Cardiovascular disease risk assessment and multidisciplinary care in prostate cancer treatment with ADT: recommendations from the APMA PCCV expert network.

PURPOSE: Androgen deprivation therapy (ADT) is the mainstay approach for prostate cancer (PCa) management. However, the most commonly used ADT modality, gonadotropin-releasing hormone (GnRH) agonists, has been associated with an increased risk of cardiovascular disease (CVD). METHODS: The PCa Cardiovascular (PCCV) Expert Network, consisting of multinational urologists, cardiologists and oncologists with expertise in managing PCa, convened to discuss challenges to routine cardiovascular risk assessment in PCa management, as well as how to mitigate such risks in the current treatment landscape. RESULTS: The experts identified several barriers, including lack of awareness, time constraints, challenges in implementing risk assessment tools and difficulties in establishing multidisciplinary teams that include cardiologists. The experts subsequently provided practical recommendations to improve cardio-oncology care for patients with PCa receiving ADT, such as simplifying cardiovascular risk assessment, individualising treatment based on CVD risk categories, establishing multidisciplinary teams and referral networks and fostering active patient engagement. A streamlined cardiovascular risk-stratification tool and a referral/management guide were developed for seamless integration into urologists' practices and presented herein. The PCCV Expert Network agreed that currently available evidence indicates that GnRH antagonists are associated with a lower risk of CVD than that of GnRH agonists and that GnRH antagonists are preferred for patients with PCa and a high CVD risk. CONCLUSION: In summary, this article provides insights and guidance to improve management for patients with PCa undergoing ADT.

[Retrospective SHI (Statutory Health Insurances) real-world study on initial GnRH antagonist and agonist therapy for advanced prostate cancer: prescription patterns and hospital costs in Germany]. / Retrospektive GKV-Versorgungsforschungsstudie über GnRH-Antagonisten/-Agonisten zur initialen Therapie des fortgeschrittenen Prostatakarzinoms ­ Verordnungsmuster und Krankenhauskosten in Deutschland.

INTRODUCTION: Androgen deprivation therapy (ADT) plays a pivotal role in the treatment of advanced or metastasised prostate cancer (PCa). The aim of this health services research was to compare real-world data on the initial use of different GnRH agonists and antagonists (GnRHa) with regard to prescription patterns, hospitalisation rates and costs. MATERIAL AND METHODS: Anonymised claims data from > 70 German health insurance funds between 2010 and 2015 (n = 4 205 227) were analysed (1 year pre-observation period, 1 index quarter with initial GnRHa prescription, ≥ 2 years of follow-up (FU)). RESULTS: The study population included 2382 PCa patients (mean age 75 years). Leuprolide (Leu) was prescribed most frequently (56.6 %). At initial GnRHa administration, 70 % of patients neither had lymph node nor distant metastases. Around 11.2 % of all patients stopped GnRHa treatment after the first prescription, 17.6 % switched their initial therapy to another substance after a mean of 457 days (median: 399 days); in the hybrid (hyb) group 100 days earlier on average than in the agonist group (p = 0.016). The prevalence ranking of the most common comorbidities was consistent over time: hypertension, hyperlipidaemia, cardiovascular disease (CVD) and diabetes. The prevalence of hypertension increased significantly in the agonist group (16.4 %) compared with the antagonist (6.9 %, p = 0.022) and hyb group (11.6 %, p = 0.006). With regard to CVD, there were no significant differences in the relative growth rate between the 3 combined therapy classes. In total, 23.9 % of all patients died within the 3-year FU. The mortality rate was lowest for triptorelin (Trp, 22.1 %) and highest for goserelin (Gos, 29.4 %, n.s.). In the index quarter, 26.4 % of patients had at least one inpatient hospitalisation [min-max: Trp 22.4 %; Gos 30.3 %], with an average length of hospital stay/patient of 3 days [Trp 2.4; Gos 4.5]. The annual hospitalisation rate was between 36.2 and 40.7 %, the average length of hospital stay in the entire FU was between 17.6 (Trp) and 20.8 days (hyb). The average hospital costs in the index quarter were approx. EUR 1200 [Trp 988; Gos 1803] and per FU year approx. EUR 3000. In the Trp cohort, total costs (index quarter + 3 years) were more than EUR 1000 below the average costs of EUR 9476 [Trp 8116; Leu 9779; n.s.]. CONCLUSION: This comparative retrospective analysis provides real-world information on initial GnRHa treatment for advanced prostate cancer, revealing differences in treatment patterns, hospitalisation rates and hospital costs in Germany.

