score (AUA) and Sexual Health Inventory for Men (SHIM) questionnaires. Late urinary symptom flare was defined as an AUA score ≥ 15 with an increase of ≥ 5 points above baseline six months after the completion of SBRT. Results One hundred patients (37 low-, 55 intermediate- and 8 high-risk according to the D’Amico classification) at a median age of 69 years (range, 48–90 years) received SBRT, with 11 patients receiving ADT. The median pre-treatment prostate-specific antigen (PSA) was 6.2 ng/ml (range, 1.9-31.6 ng/ml) and the median follow-up was 2.3 years (range, 1.4-3.5 years). At 2 years, median PSA decreased to 0.49 ng/ml (range, 0.1-1.9 ng/ml). Benign PSA bounce occurred in 31% of patients. There was one biochemical failure in a high-risk patient, yielding a two-year actuarial biochemical relapse free survival of 99%. The 2-year actuarial incidence rates of GI and GU toxicity ≥ grade 2 were 1% and 31%, respectively. A median baseline AUA symptom score of 8 significantly increased to 11 at 1 month (p = 0.001), however returned to baseline at 3 months (p = 0.60). Twenty one percent of patients experienced a late transient urinary symptom flare in the first two years following treatment. Of patients who were sexually potent prior to treatment, 79% maintained potency at 2 years post-treatment. Conclusions SBRT for clinically localized prostate cancer was well tolerated, with an early biochemical response similar to other radiation therapy treatments. Benign PSA bounces were common. Late GI and GU toxicity rates were comparable to conventionally fractionated radiation therapy and brachytherapy. Late urinary symptom flares were observed but the majority resolved with conservative management. A high percentage of men who were potent prior to treatment remained potent two years following treatment.