Dosimetric predictors of acute bowel toxicity after Stereotactic Body Radiotherapy (SBRT) in the definitive treatment of localized prostate cancer.

INTRODUCTION: SBRT is an increasingly popular treatment for localized prostate cancer, though considerable variation in technical approach is common and optimal dose constraints are uncertain. In this study, we sought to identify dosimetric and patient-related predictors of acute rectal toxicity. METHODS: Patients included in this study were treated with prostate SBRT on a prospective institutional protocol. Physician-graded toxicity and patient-reported outcomes were captured at one week, one month, and three months following SBRT. DVH data were extracted and converted into relative volume differential DVHs for NTCP modeling. Patient- and disease-related covariates along with NTCP model predictions were independently tested for significant association with physician-graded toxicity or a decline in bowel-related QoL. A multivariate model was constructed using forward selection, and significant parameter cutoff values were obtained with Fischer's exact test to group patients by risk of developing physician-graded toxicity or detriments in patient-reported QoL. RESULTS: One hundred and three patients treated for localized prostate cancer with SBRT were included in our analysis. 52% of patients experienced a clinically significant decline in bowel-related QOL within 1 week of completion of treatment, while only 27.5% of patients developed grade 2+ physician-graded rectal toxicity. Sequential feature selection multivariate logistic regression identified rectal V22.5 Gy (p = 0.001) and D19% (p = 0.001) as independent predictors of clinically significant toxicity, while rectal V20Gy (p = 0.004) and D25.3% (p = 0.007) were independently correlated with physician-graded toxicity. Global multivariate step-wise logistic regression identified only D19% (p = 0.001) and V20Gy (p = 0.004) as independent predictors of acute bowel bother or physician-graded rectal toxicity respectively. CONCLUSIONS: Moderate doses to large rectal volumes, D19% and V20Gy, were associated with an increased incidence of a clinically significant decrease in patient-reported bowel QOL and physician-scored grade 2+ rectal toxicity, respectively. These dosimetric parameters may help practitioners mitigate acute toxicity in patients treated with prostate SBRT.

Ejaculatory Function Following Stereotactic Body Radiation Therapy for Prostate Cancer.

BACKGROUND: Ejaculatory dysfunction is an important male quality of life issue which has not yet been studied in the setting of prostate stereotactic body radiation therapy (SBRT). AIM: The purpose of this study is to evaluate ejaculatory function following SBRT for prostate cancer. METHODS: Two hundred and thirty-one patients on a prospective quality of life study with baseline ejaculatory capacity treated with prostate SBRT from 2013 to 2019 were included in this analysis. Ejaculation was assessed via the Ejaculation Scale (ES-8) from the Male Sexual Health Questionnaire. Patients completed the questionnaire at 1, 3, 6, 9, 12, 18, and 24 months post-SBRT. Elderly patients (Age > 70) and those who received hormonal therapy were excluded from analysis. Patients were treated to 35-36.25 Gy in 5 fractions delivered with the CyberKnife Radiosurgical System (Accuray). OUTCOMES: Ejaculatory function was assessed by ES-8 scores (range 4-40) with lower values representing increased interference or annoyance. RESULTS: Median age at the time of treatment was 65 years. Median follow up was 24 months (IQR 19-24.5 months). 64.5% of patients had ED at baseline (SHIM < 22). The 2-year anejaculation rate was 15%. Mean composite ES-8 scores showed a decline in the first month following treatment then stabilized: 30.4 (start of treatment); 26.5 (1 month); 27.6 (3 month); 27.0 (6 month); 26.2 (9 month); 25.4 (12 month); 25.0 (18 month) and 25.4 (24 month). White race, higher pre-treatment SHIM (≥22), and higher ES-8 (≥31) at treatment start were significantly associated with a decreased probability of a clinically significant decline. Patient-reported ejaculate volume was significantly reduced at all time points post-SBRT. Ejaculatory discomfort peaked at 1 month and 9 months post-SBRT. Prior to treatment, 8.0% of men reported that they were very to extremely bothered by their ejaculatory dysfunction. The number of patients reporting this concern increased to 14.4% at one year and dropped to 11% at 24-months post-SBRT. CLINICAL TRANSLATION: Patients undergoing prostate SBRT may experience meaningful changes in ejaculatory function and should be counseled on the trajectory of these side effects. STRENGTHS & LIMITATIONS: This was a retrospective analysis of a prospectively maintained database. Subjective questionnaire responses captured limited aspects of ejaculatory function in this cohort. CONCLUSION: The high incidence of moderate to extreme bother in ejaculatory function before and after SBRT suggests a need for novel approaches to improving ejaculation. Sholklapper T, Creswell M, Cantalino J, et al. Ejaculatory Function Following Stereotactic Body Radiation Therapy for Prostate Cancer. J Sex Med 2022;19:771-780.