Assessment of the Safety of Glucocorticoid Regimens in Combination With Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer: A Randomized, Open-label Phase 2 Study.

IMPORTANCE: Abiraterone acetate is combined with prednisone, 5 mg, twice daily for metastatic castration-resistant prostate cancer (mCRPC) and with prednisone, 5 mg, once daily for newly diagnosed, high-risk, metastatic castration-sensitive prostate cancer. Understanding the physiological effects of these and other regimens is important. OBJECTIVE: To evaluate the safety of abiraterone acetate with 4 glucocorticoid regimens. DESIGN, SETTING, AND PARTICIPANTS: Open-label, randomized clinical trial (1:1:1:1) of 164 men with mCRPC from 22 hospitals in 5 countries who were randomly assigned to 1 of 4 intervention groups between June 2013 and October 2014. Analyses were conducted from August 2017 to June 2018. INTERVENTIONS: Abiraterone acetate, 1000 mg, once daily with prednisone, 5 mg, twice daily (n = 41), 5 mg once daily (n = 41), 2.5 mg twice daily (n = 40), or dexamethasone, 0.5 mg, once daily (n = 42). MAIN OUTCOMES AND MEASURES: Primary end point was no mineralocorticoid excess (grade ≥1 hypokalemia or grade ≥2 hypertension) through 24 weeks (6 cycles) from treatment. RESULTS: Of 164 men (median [range] age, 70 [50-90] years) randomized to receive abiraterone acetate, 1000 mg, daily with prednisone, 5 mg, twice daily, once daily, or 2.5 mg twice daily, or dexamethasone, 0.5 mg, once daily, 24 (70.6%) of 34 patients (95% CI, 53.8%-83.2%), 14 (36.8%) of 38 patients (95% CI, 23.4%-52.7%), 21 (60.0%) of 35 patients (95% CI, 43.6%-74.4%), and 26 (70.3%) of 37 patients (95% CI, 54.2%-82.5%), respectively, had no mineralocorticoid excess. Plasma adrenocorticotrophic hormone and urinary mineralocorticoid metabolites after 8 weeks were higher with prednisone, 2.5 mg, twice daily and 5 mg once daily than with 5 mg twice daily or dexamethasone, 0.5 mg, once daily. The level of urinary glucocorticoid metabolites appeared higher in patients who did not meet the primary end point, regardless of glucocorticoid regimen. Total lean body mass decreased in the prednisone groups and total body fat increased in the prednisone, 5 mg, twice daily and dexamethasone groups. In the dexamethasone group, there was an increase in serum insulin and homeostatic model assessment of insulin resistance, while total bone mineral density decreased. In the prednisone, 5 mg, twice daily, 5 mg once daily, 2.5 mg twice daily, and dexamethasone groups, median radiographic progression-free survival was 18.5, 15.3, 12.8, and 26.6 months, respectively. CONCLUSIONS AND RELEVANCE: Abiraterone acetate with prednisone, 5 mg, twice daily or dexamethasone, 0.5 mg, once daily met the prespecified threshold for the primary end point (95% CI excluded 50% mineralocorticoid excess); abiraterone acetate with prednisone, 5 mg, once daily or 2.5 mg twice daily did not meet the threshold. Abiraterone acetate in combination with dexamethasone appeared to be particularly active but may be associated with adverse metabolic consequences. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01867710.

Calgranulin A (S100A8) Immunostaining: A Future Candidate for Risk Assessment in Patients with Non-Muscle-Invasive Bladder Cancer (NMIBC).

INTRODUCTION: There is an urgent need to identify patients with bladder cancer (BC) who are at high risk of recurrence or progression. Calgranulin A is a strong marker for muscle-invasive or advanced BC and recent studies have shown its potential for identifying patients at risk even in non-muscle-invasive bladder cancer (NMIBC). The present study examines risks of recurrence and progression dependent on immunostaining with calgranulin A in NMIBC. METHODS: Calgranulin A protein expression was evaluated through the immunohistochemistry of 158 randomly selected, transurethrally resected BC specimens of separate patients (pTa 89, pT1 69) using tissue microarrays. Kaplan-Meier survival analysis and Cox regression were performed to determine whether calgranulin A expression is associated with recurrence-free survival (RFS), progression-free survival (PFS), or cancer-specific survival (CSS). RESULTS: Calgranulin A expression is significantly different between pTa and pT1 tumors (p = 0.000, Mann-Whitney U test) and between tumor grades (p = 0.015, Kruskal-Wallis test). Kaplan-Meier estimates produced significant results for low and high calgranulin A expression concerning RFS [5y-RFS 70.4 ± 4.0% vs. 35.9 ± 12.5%, median RFS not reached (NR) vs. 12.0 ± 4.4 month, p = 0.029, log-rank test], PFS (5y-PFS 90.3 ± 2.7% vs. 51.5 ± 14.0%, median PFS NR in both groups, p = 0.000, log-rank test), and CSS (5y-CSS 92.9 ± 2.6% vs. 70.7 ± 12.4%, median CSS NR in both groups, p = 0.005, log-rank test). Calgranulin A remained an independent factor for RFS (p = 0.024, HR 2.43) and PFS (p = 0.002, HR 5.92) according to the multivariate Cox regression model. CONCLUSIONS: Calgranulin A expression in NMIBC, detected through immunohistochemistry, is a promising marker for the identification of NMIBC patients at high risk of recurrence and progression.

