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.

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.

Practice Patterns for Women With Overactive Bladder Syndrome: Time Between Medications and Third-Line Treatments.

OBJECTIVE: The aims of this study are to determine how long it takes female patients with overactive bladder (OAB) to receive third-line treatment after starting OAB medications and identify factors associated with increased time. METHODS: This was a retrospective observational cohort study of adult female patients with OAB who received third-line treatment between 2013 and 2015 using insurance claims databases. Primary outcome was time between first OAB medication and first third-line treatment. Additional variables were patient demographics, diagnostic tests, and medical comorbidities. RESULTS: Of 3232 patients included in this study, 48.8% underwent sacral neuromodulation, 31.6% percutaneous tibial nerve stimulation, and 23% intradetrusor onabotulinumtoxin A injections. Twenty-one percent of patients filled medication prescriptions for 3 or more antimuscarinic medications, 30.4% took mirabegron, and 32.3% had advanced diagnostic tests suggestive of a specialist evaluation prior to starting medications. Median time to third-line treatment was 37.7 (interquartile range, 14.9, 16.3) months. Adjusted linear regression model revealed 2 predominant predictors of time to third-line treatments: each antimuscarinic medication trial was associated with 5.3 (95% confidence interval, 4.4-6.3) more months before third-line treatment (P < 0.001), and advanced diagnostic evaluations prior to starting medications were associated with 28.2 (95% confidence interval, 21-35) fewer months before third-line treatment (P < 0.001). CONCLUSIONS: Women with OAB who undergo third-line therapy do so on average more than 3 years after starting medications. Time to third-line treatment is largely driven by the number of antimuscarinic medications tried and timing of diagnostic evaluation by a specialist. Based on these results, we suggest providers consider limiting antimuscarinic trials to 2 medications prior to moving on to other treatment options.

Hospital-level Variation in the Quality of Benign Inpatient Urologic Surgery.

OBJECTIVE: To examine hospital-level variation in outcomes following benign urologic surgeries given that hospital-level variation in surgical outcomes can portend quality and appropriateness of care concerns and identify quality improvement opportunities in perioperative care. MATERIALS AND METHODS: Using the Washington State Comprehensive Hospital Abstract Reporting System, we identified patients who underwent transurethral resection of the prostate (TURP), percutaneous nephrostolithotomy (PCNL), and pyeloplasty from 2003 to 2008. We classified prolonged postoperative length of stay (LOS) as that exceeding the 75th percentile, and we measured the rate of Agency for Healthcare Quality Patient Safety Indicators, readmissions, and death. We calculated hospital-specific observed-to-expected event rates using random effects multilevel multivariable models adjusted for age and comorbidity. RESULTS: We identified 6699 TURP patients at 54 hospitals, 2541 PCNL patients at 45 hospitals, and 584 pyeloplasty patients at 36 hospitals. Complication rates were highest after PCNL (22.9% prolonged LOS vs 17.3% for TURP and 13.9% for pyeloplasty, P < .001; 3.4% 90-day mortality vs 0.6% for TURP and 0% for pyeloplasty). Hospital-level variation was most substantial for LOS after TURP and pyeloplasty (8.1% and 14.3% of variance in prolonged LOS, respectively). CONCLUSION: Hospital-level variation is common after benign inpatient urologic surgeries and may relate to difference in perioperative provider practice patterns. The morbidity of PCNL in this study was higher than expected and merits further investigation.

The burden of bladder cancer care: direct and indirect costs.

PURPOSE OF REVIEW: Bladder cancer is a common, complex, and costly disease. Every year in the USA, bladder cancer is responsible for 70 ,000 diagnosed cases and over 15, 000 deaths. Once diagnosed, patients with nonmuscle invasive bladder cancer (NMIBC) are committed to a lifetime of invasive procedures and potential hospitalizations that result in substantial direct and indirect costs. RECENT FINDINGS: Bladder cancer is the most costly cancer among the elderly, estimated at nearly $4 billion per year, and has the highest cost of any cancer when categorized on a per patient basis. The direct economic cost of NMIBC is fueled by the need for lifelong cystoscopic examination and variations in treatment algorithms. This fiscal burden is further compounded by the indirect impact on psychological health and quality of life of patients and their families. Despite the development of new technologies, such as novel urinary biomarkers and innovative cystoscopic methods, no alternative to cystoscopic surveillance has been established. SUMMARY: The management of patients with NMIBC is responsible for a substantial financial burden with indirect costs that extend beyond quantifiable direct costs.

Implementation of a "real-world" learning health care system: Washington State's Comparative Effectiveness Research Translation Network (CERTAIN).

BACKGROUND: Learning health care systems apply the experiences of prior patients to inform care and help to guide decision making for current patients. These systems should help to deliver more effective, efficient, and appropriate care. Most examples of learning systems derive from integrated care delivery systems and examples of such systems in the community at large have been lacking. METHODS: The comparative effectiveness research translation network (CERTAIN) is a learning system bringing together hospitals and outpatient clinics across Washington State. CERTAIN leverages existing medical record-based data collection taking place at nearly all statewide hospitals and links this data collection with patient-reported information about function and quality of life. RESULTS: We have described the components of the CERTAIN infrastructure, the elements of a pilot project evaluating treatments of claudication, and the opportunities and challenges of developing and implementing a "real world" learning system. Examples in the areas of vascular disease, spine care, gastrointestinal disease, and urology. CONCLUSION: Learning health care systems face many operational challenges but hold great promise for discovery and implementation of more effective clinical practices.

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.

Mental health of low income uninsured men with prostate cancer.

PURPOSE: We evaluated mental health outcomes in a cohort of low income, uninsured men with prostate cancer and identified factors that influence mental health. MATERIALS AND METHODS: We performed a retrospective cohort study of 277 subjects enrolled in a program that provides free care to men with prostate cancer who have an annual income of no more than 200% of the federal poverty level. We compared scores on the 5-item RAND Mental Health Inventory (MHI-5) to those in individuals with other chronic diseases. We also examined the relationship between MHI-5 scores and validated measures of general and disease specific health related quality of life. Disease specific quality of life included measures of distress related to urinary, sexual and bowel habits. Multivariate analyses were performed to evaluate factors associated with mental health score. RESULTS: Most men studied were Hispanic (51.6%) and had at most a high school education (85.9%). Mean MHI-5 score +/- SD was 68 +/- 23 on a 100-point scale, significantly worse than cohorts of men with diabetes, congestive heart failure and chronic pulmonary disease. Hispanic ethnicity, urinary bother and bowel bother were negatively associated with mental health. Spirituality and physical functioning were positively associated with mental health. CONCLUSIONS: Economically disadvantaged men with prostate cancer report worse mental health than people with other chronic diseases. Patients especially at risk are those with significant urinary or bowel distress, poor physical health, low spirituality and Hispanic ethnicity.