Limited Relevance of the Very Low Risk Prostate Cancer Classification in the Modern Era: Results from a Large Institutional Active Surveillance Cohort.

Although the American Urological Association recently dropped the very low-risk (VLR) subcategory for low-risk prostate cancer (PCa) and the European Association of Urology does not substratify low-risk PCa, the National Comprehensive Cancer Network (NCCN) guidelines still maintain this stratum, which is based on the number of positive biopsy cores, tumor extent in each core, and prostate-specific antigen density. This subdivision may be less applicable in the modern era in which imaging-targeted prostate biopsies are common practice. In our large institutional active surveillance cohort of patients diagnosed from 2000 to 2020 (n = 1276), the number of patients meeting NCCN VLR criteria decreased significantly in recent years, with no patient meeting VLR criteria after 2018. By contrast, the multivariable Cancer of the Prostate Risk Assessment (CAPRA) score effectively substratified patients over the same period and was predictive of upgrading on repeat biopsy to Gleason grade group ≥2 on multivariable Cox proportional-hazards regression modeling (hazard ratio 1.21, 95% confidence interval 1.05-1.39; p < 0.01), independent of age, genomic test results, and magnetic resonance imaging findings. These findings suggest that the NCCN VLR criteria are less applicable in the targeted biopsy era, and that the CAPRA score or similar instruments are better contemporary risk stratification tools for men on active surveillance. PATIENT SUMMARY: We investigated whether the National Comprehensive Cancer Network classification of very low risk (VLR) for prostate cancer is relevant in the modern era. We found that in a large group of patients on active surveillance, no man diagnosed after 2018 satisfied the VLR criteria. However, the Cancer of the Prostate Risk Assessment (CAPRA) score discriminated patients by cancer risk at diagnosis and was predictive of outcomes on active surveillance, and thus may be a more relevant classification scheme in the modern era.

Patient engagement in a mobile health intervention to improve preparedness for prostate biopsy.

OBJECTIVE: We designed and implemented a peri-procedural text message (SMS) program for patients undergoing transrectal prostate biopsy and aimed to evaluate predictors of patient enrollment and engagement with the SMS program. METHODS: We designed an SMS-based program with 8 messages containing web-based modules with educational content and reminders confirming MRI for fusion biopsy, antibiotic adherence, enema use, and anticoagulation cessation. Data on patient demographics, enrollment, and engagement with modules were collected from June 1, 2018 to February 28, 2021. Engagement was defined as a patient clicking a link delivered via SMS to access modules. We made multivariable models to identify predictors of patient enrollment and engagement. RESULTS: Of the 1,760 prostate biopsies between June 2018 and March 2021, 1,383 (78.6%) were enrolled in SMS, 182 (10.3%) in email, 106 (6.0%) in both, and 240 (13.6%) were not enrolled. Of 1418 patients enrolled, 1,270 (89.6%) engaged with at least one module. African American patients had 50% lower odds of being enrolled (OR = 0.50, 95% CI 0.28-0.96; P = 0.03), but once enrolled there were no differences in engagement. Patients for whom English was not listed as their primary language had 60% lower odds of engagement (OR = 0.40, 95% CI 0.17-1.00, P = .04) and patients who were single or divorced had a 40% lower odds of engagement (OR = 0.60, 95% CI 0.41-0.91, P = 0.01). CONCLUSIONS: A cohort of older men undergoing prostate biopsy were able to engage with a text message-based education and reminder program. Future efforts must address barriers to enrollment for Black or African American men and improve accessibility to non-English speaking patients.

Long-Term Results of NRG Oncology/RTOG 0321: A Phase II Trial of Combined High Dose Rate Brachytherapy and External Beam Radiation Therapy for Adenocarcinoma of the Prostate.