Steep Infundibulopelvic Angle as a New Risk Factor for Flexible Ureteroscope Damage and Complicated Postoperative Course.

OBJECTIVE: The increasing number of flexible ureterorenoscopy (fURS) procedures, the fragility of devices, and their growing repair costs represent a substantial burden for urological departments worldwide. No risk factors of flexible ureteroscope damage have been identified so far. The objective of this study was to investigate the impact of infundibulopelvic angle (IPA) on device damage and on other intraoperative and postoperative factors such as length of hospital stay, surgical complications, stone-free rate (SFR), operation, and fluoroscopy time. MATERIALS AND METHODS: In a retrospective monocentric study, IPA was measured based on intraoperative retrograde pyelography images taken during fURS. All procedures were conducted with modern reusable flexible ureteroscopes: Karl Storz Flex-X2 or Olympus URF-V. Statistical analysis was performed in RStudio (version 1.0.136) with the unpaired t-test and Mann-Whitney U test. Pearson correlation coefficient (Pearson's r) was measured whenever applicable. RESULTS: In total, 381 fURS performed between September 2013 and March 2017 were analyzed: 260 (68.24%) for kidney stone operation and 121 (31.76%) for diagnostic purposes; of these, 38 (9.97%) devices were postoperatively deemed defective. IPA values were significantly steeper in cases with flexible ureteroscope damage compared to cases without damage (median 42.5 degrees vs 56.0, p < 0.001). Steeper IPA was significantly associated with the occurrence of Clavien-Dindo ≥2 complications (median 51.0 degrees vs 55.0, p = 0.005) as well as prolonged hospital stay (median 51.0 degrees vs 55.0, p = 0.014). No influence on SFR was observed (p > 0.05). IPA did not correlate with operation or fluoroscopy time. CONCLUSIONS: Steep IPA can be considered the first risk factor predicting both flexible ureteroscope damage and an unfavorable postoperative course. A better understanding of damage mechanisms is the key for the proper indications to use costly single-use devices.

Retrospective Cost Analysis of a Single-Center Reusable Flexible Ureterorenoscopy Program: A Comparative Cost Simulation of Disposable fURS as an Alternative.

OBJECTIVE: The increasing number of flexible ureterorenoscopy (fURS) procedures, the fragility of devices, and their growing maintenance and repair costs represent a substantial burden for urologic departments. Disposable single-use fURS devices offer many advantages over reusable fURS. Among them, the LithoVue™ model shows the best clinical utility. In our study, we assessed the economic aspects of reusable fURS application compared with the potential costs and benefits of single-use fURS (LithoVue™). Indications for single-use fURS were proposed based on potential risk factors of reusable fURS damage. MATERIALS AND METHODS: This single-center retrospective analysis compared the actual cost of reusable fURS procedures with the potential costs of LithoVue™ based on the price offered by the manufacturer. Consecutive case analysis of damaged fURS was performed to determine potential risk factors associated with fURS damage. RESULTS: The study group consisted of 423 reusable fURS procedures conducted between January 2013 and December 2016. During this period, 102 (24.11%) diagnostic fURS and 321 (75.89%) fURS for kidney stone therapy were performed. In 32 of 423 (7.57%) fURS cases, devices were postoperatively deemed defective, 9 of which were used for diagnostic procedures (9/102; 8.82%), 7 for stone removal (7/148; 4.73%), and 16 for stone removal and laser (Ho:YAG) application (16/173; 9.25%). The average cost per reusable fURS procedure was found to be €503.26. CONCLUSIONS: Disposable fURS is a more expensive option for high-volume centers. Based on our case analysis, laser disintegration treatment of multiple, large stones in the lower kidney pole of recurrent stone formers, as well as a steep infundibulopelvic angle (IPA ≤50°), seems to be the main risk factor for fURS damage. For these cases, disposable fURS may be a cost-effective alternative; however, a prospective comparison of economic outcomes between disposable and reusable fURS, together with confirmation of the proposed damage risk factors, is needed.