Discovery of Metabolic Biomarkers Predicting Radiation Therapy Late Effects in Prostate Cancer Patients.

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.

Erectile function after stereotactic body radiotherapy for localized prostate cancer.

OBJECTIVE: To elucidate the functional erection rate after prostate stereotactic body radiotherapy (SBRT) and to develop a comprehensive prognostic model of outcomes after treatment. PATIENTS AND METHODS: Between 2008 and 2013, 373 consecutive men with localized prostate cancer were treated with SBRT at a single academic institution as part of a prospective clinical trial or prospective registry. Prospective longitudinal patient-reported health-related quality of life (HRQoL) data was collected using the Expanded Prostate Cancer Index Composite (EPIC)-26 instrument. Functional erections were strictly defined as 'firm enough for intercourse' according to EPIC-26. Detailed comorbidity data were also collected. Logistic regression models were used to predict 24- and 60-month functional erection rates. Observed erection rates after SBRT were compared with those after other radiation therapies (external beam radiation therapy [EBRT] and brachytherapy) using prospectively validated models. RESULTS: The median (interquartile range) follow-up was 56 (37-73) months and the response rate at 2 years was 84%. For those with functional erections at baseline, 57% and 45% retained function at 24 and 60 months, respectively. On multivariable analysis for 24-month erectile function, significant variables included higher baseline sexual HRQoL (adjusted odds ratio [aOR] 1.55 per 10 points, 95% confidence interval [CI] 1.37-1.74; P < 0.001) and older age (aOR 0.66 per 10 years, 95% CI 0.43-1.00; P = 0.05). At 60 months, baseline HRQoL and age remained associated with erectile function, along with body mass index (aOR 0.45, 95% CI 0.26-0.78; P < 0.001). The 24- and 60-month models had excellent discrimination (c-index 0.81 and 0.84, respectively). Erection rates after SBRT were not statistically different from model-predicted rates after EBRT or brachytherapy for the whole cohort and the cohort with baseline erectile function. CONCLUSIONS: Intermediate- to long-term post-SBRT erectile function results are promising and not significantly different from other radiotherapy techniques. Clinicians can use our prognostic model to counsel patients regarding expected erectile function after SBRT.

Predictors of multidomain decline in health-related quality of life after stereotactic body radiation therapy (SBRT) for prostate cancer.

BACKGROUND: Stereotactic body radiation therapy (SBRT) for localized prostate cancer involves high-dose-per-fraction radiation treatments. Its use is increasing, but concerns remain about treatment-related toxicity. The authors assessed the incidence and predictors of a global decline in health-related quality of life (HRQOL) after prostate SBRT. METHODS: From 2008 to 2014, 713 consecutive men with localized prostate cancer received treatment with SBRT according to a prospective institutional protocol. Expanded Prostate Cancer Index Composite (EPIC-26) HRQOL data were collected at baseline and longitudinally for 5 years. EPIC-26 is comprised of 5 domains. The primary endpoint was defined as a decline exceeding the clinically detectable threshold in ≥4 EPIC-26 domains, termed multidomain decline. RESULTS: The median age was 69 years, 46% of patients had unfavorable intermediate-risk or high-risk disease, and 20% received androgen-deprivation therapy. During 1 to 3 months and 6 to 60 months after SBRT, 8% to 15% and 10% to 11% of patients had multidomain declines, respectively. On multivariable analysis, lower baseline bowel HRQOL (odds ratio, 1.8; 95% confidence interval, 1.2-2.7; P < .01) and baseline depression (odds ratio, 5.7; 95% confidence interval, 1.3-24.3; P = .02) independently predicted for multidomain decline. Only 3% to 4% of patients had long-term multidomain declines exceeding twice the clinical threshold, and 30% of such declines appeared to be related to prostate cancer treatment or progression of disease. CONCLUSIONS: Prostate SBRT has minimal long-term impact on multidomain decline, and the majority of more significant multidomain declines appear to be unrelated to treatment. This emphasizes the importance of focusing not only on the side effects of prostate cancer treatment but also on other comorbid illnesses that contribute to overall HRQOL. Cancer 2017;123:1635-1642. © 2017 American Cancer Society.

