A Phase 1/2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Muscle-Invasive Bladder Cancer.

INTRODUCTION: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard for muscle-invasive bladder cancer (MIBC), however, NAC confers only a small survival benefit and new strategies are needed to increase its efficacy. Pre-clinical data suggest that in response to DNA damage the tumor microenvironment (TME) adopts a paracrine secretory phenotype dependent on mTOR signaling which may provide an escape mechanism for tumor resistance, thus offering an opportunity to increase NAC effectiveness with mTOR blockade. PATIENTS & METHODS: We conducted a phase I/II clinical trial to assess the safety and efficacy of gemcitabine-cisplatin-rapamycin combination. Grapefruit juice was administered to enhance rapamycin pharmacokinetics by inhibiting intestinal enzymatic degradation. Phase I was a dose determination/safety study followed by a single arm Phase II study of NAC prior to radical cystectomy evaluating pathologic response with a 26% pCR rate target. RESULTS: In phase I, 6 patients enrolled, and the phase 2 dose of 35 mg rapamycin established. Fifteen patients enrolled in phase II; 13 were evaluable. Rapamycin was tolerated without serious adverse events. At the preplanned analysis, the complete response rate (23%) did not meet the prespecified level for continuing and the study was stopped due to futility. With immunohistochemistry, successful suppression of the mTOR signaling pathway in the tumor was achieved while limited mTOR activity was seen in the TME. CONCLUSION: Adding rapamycin to gemcitabine-cisplatin therapy for patients with MIBC was well tolerated but failed to improve therapeutic efficacy despite evidence of mTOR blockade in tumor cells. Further efforts to understand the role of the tumor microenvironment in chemotherapy resistance is needed.

Effects of acupuncture to decrease adverse events in patients with high-risk non-muscle invasive bladder cancer receiving induction intravesical BCG therapy: Study protocol for a randomized, controlled pilot and feasibility study.

Background: Treatment-related serious adverse events (SAEs) are common in patients receiving intravesical Bacillus Calmette-Guerin (BCG) for the treatment of high-risk nonmuscle-invasive bladder cancer (NMIBC). Here we describe the protocol of a randomized, attention/waitlist-controlled feasibility pilot study testing the use of acupuncture to decrease SAEs and treatment interruptions in this population. The primary objectives are to evaluate the feasibility and efficacy of conducting pre-procedure acupuncture in a Urology Clinic. Methods: A total of 45 patients will be recruited and randomized in a 2:1 ratio (treatment arm: attention/waitlist control). Eligibility criteria include 1) age 18 years or older, 2) English-speaking, 3) high-risk NMIBC, 4) no acupuncture in the previous 3 months, and 5) willing and able to participate in trial activities. Patients in the treatment arm will receive acupuncture prior to weekly BCG for a total of six weeks. Methods were developed to train and monitor research acupuncturists and included online and in-person training, study manuals, and monthly meetings throughout the study period. Feasibility assessments include evaluation of the recruitment, retention and protocol adherence to acupuncture treatment, and measurement of CTCAE v5.0 adverse events specific to acupuncture, and clinic staff surveys regarding the intervention impact on clinic workflow. Efficacy measures will be compared between treatment and control groups including: EORTC-QLQ-NMIBC-24, EORTC-QLQ-C30, CTCAE v5.0, medication journal, healthcare utilization, current use of complementary, alternative, and integrative therapies, and acupuncture expectancy and treatment preference. Trial results will inform the design of a multi-center trial to expand testing of the protocol to a larger patient cohort.

Underutilization of Surgical Standard of Care for Insured Men with Invasive Penile Cancer.