PURPOSE: To report the long-term outcome of patients with prostate cancer treated with external beam radiation therapy and high dose rate (HDR) brachytherapy from a prospective multi-institutional trial conducted by NRG Oncology/RTOG. METHODS AND MATERIALS: Patients with clinically localized (T1c-T3b) prostate cancer without prior history of transurethral resection of prostate or hip prosthesis were eligible for this study. All patients were treated with a combination of 45 Gy in 25 fractions from external beam radiation therapy and one HDR implant delivering 19 Gy in 2 fractions. Adverse events (AE) were collected using Common Toxicity Criteria for Adverse Events, version 3. Cumulative incidence was used to estimate time to severe late gastrointestinal (GI)/genitourinary (GU) toxicity, biochemical failure, disease-specific mortality, local failure, and distant failure. Overall survival was estimated using the Kaplan-Meier method. RESULTS: One hundred and twenty-nine patients were enrolled from July 2004 to May 2006. AE data was available for 115 patients. Patients were National Comprehensive Cancer Network (NCCN) intermediate to very high risk. The median age was 68, T1c-T2c 91%, T3a-T3b 9%, PSA ≤10 70%, PSA >10 to ≤20 30%, GS 6 10%, GS 7 72%, and GS 8 to 10 18%. Forty-three percent of patients received hormonal therapy. At a median follow-up time of 10 years, there were 6 (5%) patients with grade 3 GI and GU treatment-related AEs, and no late grade 4 to 5 GI and GU AEs. At 5 and 10 years, the rate of late grade 3 gastrointestinal and genitourinary AEs was 4% and 5%, respectively. Five- and 10-year overall survival rates were 95% and 76%. Biochemical failure rates per Phoenix definition at 5 and 10 years were 14% and 23%. The 10-year rate of disease-specific mortality was 6%. At 5 and 10 years, the rates of distant failure were 4% and 8%, respectively. The rates of local failure at 5 and 10 years were 2% at both time points. CONCLUSIONS: Combined modality treatment using HDR prostate brachytherapy leads to excellent long-term clinical outcomes in this prospective multi-institutional trial.

Impact of Staging 68Ga-PSMA-11 PET Scans on Radiation Treatment Plansin Patients With Prostate Cancer.

OBJECTIVE: To evaluate the impact of staging 68Ga-PSMA-11 PET imaging on radiotherapy (RT) dose and volumes in patients with prostate cancer. METHODS: Forty-five patients (89% high or very high risk by NCCN criteria) who underwent 68Ga-PSMA-11 PET imaging prior to definitive treatment for prostate cancer between December 2015 and December 2016 were included. Locations of 68Ga-PSMA-11-avid lesions were compared to Radiation Therapy Oncology Group consensus pelvic nodal volumes (clinical target volume [CTV]); coverage of lesions outside the consensus CTV was considered a major change, while dose-escalation to lesions within the consensus CTV was considered a minor change. RESULTS: All patients had 68Ga-PSMA-11 PET uptake in the prostate. Twenty-five patients (56%) had N1/M1a disease on 68Ga-PSMA-11 PET scan, of whom 21 (47%) were previously N0. Six patients (13%) had bone metastases on 68Ga-PSMA-11 PET scan, of whom 4 had prior negative bone scans. Eight patients (18%) had lymph node metastases outside the consensus CTV. Twelve patients (27%) received a RT boost to nodes within the consensus CTV. Six patients (13%) had limited bone metastases treated with focal RT. Overall PSMA PET imaging resulted in major and/or minor changes to RT plans in 24 patients (53%). CONCLUSION: 68Ga-PSMA-11 PET imaging resulted in RT changes in 53% of patients. Prospective investigation is needed to evaluate the clinical benefit of RT changes based on staging 68Ga-PSMA-11 PET imaging.

A novel urethral sparing technique for high-dose-rate prostate brachytherapy after transurethral resection of the prostate.

PURPOSE: The purpose of this study was to assess retrospectively the variability of the urethral dose optimized using a Foley catheter versus urethral contrast injected using a new modified triple-lumen catheter, in CT-based high-dose-rate (HDR) prostate brachytherapy of posttransurethral resection of prostate (TURP) patients. METHODS AND MATERIALS: At our institution, there were six post-TURP patients with prostate carcinoma between July 2014 and April 2016 who underwent transperineal interstitial HDR brachytherapy (16 needles). A custom modified triple-lumen catheter was placed to inject contrast into the TURP defect. Three-dimensional optimal plans using inverse planning simulated annealing algorithm was generated according to radiation therapy oncology group dose requirements. Alternative plans were retroactively generated for comparison using standard technique based on a Foley catheter as a urethral constraint volume for each patient with the same weighting factors. We compared the dosimetry parameters in each planning using Wilcoxon's ranked sum nonparametric test. RESULTS: The median followup of all patients was 17.5 months. No significant genitourinary or gastrointestinal toxicity was noted using this technique. In the dosimetric analysis, the prostate V100 values and TURP urethral V100 were significantly different between plans with and without the contrast (V100 [mean]: 92.4 [%] vs. 94.4 [%], p = 0.046; TURP UV100 [mean]: 1.4 cc vs. 2.2 cc, p = 0.028). There were no statistical differences in the mean values of planning target volume V150%, V200%, and D90, and each bladder V75 and rectum V75. CONCLUSIONS: Post-TURP HDR brachytherapy with urethral contrast showed significantly more volume effect of the TURP defect than that with a Foley catheter alone. Better visualization of the TURP defect should lead to more accurate urethral sparing administration of HDR brachytherapy which is necessary to prevent urethral complication.