Late urinary toxicity modeling after stereotactic body radiotherapy (SBRT) in the definitive treatment of localized prostate cancer.

BACKGROUND: Late urinary symptom flare has been shown to occur in a small subset of men treated with ultra- hypofractionated stereotactic body radiotherapy (SBRT) for prostate cancer. The purpose of this study was to use normal tissue complication probability modeling in an effort to derive SBRT specific dosimetric predictor's of late urinary flare. MATERIAL AND METHODS: Two hundred and sixteen men were treated for localized prostate cancer using ultra- hypofractionated SBRT. A dose of 35-36.25 Gy in 5 fractions was delivered to the prostate and proximal seminal vesicles. Functional surveys were conducted before and after treatment to assess late toxicity. Phenomenologic NTCP models were fit to bladder DVHs and late urinary flare outcomes using maximum likelihood estimation. RESULTS: Twenty-nine patients experienced late urinary flare within two years of completion of treatment. Fitting of bladder DVH data to a Lyman NTCP model resulted in parameter estimates of m, TD50, and n of 0.19 (0-0.47), 38.7 Gy (31.1-46.4), and 0.13 (-0.14-0.41), respectively. Subsequent fit to a hottest volume probit model revealed a significant association of late urinary flare with dose to the hottest 12.7% of bladder volume. Multivariate analysis resulted in a final model that included patient age and hottest volume probit model predictions. Kaplan-Meier analysis demonstrated a two-year urinary flare free survival of 95.7% in patients 65 years or older with a bladder D12.7% of 33.5 Gy or less, compared to 74.5% in patients meeting none of these criteria. CONCLUSION: NTCP modeling of late urinary flare after ultra-hypofractionated prostate SBRT demonstrates a relatively small volume effect for dose to the bladder, suggesting that reduction of volume receiving elevated dose will result in decreased incidence of late urinary toxicity. Future studies will be needed to examine the impact of dose to other potential sources of late genitourinary toxicity.

Prostate specific antigen kinetics following robotic stereotactic body radiotherapy for localized prostate cancer.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has emerged as an effective treatment for localized prostate cancer. However, prostate specific antigen (PSA) kinetics after prostate SBRT have not been well characterized. The purpose of this study was to analyze the trend in PSA decline following robotic SBRT from a prospective cohort of patients. MATERIAL AND METHODS: In total 175 patients were treated definitively for localized prostate cancer to a dose of 35-36.25 Gy in 5 fractions using robotic SBRT in the absence of androgen deprivation therapy (ADT). PSA and testosterone were collected at regular intervals following treatment and patients were assessed for biochemical failure and benign PSA bounce. A PSA nadir threshold of 0.5 ng/ml was used as a predictor of long-term disease-free survival. Multivariate logistic regression was used to assess the effect of disease specific covariates on the likelihood of achieving a PSA nadir less than threshold. PSA kinetics were analyzed a multi-component exponential model accounting for benign and malignant sources of PSA. RESULTS AND CONCLUSION: At a median follow-up of 3 years, 70% of patients achieved a PSA nadir below 0.5 ng/ml with a median PSA nadir of 0.3 ng/ml at a median time to nadir of 30 months. In our cohort, 36.2% experienced a benign PSA bounce. Absence of PSA bounce, initial PSA, and testosterone at the time of nadir proved to be significant predictors of achieving a PSA nadir below threshold. PSA kinetics after prostate SBRT were well described with a functional volume model with fitted half-lives of 4.4 and 14.8 months for malignant and benign sources of PSA, respectively. Patients treated with prostate SBRT experience an initial period of rapid PSA decline followed by a slow decline which will likely result in lower PSA nadirs after longer follow-up. The long-term disease specific impacts of these results remain to be determined.