PURPOSE: Prior studies of mixed insurance populations have demonstrated poor adherence to surgical standard of care (SOC) for penile cancer. We used data from the Surveillance, Epidemiology and End Results (SEER) cancer registry linked to Medicare to calculate SOC adherence to surgical treatment of penile cancer in insured men over the age of 65, focusing on potential social and racial disparities. METHODS: This is an observational analysis of patients with T2-4 penile cancer of any histologic subtype without metastasis in the SEER-Medicare database (2004-2015). SOC was defined as penectomy (partial or radical) with bilateral inguinal lymph node dissection (ILND) based on the National Comprehensive Cancer Network guidelines. We calculated proportions of those receiving SOC and constructed multivariate models to identify factors associated with receiving SOC. RESULTS: A total of 447 men were included. Of these men, 22.1% (99/447) received SOC while 18.8% (84/447) received no treatment at all. Only 23.3% (104/447) had ILND while 80.9% (362/447) underwent total or partial penectomy. Race and socioeconomic status (SES) were not associated with decreased SOC. Increasing age (OR 0.93, 95%CI:0.89-0.96), Charlson Comorbidity Index score ≥ 2 (OR 0.53, 95%CI:0.29-0.97), and T3-T4 disease (OR 0.34, 95%CI:0.18-0.65) were associated with not receiving SOC on adjusted analysis. CONCLUSIONS: Rates of SOC are low among insured men 65 years of age or older with invasive penile cancer, regardless of race or SES. This finding is largely driven by low rates of ILND. Strategies are needed to overcome barriers to SOC treatment for men with invasive penile cancer.

Improving risk stratification among veterans diagnosed with prostate cancer: impact of the 17-gene prostate score assay.

BACKGROUND: Active surveillance (AS) has been widely implemented within Veterans Affairs' medical centers (VAMCs) as a standard of care for low-risk prostate cancer (PCa). Patient characteristics such as age, race, and Agent Orange (AO) exposure may influence advisability of AS in veterans. The 17-gene assay may improve risk stratification and management selection. OBJECTIVES: To compare management strategies for PCa at 6 VAMCs before and after introduction of the Oncotype DX Genomic Prostate Score (GPS) assay. STUDY DESIGN: We reviewed records of patients diagnosed with PCa between 2013 and 2014 to identify management patterns in an untested cohort. From 2015 to 2016, these patients received GPS testing in a prospective study. Charts from 6 months post biopsy were reviewed for both cohorts to compare management received in the untested and tested cohorts. SUBJECTS: Men who just received their diagnosis and have National Comprehensive Cancer Network (NCCN) very low-, low-, and select cases of intermediate-risk PCa. RESULTS: Patient characteristics were generally similar in the untested and tested cohorts. AS utilization was 12% higher in the tested cohort compared with the untested cohort. In men younger than 60 years, utilization of AS in tested men was 33% higher than in untested men. AS in tested men was higher across all NCCN risk groups and races, particular in low-risk men (72% vs 90% for untested vs tested, respectively). Tested veterans exposed to AO received less AS than untested veterans. Tested nonexposed veterans received 19% more AS than untested veterans. Median GPS results did not significantly differ as a factor of race or AO exposure. CONCLUSIONS: Men who receive GPS testing are more likely to utilize AS within the year post diagnosis, regardless of age, race, and NCCN risk group. Median GPS was similar across racial groups and AO exposure groups, suggesting similar biology across these groups. The GPS assay may be a useful tool to refine risk assessment of PCa and increase rates of AS among clinically and biologically low-risk patients, which is in line with guideline-based care.

Identification of underserved areas for urologic cancer care.

BACKGROUND: The delivery of urologic oncology care is susceptible to regional variation. In the current study, the authors sought to define patterns of care for patients undergoing genitourinary cancer surgery to identify underserved areas for urologic cancer care in Washington State. METHODS: The authors accessed the Washington State Comprehensive Hospital Abstract Reporting System from 2003 through 2007. They identified patients undergoing radical prostatectomy, radical cystectomy (RC), partial nephrectomy (PN), radical nephrectomy, and transurethral resection of the prostate (TURP). TURP was included for comparison as a reference procedure indicative of access to urologic care. Hospital service areas (HSAs) are where the majority of local patients are hospitalized; hospital referral regions (HRR) are where most patients receive tertiary care. The authors created multivariate hierarchical logistic regression models to examine patient and HSA characteristics associated with the receipt of urologic oncology care out of the HRR for each procedure. RESULTS: Greater than one-half of patients went out of their HRR in 7 HSAs (11%) for radical prostatectomy, 3 HSAs (5%) for radical nephrectomy, 10 HSAs (15%) for PN, and 14 HSAs (22%) for RC. No HSAs had high export rates for TURP. Few patient factors were found to be associated with surgical care out of the HRR. High-export HSAs for PN and RC exhibited lower socioeconomic characteristics than low-export HSAs, adjusting for HSA population, race, and HSA procedure rates for PN and RC. CONCLUSIONS: Patients living in areas with lower socioeconomic status have a greater need to travel for complex urologic surgery. Consideration of geographic delineation in the delivery of urologic oncology care may aid in regional quality improvement initiatives.