Gene expression and biological pathways in tissue of men with prostate cancer in a randomized clinical trial of lycopene and fish oil supplementation.

BACKGROUND: Studies suggest that micronutrients may modify the risk or delay progression of prostate cancer; however, the molecular mechanisms involved are poorly understood. We examined the effects of lycopene and fish oil on prostate gene expression in a double-blind placebo-controlled randomized clinical trial. METHODS: Eighty-four men with low risk prostate cancer were stratified based on self-reported dietary consumption of fish and tomatoes and then randomly assigned to a 3-month intervention of lycopene (n = 29) or fish oil (n = 27) supplementation or placebo (n = 28). Gene expression in morphologically normal prostate tissue was studied at baseline and at 3 months via cDNA microarray analysis. Differential gene expression and pathway analyses were performed to identify genes and pathways modulated by these micronutrients. RESULTS: Global gene expression analysis revealed no significant individual genes that were associated with high intake of fish or tomato at baseline or after 3 months of supplementation with lycopene or fish oil. However, exploratory pathway analyses of rank-ordered genes (based on p-values not corrected for multiple comparisons) revealed the modulation of androgen and estrogen metabolism in men who routinely consumed more fish (p = 0.029) and tomato (p = 0.008) compared to men who ate less. In addition, modulation of arachidonic acid metabolism (p = 0.01) was observed after 3 months of fish oil supplementation compared with the placebo group; and modulation of nuclear factor (erythroid derived-2) factor 2 or Nrf2-mediated oxidative stress response for either supplement versus placebo (fish oil: p = 0.01, lycopene: p = 0.001). CONCLUSIONS: We did not detect significant individual genes associated with dietary intake and supplementation of lycopene and fish oil. However, exploratory analyses revealed candidate in vivo pathways that may be modulated by these micronutrients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00402285.

Nutritional supplements, COX-2 and IGF-1 expression in men on active surveillance for prostate cancer.

BACKGROUND: Nutritional factors are associated with reduced risk of prostate cancer progression, yet mechanisms remain unclear. We examined the effects of lycopene and fish oil supplements versus placebo on the normal prostate microenvironment, among men pursuing active surveillance for low-burden prostate cancer. We hypothesized that lycopene or fish oil supplements would down-regulate insulin-like growth factor-1 (IGF-1) and cyclooxygenase 2 (COX-2) gene expression, respectively, reflecting putative proliferation (IGF-1) and inflammatory (COX-2) pathways relevant to carcinogenesis. METHODS: We conducted a 3-month randomized, double-blinded, clinical trial comparing prostate tissue gene expression profiles (assessed by qRT-PCR) among men with favorable-risk prostate cancer receiving either 30 mg/day lycopene, 3 g/day fish oil (including 1,098 mg eicosapentaenoic and 549 mg docosahexaenoic fatty acids) or placebo. RESULTS: Among 69 men (22 assigned to lycopene, 21 to fish, and 26 to placebo), there was no difference in the change from baseline to the 3 months in IGF-1 expression level between the placebo and lycopene arms (p = 0.93) nor in COX-2 expression between the placebo and fish arms (p = 0.99). CONCLUSION: Compared to placebo, 3-month intervention with lycopene or fish oil did not significantly change IGF-1 and COX-2 gene expression in the normal prostate microenvironment in men with low-burden prostate cancer. Further analysis of global gene expression profiles may shed light on the bioactivity and relevance of these nutrients in prostate cancer.

Saw palmetto for benign prostatic hyperplasia.

BACKGROUND: Saw palmetto is used by over 2 million men in the United States for the treatment of benign prostatic hyperplasia and is commonly recommended as an alternative to drugs approved by the Food and Drug Administration. METHODS: In this double-blind trial, we randomly assigned 225 men over the age of 49 years who had moderate-to-severe symptoms of benign prostatic hyperplasia to one year of treatment with saw palmetto extract (160 mg twice a day) or placebo. The primary outcome measures were changes in the scores on the American Urological Association Symptom Index (AUASI) and the maximal urinary flow rate. Secondary outcome measures included changes in prostate size, residual urinary volume after voiding, quality of life, laboratory values, and the rate of reported adverse effects. RESULTS: There was no significant difference between the saw palmetto and placebo groups in the change in AUASI scores (mean difference, 0.04 point; 95 percent confidence interval, -0.93 to 1.01), maximal urinary flow rate (mean difference, 0.43 ml per minute; 95 percent confidence interval, -0.52 to 1.38), prostate size, residual volume after voiding, quality of life, or serum prostate-specific antigen levels during the one-year study. The incidence of side effects was similar in the two groups. CONCLUSIONS: In this study, saw palmetto did not improve symptoms or objective measures of benign prostatic hyperplasia. (ClinicalTrials.gov number, NCT00037154.).