Correlation of HOXD3 promoter hypermethylation with clinical and pathologic features in screening prostate biopsies.

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.

Circulatory miR-628-5p is downregulated in prostate cancer patients.

Prostate cancer (PCa) is a major health concern for men in the USA. Aberrant expression of microRNAs (miRNAs) has been associated with the pathogenesis of various cancers, including PCa. Circulatory forms of miRNAs have been detected in serum and hold promise as minimally invasive cancer biomarkers. This study aimed to identify potential circulatory miRNAs that can provide insights into new mechanisms for clinical diagnosis of PCa and can serve as potential biomarkers and/or therapeutic targets. Candidate serum miRNAs were detected by using PCR microarray in a learning set of six African American (AA) and six Caucasian American (CA) PCa patients. Discriminating performance of candidate miRNAs was validated by qRT-PCR in serum samples from 36 AA (24 PCa patients and 12 controls) and 36 CA (16 PCa patients and 20 controls). From the miRNA profiling experiments, three differentially expressed miRNAs (miR-25, miR-101, and miR-628-5p) were selected for future validation. In the validation set, there was an overall low expression of miR-25 (p < 0.01), miR-101 (p < 0.001), and miR-628-5p (p < 0.0001) in serum of PCa patients as compared with normal individuals. Subdivision on the basis of ethnicity showed that serum expression levels of miR-628-5p were significantly downregulated in both AA and CA PCa patients when compared with their respective controls. Our results demonstrate that the three miRNAs, particularly miR-628-5p, may be further developed as a biomarker, which can serve as novel noninvasive biomarker for PCa diagnosis and prognosis.

Prognostic utility of biopsy-based PTEN and ERG status on biochemical progression and overall survival after SBRT for localized prostate cancer.

Introduction/background: Phosphatase and tensin homolog (PTEN) genomic deletions and transmembrane protease, serine 2/v-ets avian erthyroblastosis virus E26 oncogene homolog (ERG) rearrangements are two of the most common genetic abnormalities associated with prostate cancer. Prior studies have demonstrated these alterations portend worse clinical outcomes. Our objective is to evaluate the impact of biopsy-determined PTEN losses and TMPRSS2-ERG fusion on biochemical progression-free survival (bPFS) and overall survival (OS) in patients who receive SBRT for localized prostate cancer. Methods/materials: Patients received SBRT for localized prostate cancer on a prospective quality-of-life (QoL) and cancer outcomes study. For each patient, the single biopsy core with the highest grade/volume of cancer was evaluated for PTEN and ERG abnormalities. Differences in baseline patient and disease characteristics between groups were analyzed using ANOVA for age and χ2 for categorical groupings. bPFS and OS were calculated using the Kaplan Meier (KM) method with Log-Rank test comparison between groups. Predictors of bPFS and OS were identified using the Cox proportional hazards method. For all analyses, p <0.05 was considered statistically significant. Results: Ninety-nine consecutive patients were included in the analysis with a median follow-up of 72 months. A statistically significant improvement in bPFS (p = 0.018) was observed for wild type ERG patients with an estimated 5-year bPFS of 94.1% vs. 72.4%. Regarding PTEN mutational status, significant improvements in were observed in both bPFS (p = 0.006) and OS (p < 0.001), with estimated 5-year bPFS rates of 91.0% vs. 67.9% and 5-year OS rates of 96.4% vs. 79.4%. When including both ERG and PTEN mutational status in the analysis, there were statistically significant differences in both bPFS (p = 0.011) and OS (p < 0.001). The estimated 5-year bPFS rates were 100%, 76.6%, 72.9%, and 63.8% for patients with ERG+/PTEN+, ERG-/PTEN+, ERG+/PTEN-, and ERG-/PTEN- phenotypes respectively. The estimated 5-year OS rates were 93.9%, 100%, 80.0%, and 78.7% for patients with ERG+/PTEN+, ERG-/PTEN+, ERG+/PTEN-, and ERG-/PTEN- phenotypes respectively. Conclusion: ERG rearrangements and PTEN deletions detected on biopsy samples are associated with poorer oncologic outcomes in prostate cancer patients treated with SBRT and merit further study in a dedicated prospective trial.