Coffee and tea consumption in relation to prostate cancer prognosis.

BACKGROUND: Bioactive compounds found in coffee and tea may delay the progression of prostate cancer. METHODS: We investigated associations of pre-diagnostic coffee and tea consumption with risk of prostate cancer recurrence/progression. Study participants were men diagnosed with prostate cancer in 2002-2005 in King County, Washington, USA. We assessed the usual pattern of coffee and tea consumption two years before diagnosis date. Prostate cancer-specific outcome events were identified using a detailed follow-up survey. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). RESULTS: The analysis of coffee intake in relation to prostate cancer recurrence/progression included 630 patients with a median follow-up of 6.4 years, during which 140 prostate cancer recurrence/progression events were recorded. Approximately 61 % of patients consumed at least one cup of coffee per day. Coffee consumption was associated with a reduced risk of prostate cancer recurrence/progression; the adjusted HR for ≥4 cups/day versus ≤1 cup/week was 0.41 (95 % CI: 0.20, 0.81; p for trend = 0.01). Approximately 14 % of patients consumed one or more cups of tea per day, and tea consumption was unrelated to prostate cancer recurrence/progression. CONCLUSION: Results indicate that higher pre-diagnostic coffee consumption is associated with a lower risk of prostate cancer recurrence/progression. This finding will require replication in larger studies.

Long-term use of supplemental vitamins and minerals does not reduce the risk of urothelial cell carcinoma of the bladder in the VITamins And Lifestyle study.

PURPOSE: Urothelial carcinoma has the highest lifetime treatment cost of any cancer, making it an ideal target for preventative therapies. Previous work has suggested that certain vitamin and mineral supplements may reduce the risk of urothelial carcinoma. We used the prospective VITamins And Lifestyle cohort to examine the association of all commonly taken vitamin and mineral supplements as well as 6 common anti-inflammatory supplements with incident urothelial carcinoma in a United States population. MATERIALS AND METHODS: A total of 77,050 eligible VITAL participants completed a detailed questionnaire at baseline on supplement use and cancer risk factors. After 6 years of followup 330 incident urothelial carcinoma cases in the cohort were identified via linkage to the Seattle-Puget Sound SEER cancer registry. We analyzed use of supplemental vitamins (multivitamins, beta-carotene, retinol, folic acid, and vitamins B1, B3, B6, B12, C, D and E), minerals (calcium, iron, magnesium, zinc and selenium) and anti-inflammatory supplements (glucosamine, chondroitin, saw palmetto, ginkgo biloba, fish oil and garlic). For each supplement the hazard ratios (risk ratios) for urothelial carcinoma comparing each category of users to nonusers, and 95% CIs, were determined using Cox proportional hazards regression, adjusted for potential confounders. RESULTS: None of the vitamin, mineral or anti-inflammatory supplements was significantly associated with urothelial carcinoma risk in age adjusted or multivariate models. CONCLUSIONS: The results of this study do not support the use of commonly taken vitamin or mineral supplements or 6 common anti-inflammatory supplements for the chemoprevention of urothelial carcinoma.

Virtual reality as an adjunctive pain control during transurethral microwave thermotherapy.

The management of pain during clinic transurethral microwave thermotherapy (TUMT) can be challenging. Pain can lead to increased pelvic blood flow, which dissipates the energy delivered, limiting the amount of heat delivered to the prostate. In this report, we describe the novel use of virtual reality distraction as an adjunctive mechanism for local anesthesia during TUMT in a 67-year-old man. This report is novel in being, to our knowledge, the first to demonstrate the efficacy of virtual reality in an elderly patient and the first documented use for a urologic clinic procedure. We believe it is also the first to demonstrate efficacy for the control of thermally induced pain.