68Ga-PSMA I&T PET/CT for assessment of prostate cancer: evaluation of image quality after forced diuresis and delayed imaging.

OBJECTIVE: Urinary radiotracer excretion of 68Ga-Labelled prostate-specific membrane antigen (PSMA) ligands may complicate the assessment of the prostate region and differentiation of lymph nodes from ureteral activity. The aim of this study was to assess the value of delayed imaging after forced diuresis. MATERIALS AND METHODS: Sixty-six patients underwent 68Ga-PSMA I&T PET/CT for evaluation of prostate cancer at 60 min post-injection. In subgroups of patients, this was amended by delayed imaging after 180 min post-injection, preceded by furosemide and oral hydration early, at the time of tracer injection, or delayed, at 100 min post-injection. Urinary tracer activity within the bladder and focal ureteral activity was analyzed. RESULTS: After forced diuresis, linear and focal visualization of ureters was significantly reduced. After delayed furosemide, mean and peak bladder activity decreased (p < 0.001), and image quality of the prostate region improved on delayed images (p < 0.001). Early furosemide co-injection with tracer resulted in increased mean and peak bladder activity (p < 0.001) and in deteriorated image quality of the prostate region on delayed images (p = 0.008). CONCLUSION: Ga-PSMA I&T PET/CT delayed imaging after forced diuresis can improve the assessment of prostate region and pelvic lymph nodes by removing excreted tracer from the lower urinary tract. KEY POINTS: • Forced diuresis can improve image quality in 68 Ga-PSMA I&T. • After forced diuresis, linear and focal visualization of ureters was reduced. • Timing of diuresis relative to 68 Ga-PSMA I&T injection is important. • Early furosemide co-injection with tracer resulted in deteriorated image quality on delayed images. • After delayed furosemide, image quality improved on delayed images.

Treatment costs for advanced prostate cancer using luteinizing hormone-releasing hormone agonists: a solid biodegradable leuprorelin implant versus other formulations.

AIM: To compare treatment costs with alternative luteinizing hormone-releasing hormone (LHRH) agonist preparations and determine whether a leuprorelin solid implant is associated with potential cost savings. PATIENTS & METHODS: A hypothetical population of 1000 prostate cancer patients was apportioned between the three most commonly-prescribed LHRH agonist preparations. Differentiated annual costs for 1- and 3-monthly formulations were calculated for France, Germany, Italy, Spain, the UK (EU5) and Sweden, and compared with the leuprorelin solid implant. RESULTS: Compared with alternative formulations, leuprorelin solid implants had potential annual cost savings/1000 patients of €353,000 (EU5) and €699,000 (Sweden; 1-month formulations), and €259,000 (EU5) and €300,000 (Sweden; 3-month formulations). CONCLUSION: The leuprorelin solid implant was associated with potential cost savings compared with the most commonly used LHRH agonist preparations.

Bladder preserving strategies for muscle-invasive bladder cancer.

PURPOSE OF REVIEW: On average 20-30% of patients with non muscle-invasive bladder cancer will subsequently develop muscle-invasive disease with approximately 50% of the patients already bearing occult regional or distant metastases at that time. Few interdisciplinary centres are demonstrating multimodality bladder sparing approaches as equally effective when compared with radical cystectomy for muscle-invasive bladder cancer. RECENT FINDINGS: So far no investigation could demonstrate prospective controlled data on long-term oncologic and functional outcomes comparing bladder-conserving strategies with radical cystectomy. It is evident that multimodality treatment regimens including a thoroughly performed transurethral resection of the bladder tumour, external beam radiation therapy, and chemotherapy can produce an increased amount of total costs in addition to the prolonged hospitalization of the patient during a trimodality bladder sparing approach. Therefore, in addition to the long-term oncological and functional outcome, the high costs of this approach together with the need for a very close cooperation between clinical disciplines and a highly compliant patient have to be taken in consideration. SUMMARY: Without prospective controlled trials evaluating the long-term oncological results and the health-related quality of life for the multimodality treatment regimen for muscle-invasive bladder cancer, the radical surgical approach should still be considered as the standard treatment. Multimodality bladder preserving strategies might be a therapeutic option for carefully selected patients.