Impact of neoadjuvant relugolix on patient-reported sexual function and bother.

Introduction: Sexual function following local treatment for prostate cancer is an important quality of life concern. Relugolix is a novel oral GnRH receptor antagonist used in combination with radiation therapy in the treatment of unfavorable prostate cancer. It has been shown to achieve rapid and profound testosterone suppression. As a result, these very low testosterone levels may impact both sexual functioning and perceptions. This prospective study sought to assess neoadjuvant relugolix-induced sexual dysfunction prior to stereotactic body radiation therapy (SBRT). Methods: Between March 2021 and September 2023, 87 patients with localized prostate cancer were treated with neoadjuvant relugolix followed by SBRT per an institutional protocol. Sexual function and bother were assessed via the sexual domain of the validated Expanded Prostate Index Composite (EPIC-26) survey. Responses were collected for each patient at pre-treatment baseline and after several months of relugolix. A Utilization of Sexual Medications/Devices questionnaire was administered at the same time points to assess erectile aid usage. Results: The median age was 72 years and 43% of patients were non-white. The median baseline Sexual Health Inventory for Men (SHIM) score was 13 and 41.7% of patients utilized sexual aids prior to relugolix. Patients initiated relugolix at a median of 4.5 months (2-14 months) prior to SBRT. 95% and 87% of patients achieved effective castration (≤ 50 ng/dL) and profound castration (< 20 ng/dl) at SBRT initiation, respectively. Ability to have an erection, ability to reach orgasm, quality of erections, frequency of erections, and overall sexual function significantly declined following relugolix. There was a non- significant increase in sexual bother. Discussion: In concordance with known side effects of androgen deprivation therapy (ADT), neoadjuvant relugolix was associated with a significant decline in self-reported sexual function. However, patients indicated only a minimal and non-significant increase in bother. Future investigations should compare outcomes while on relugolix directly to GnRH agonist-induced sexual dysfunction.

Stereotactic Body Radiation Therapy for Clinically Localized Prostate Cancer in Men With Hip Prostheses: A Cautionary Note.

PURPOSE: Stereotactic body radiation therapy (SBRT) has been established as a safe and effective treatment for prostate cancer. SBRT requires high accuracy to reduce treatment margins. Metal hip prostheses create artifacts that distort pelvic imaging and potentially decrease the accuracy of target/organ at risk (OAR) identification and radiation dose calculations. Data on the safety and efficacy of SBRT after hip replacement is limited. This single-institution study sought to evaluate the safety and local control following SBRT for prostate cancer in men with hip replacements. METHODS: 23 patients treated with localized prostate cancer and a history of pre-treatment hip replacement, treated with SBRT from 2007 to 2017 at MedStar Georgetown University Hospital were included in this retrospective analysis. Treatment was administered with the CyberKnife® (Accuray Incorporated, Sunnyvale, CA) at doses of 35 Gy or 36.25 Gy in 5 fractions. The targets and OARs were identified and contoured by a single experienced Radiation Oncologist (SPC). The adequacy of the CT and T2W MRI images for treatment planning was assessed with a three-point scale (good, adequate, or suboptimal). During treatment planning, care was taken to avoid treatment beams that directly traversed the hip prosthesis. Toxicities were recorded and scored using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v.4.0). Local recurrence was confirmed by magnetic resonance imaging and/or prostate biopsy. RESULTS: The median follow-up was seven years. The patients were elderly (median age = 71 years) with a high rate of comorbidities (Charlson Comorbidity Index > 2 in 25%). Four patients had bilateral hip replacements. The majority of patients were low to intermediate risk per the D'Amico classification. Around 13% received upfront ADT. In total, 13 patients were treated with 35 Gy, and 10 were treated with 36.25 Gy. The rates of late > Grade 3 GU toxicity and > Grade 2 GI toxicity were 8.6% and 4.3%, respectively. There were no Grade 4 or 5 toxicities. Six patients (26%) developed a local recurrence at a median time of 7.5 years. Of these six patients, four had unilateral hip replacements and two had bilateral. Three underwent salvage cryotherapy and three received salvage ADT. CONCLUSIONS:  In the general population, high-grade toxicities and local recurrences are uncommon following prostate SBRT. However, in this cohort of patients with prior hip replacements, prostate SBRT had higher than expected rates of late toxicity and local recurrence. In the opinion of the authors, such patients should be counseled regarding an elevated risk of late toxicity and local recurrence with prostate SBRT. With its ultrasound guidance, brachytherapy would have the advantage of circumventing the need for MRI/CT-based imaging and thus may represent a preferable radiation alternative in this patient population. If these patients are treated with SBRT, they should be monitored closely for local recurrence so early salvage can be performed. We hope that recent advances in metal artifact reduction techniques and dose-calculation algorithms will improve future outcomes.