Local anesthesia during 10 core biopsy of the prostate: comparison of 2 methods.

PURPOSE: We investigated the effectiveness of a new method, intraprostatic administration of local anesthesia vs traditional periprostatic injection for decreasing the discomfort caused by transrectal ultrasound guided, 10 core biopsy of the prostate. MATERIALS AND METHODS: We studied 71 patients who received intraprostatic anesthesia between October 2002 and March 2003, and 99 who received periprostatic anesthesia between October 2001 and September 2002 before prostate biopsy. After biopsy patients were given a questionnaire, which consisted of 5 questions about pain and 3 about morbidity, and were asked to complete it and mail it to our department. RESULTS: The mean score +/- SD for the degree of pain during biopsy in the periprostatic groups was 2.6 +/- 1.1 and that in the intraprostatic group was 1.9 +/- 1.1, which was significantly different (p <0.001). Other items, including the degree of pain after biopsy, duration and location of pain, and medicine intake for pain, were not significantly different between the 2 groups. There was no significant difference in morbidity, including hematuria, hemospermia and rectal bleeding, between the 2 groups. CONCLUSIONS: Intraprostatic administration of local anesthesia significantly decreases the pain associated with prostate biopsy compared with periprostatic nerve block. It is a simple, safe and rapid technique that should be considered in all patients undergoing transrectal ultrasound guided prostate biopsy.

Ferromagnetic thermal ablation of locally recurrent prostate cancer: prostate specific antigen results and immediate/intermediate morbidities.

PURPOSE: Curative options for locally recurrent prostate cancer following external beam radiotherapy are limited due to the significant morbidity associated with surgical therapy. ThermoRods (Ablation Technologies, San Diego, California) are permanently implantable, 14 mm cobalt-palladium alloy rods that produce heat through oscillation of a magnetic field. The rod is designed to self-regulate the temperature to 70C by a temperature dependent magnetic transition (Curie effect). We determined whether patients with prostate cancer and local failure could be treated with thermal ablation of the prostate using this novel technology. MATERIALS AND METHODS: A total of 14 men with an average age of 72 years (range 62 to 81) were enrolled in the study. All had biopsy proven prostate cancer with increasing prostate specific antigen (PSA) (1.0 to 10.3 ng/ml). The seminal vesicles were not routinely biopsied. Metastatic disease was assayed in all men with bone scan and in later patients with abdominopelvic computerized tomography. Patients had ThermoRods placed under transrectal ultrasound guidance, similar to brachytherapy. The pre-plan was rigorously followed to produce a 3-dimensional array with rods separated by 1 cm across the short axis. Patients were treated in a magnetic field for 1 hour. Urethral and rectal temperatures were also monitored and cooled appropriately. Serial PSA measurements and 6 month posttreatment biopsies were obtained after the procedure. RESULTS: Average time since radiation was 4.5 years. PSA nadir values after radiation were between 0.3 and 2.2 ng/ml. Prostatic temperatures were homogeneously increased greater than 50C, while rectal and urethral temperatures did not exceed 44C at any point. The urethral catheter was removed 2 weeks postoperatively in all cases. Six months after the procedure 8 of the 14 men (57%) had a PSA decrease to less than 0.1 ng/ml. Complications included urinary retention as well as incontinence. Incontinence was generally temporary and only 1 patient (7%) had long-term incontinence. Most patients were impotent after treatment. Of the patients 21% experienced urinary retention. Five patients (36%) needed to undergo secondary procedures after therapy, including transurethral prostate resection in 2, balloon dilation in 1, cystoscopic removal of necrotic tissue in 1 and bladder irrigation in 1. CONCLUSIONS: This novel means of thermal ablation produces significant PSA decreases in patients. Morbidity is predominantly in the form of incontinence and impotence. Incontinence is generally temporary. The use of ferromagnetic rods enables the precise control of tissue destruction with the sparing of immediately adjacent structures. The technology uses skills familiar to the urologist and avoids radiation. The durability of the PSA response and incidence of late morbidity remain to be defined.