Early biochemical outcomes following neoadjuvant/adjuvant relugolix with stereotactic body radiation therapy for intermediate to high risk prostate cancer.

Introduction: Injectable GnRH receptor agonists have been shown to improve cancer control when combined with radiotherapy. Prostate SBRT offers an abbreviated treatment course with comparable efficacy to conventionally fractionated radiotherapy. Relugolix is a new oral GnRH receptor antagonist which achieves rapid, sustained testosterone suppression. This prospective study sought to evaluate early testosterone suppression and PSA response following relugolix and SBRT for intermediate to high prostate cancer. Methods: Relugolix was initiated at least 2 months prior to SBRT. Interventions to improve adherence were not utilized. PSA and total testosterone levels were obtained prior to and 1-4 months post SBRT. Profound castration was defined as serum testosterone ≤ 20 ng/dL. Early PSA nadir was defined as the lowest PSA value within 4 months of completion of SBRT. Per prior trials, we examined the percentage of patients who achieved PSA level of ≤ 0.5 ng/mL and ≤ 0.2 ng/mL during the first 4 months post SBRT. Results: Between July 2021 and January 2023, 52 men were treated at Georgetown with relugolix (4-6 months) and SBRT (36.25-40 Gy in 5 fractions) per an institutional protocol (IRB 12-1775). Median age was 71 years. 26.9% of patients were African American and 28.8% were obese (BMI ≥30 kg/m2). The median pretreatment PSA was 9.1 ng/ml. 67% of patients were ≥ Grade Group 3. 44 patients were intermediate- and 8 were high-risk. Patients initiated relugolix at a median of 3.6 months prior to SBRT with a median duration of 6.2 total months. 92.3% of patients achieved profound castration during relugolix treatment. Poor drug adherence was observed in 2 patients. A third patient chose to discontinue relugolix due to side effects. By post-SBRT month 4, 87.2% and 74.4% of patients achieved PSA levels ≤ 0.5 ng/ml and ≤ 0.2 ng/ml, respectively. Discussion: Relugolix combined with SBRT allows for high rates of profound castration with low early PSA nadirs. We observed a 96% testosterone suppresion rate without the utilization of scheduled cues/reminders. This finding supports the notion that patients with localized prostate cancer can consistently and successfully follow an oral ADT protocol without daily reminders. Given relugolix's potential benefits over injectable GnRH receptor agonists, its usage may be preferred in specific patient populations (fear of needles, prior cardiovascular events). Future studies should focus on boundaries to adherence in specific underserved populations.

Intensity modulated radiation therapy with stereotactic body radiation therapy boost for unfavorable prostate cancer: five-year outcomes.

Purpose: Intensity-modulated radiation therapy (IMRT) with brachytherapy boost for unfavorable prostate cancer has been shown to improve biochemical relapse-free survival compared to IMRT alone. Stereotactic body radiation therapy (SBRT) is a less-invasive alternative to brachytherapy. Early outcomes utilizing SBRT boost suggest low rates of high-grade toxicity with a maintained patient-reported quality of life. Here, we report the 5-year progression-free survival (PFS) and prostate cancer-specific survival (PCSS) of patients treated with IMRT plus SBRT boost. Materials and methods: Between 2008 and 2020, 255 patients with unfavorable prostate cancer were treated with robotic SBRT (19.5 Gy in three fractions) followed by fiducial-guided IMRT (45-50.4 Gy) according to an institutional protocol. For the first year, the patient's PSA level was monitored every 3 months, biannually for 2 years, and annually thereafter. Failure was defined as nadir + 2 ng/mL or a rising PSA with imaging suggestive of recurrence. Detection of recurrence also included digital rectal examination and imaging studies, such as MRI, CT, PET/CT, and/or bone scans. PFS and PCSS were calculated using the Kaplan-Meier method. Results: The median follow-up period was 71 months. According to the NCCN risk classification, 5% (13/255) of the patients had favorable intermediate-risk disease, 23% (57/255) had unfavorable intermediate-risk disease, 40% (102/255) had high-risk disease, and 32% (83/255) had very high-risk disease. Androgen deprivation therapy was administered to 80% (204/255) of the patients. Elective pelvic lymph node IMRT was performed in 28 (10%) patients. The PFS for all patients at 5 years was 81% (favorable intermediate risk, 91%; unfavorable intermediate risk, 89%; high-risk, 78%; and very-high risk, 72%). The PCSS for all patients at 5 years was 97% (favorable intermediate risk, 100%; unfavorable intermediate risk, 100%; high risk, 100%; and very high risk, 89%). Conclusion: The incidence of failure following IMRT plus SBRT for unfavorable prostate cancer remains low at 5 years.

Asymmetric synthesis and evaluation of a hydroxyphenylamide voltage-gated sodium channel blocker in human prostate cancer xenografts.

Voltage-gated sodium channels are known to be expressed in neurons and other excitable cells. Recently, voltage-gated sodium channels have been found to be expressed in human prostate cancer cells. α-Hydroxy-α-phenylamides are a new class of small molecules that have demonstrated potent inhibition of voltage-gated sodium channels. The hydroxyamide motif, an isostere of a hydantoin ring, provides an active scaffold from which several potent racemic sodium channel blockers have been derived. With little known about chiral preferences, the development of chiral syntheses to obtain each pure enantiomer for evaluation as sodium channel blockers is important. Using Seebach and Frater's chiral template, cyclocondensation of (R)-3-chloromandelic acid with pivaldehyde furnished both the cis- and trans-2,5-disubsituted dioxolanones. Using this chiral template, we synthesized both enantiomers of 2-(3-chlorophenyl)-2-hydroxynonanamide, and evaluated their ability to functionally inhibit hNa(v) isoforms, human prostate cancer cells and xenograft. Enantiomers of lead demonstrated significant ability to reduce prostate cancer in vivo.

Rationale for Utilization of Hydrogel Rectal Spacers in Dose Escalated SBRT for the Treatment of Unfavorable Risk Prostate Cancer.

In this review we outline the current evidence for the use of hydrogel rectal spacers in the treatment paradigm for prostate cancer with external beam radiation therapy. We review their development, summarize clinical evidence, risk of adverse events, best practices for placement, treatment planning considerations and finally we outline a framework and rationale for the utilization of rectal spacers when treating unfavorable risk prostate cancer with dose escalated Stereotactic Body Radiation Therapy (SBRT).

Leptin modulated microRNA-628-5p targets Jagged-1 and inhibits prostate cancer hallmarks.

MicroRNAs (miRNAs) are single-stranded non-coding RNA molecules that play a regulatory role in gene expression and cancer cell signaling. We previously identified miR-628-5p (miR-628) as a potential biomarker in serum samples from men with prostate cancer (PCa) (Srivastava et al. in Tumour Biol 35:4867-4873, 10.1007/s13277-014-1638-1, 2014). This study examined the detailed cellular phenotypes and pathways regulated by miR-628 in PCa cells. Since obesity is a significant risk factor for PCa, and there is a correlation between levels of the obesity-associated hormone leptin and PCa development, here we investigated the functional relationship between leptin and miR-628 regulation in PCa. We demonstrated that exposure to leptin downregulated the expression of miR-628 and increased cell proliferation/migration in PCa cells. We next studied the effects on cancer-related phenotypes in PCa cells after altering miR-628 expression levels. Enforced expression of miR-628 in PCa cells inhibited cell proliferation, reduced PCa cell survival/migration/invasion/spheroid formation, and decreased markers of cell stemness. Mechanistically, miR-628 binds with the JAG1-3'UTR and inhibits the expression of Jagged-1 (JAG1). JAG1 inhibition by miR-628 downregulated Notch signaling, decreased the expression of Snail/Slug, and modulated epithelial-mesenchymal transition and invasiveness in PC3 cells. Furthermore, expression of miR-628 in PCa cells increased sensitivity towards the drugs enzalutamide and docetaxel by induction of cell apoptosis. Collectively our data suggest that miR-628 is a key regulator of PCa carcinogenesis and is modulated by leptin, offering a novel therapeutic opportunity to inhibit the growth of advanced PCa.

Association of baseline self-reported fatigue with overall survival after stereotactic body radiation therapy for localized prostate cancer.

Introduction: Stereotactic Body Radiation Therapy (SBRT) has emerged as a definitive therapy for localized prostate cancer (PCa). However, more data is needed to predict patient prognosis to help guide which patients will benefit most from treatment. The FACIT-Fatigue (FACIT-F) is a well validated, widely used survey for assessing fatigue. However, the role of fatigue in predicting PCa survival has yet to be studied. Herein, we investigate the role of FACIT-F as a baseline predictor for overall survival (OS) in patients undergoing SBRT for localized PCa. Methods: A retrospective review was conducted of 1358 patients who received SBRT monotherapy between January 2008 to April 2021 at an academic, tertiary referral center. FACIT-F scores (range 0 to 52) were summed for patients who answered all 13-items on the survey. FACIT-F total scores of ≥35 represented severe fatigue. Patients receiving androgen deprivation therapy were excluded. Differences in fatigue groups were evaluated using chi-squared tests. OS rates were determined using the Kaplan-Meier method and predictors of OS were evaluated using Cox proportional hazard method. Results: Baseline full FACIT-F scores and survival data was available for 891 patients. 5-year OS was 87.6% and 95.2%, respectively, for the severely fatigued and non-fatigued groups. Chi-squared analysis of fatigue groups showed no significant difference in the following categories: D'Amico risk group, age, ethnicity, grade group, T-stage, or PSA density. Severe fatigue was associated with a significant decrease in OS (hazard ratio 2.76; 95%CI 1.55 - 4.89). The Cox proportional hazard model revealed that age and FACIT-F were both statistically significant (p <0.05). Conclusion: Baseline FACIT-F scores are significantly associated with OS. Higher FACIT-F scores, representing less fatigued patients, are associated with an overall survival benefit. These results indicate that the FACIT-F survey could serve as an additional metric for clinicians in determining prognostic factors for patients undergoing SBRT.

Patient-Reported Financial Burden Following Stereotactic Body Radiation Therapy for Localized Prostate Cancer.

Introduction and Objectives: In patients with localized prostate cancer, 5-fraction, stereotactic body radiation therapy (SBRT) has been found to offer comparable oncologic outcomes and potential for improved treatment compliance compared to conventional, 40-plus fraction radiation therapy (RT). Recent studies of oncologic patient experiences have highlighted both the impact of therapy-associated financial toxicity (FT) on treatment adherence and health-related quality of life (HRQOL). Methods: A cross-sectional assessment of FT after SBRT was performed using the 12-item COST questionnaire. The total questionnaire score (range 0-44) was used to evaluate the FT grade (0-3), with a higher COST value representing lower grade. The patient zip code was used to approximate the distance from the index hospital. Univariate and multivariate analyses of the average COST score (0-4) are performed. Results: The response rate was 57.5% (332 of 575 consented patients) with 90.7%, 8.2%, and 1.1% experiencing grade 0, 1, and 2 FT, respectively, with no grade 3. Unemployment or disability, non-white race, low income, and concurrent hormonal therapy were associated with a statistically significant worse FT (lower COST value) on univariate and multivariate analyses (p < 0.05). Education level and insurance status significant were evaluated on univariate analysis only. There was a non-statistically significant difference in age, marital status, time since treatment, and distance from the index hospital. Conclusions: SBRT was associated with low FT. However, statistically significant socioeconomic disparities in FT remain despite ultra-hypofractionated treatment.