Use of statins and prostate cancer recurrence among patients treated with radical prostatectomy.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Statins have shown broad spectrum anti-cancer properties in laboratory studies. In epidemiological studies, use of statins has been associated with reduced risk of advanced prostate cancer. However, the effects of statins on prostate cancer disease progression following curative treatment have not been extensively studied, and previous studies reported conflicting results. This study found no clear association between overall statin use and risk of disease progression, as well as lack of a monotone dose-response relationship between the use of statins, whether it was use before or after prostatectomy, and prostate cancer disease progression. OBJECTIVE: To investigate whether use of HMG-CoA reductase inhibitors ('statins'), which have shown broad spectrum anti-cancer properties in laboratory studies, is associated with a reduced risk of recurrence in patients with prostate cancer who undergo radical prostatectomy. PATIENTS AND METHODS: All men with incident prostate cancer diagnosed between 2004 and 2005 who subsequently underwent radical prostatectomy by the end of 2005 in the Kaiser Permanente Southern California (KPSC) health plan were identified using KPSC's cancer registry. Subjects were followed for up to 5 years after prostatectomy for (i) biochemical recurrence, defined as a single PSA measurement >0.2 ng/mL, and (ii) clinical disease progression, defined as diagnosis of metastatic disease or prostate-cancer-related death. Information on statin use, demographics, comorbidities, patho-clinical factors and outcomes were ascertained from KPSC's electronic medical records. The effects of statin use prior to and after prostatectomy were both examined using bivariate and multivariate Cox models, adjusting for known prognostic factors. For postoperative statin exposure, a time-dependent Cox model was used. RESULTS: A total of 1200 men were included; 37% had preoperative and 56% had postoperative statin use. Neither preoperative nor postoperative statin use was associated with biochemical recurrence (hazard ratio [HR] = 1.00 [0.72-1.39] and 1.05 [0.76-1.46], respectively) or clinical disease progression (HR = 0.63 [0.31-1.27] and 1.20 [0.63-2.30], respectively). No clear dose-response relationship was found for duration of use. CONCLUSIONS: Statin use may not prevent prostate cancer progression following radical prostatectomy. These findings do not provide support for the pursuit of a prospective clinical trial of statin use as a secondary prevention among surgically treated patients with prostate cancer.

Disparities in Stage at Diagnosis in an Equal-access Integrated Delivery System: A Retrospective Cohort Study of 7244 Patients With Bladder Cancer.

BACKGROUND: Disparities in bladder cancer survival by race/ethnicity and gender are likely related to differences in diagnosis. We assessed disparities in stage at diagnosis and potential contributing factors within a large, integrated delivery system. PATIENTS AND METHODS: We conducted a retrospective cohort study of 7244 patients with bladder cancer age ≥ 21 years diagnosed from January 2001 to June 2015 within Kaiser Permanente Southern California. Bivariate analyses compared stage at diagnosis - as well as comorbidities, health plan membership length, and health care utilization prior to diagnosis - by race/ethnicity, gender, and age. Multivariable generalized linear mixed models with urologist as a random effect were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for diagnosis of muscle-invasive bladder cancer (MIBC) versus non-muscle-invasive bladder cancer. RESULTS: In multivariable analyses, stage at diagnosis varied significantly by race/ethnicity (P < .001). Non-Hispanic black patients had significantly higher odds of being diagnosed with MIBC than non-Hispanic white patients (OR, 1.33; 95% CI, 1.05-1.67), whereas Asian patients had significantly lower odds (OR, 0.67; 95% CI, 0.49-0.91). Women were significantly more likely to be diagnosed with MIBC than men (OR, 1.40; 95% CI, 1.22-1.61). Non-Hispanic black women had the highest proportion (39%) of MIBC diagnoses. Among Hispanic and Asian patients, a greater proportion of diagnoses occurred at younger ages. CONCLUSIONS: Health care coverage within an equal-access system did not eliminate disparities in stage at diagnosis by race/ethnicity or gender. Studies are needed to identify etiologic factors and aspects of care delivery (eg, patient-physician interactions) that may affect the diagnostic process to inform efforts to improve health equity.

Salvage Cryoablation for Radiorecurrent Prostate Cancer: Initial Experience at a Regional Health Care System.

CONTEXT: Local recurrence after radiotherapy for prostate cancer remains challenging to treat effectively. Although oncologic control is highest with salvage prostatectomy, the procedure is associated with substantial morbidity. OBJECTIVE: To identify factors associated with successful salvage cryoablation for radiorecurrent prostate cancer. DESIGN: We retrospectively reviewed the medical records of patients who underwent salvage cryoablation at our institution between 2005 and 2015. All patients had biopsy-proven local recurrence after radiotherapy. Patients with seminal vesicle invasion or metastases were excluded. Complete follow-up was obtained for all patients. MAIN OUTCOME MEASURES: Primary study endpoint was biochemical progression-free survival based on the Phoenix criteria. RESULTS: Seventy-five patients underwent salvage cryotherapy. Mean patient age was 69.3 years. The overall biochemical salvage rate was 50.7% at a median follow-up of 3.9 years. The following factors were independently associated with successful cryotherapy: Precryotherapy Gleason score of 3 + 3 or 3 + 4, low precryotherapy prostate-specific antigen (PSA), low precryotherapy PSA density, longer time to PSA nadir after radiotherapy, and low postcryotherapy PSA nadir. A postcryotherapy PSA nadir of 0.5 ng/mL or less was associated with a biochemical progression-free survival of 79.7% at 3 years and 64.7% at 5 years, whereas a postcryotherapy PSA nadir above 0.5 was associated with a biochemical progression-free survival of 5.6% at 3 years and 0% at 5 years (p < 0.0001). CONCLUSION: Approximately 50% of the patients achieved biochemical salvage with cryoablation at 5 years. Nadir PSA after salvage was the strongest predictor of biochemical progression-free survival in our cohort.

Care Quality and Variability in the Use of Intravesical Therapy for Initial Treatment of Nonmuscle Invasive Bladder Cancer Within a Large, Diverse Integrated Delivery System.

OBJECTIVES: To examine treatment variability, disparities, and quality among newly diagnosed nonmuscle invasive bladder cancer (NMIBC) patients, and to identify factors associated with treatment use in a large, diverse integrated delivery system. METHODS: Retrospective cohort study of 5386 NMIBC patients diagnosed between January 2001 and June 2015 within Kaiser Permanente Southern California. Electronic health data were used to identify treatment outcomes and patient, provider, and tumor characteristics. Outcomes were use of (1) postoperative intravesical chemotherapy, (2) induction Bacille Calmette-Guérin (BCG) immunotherapy, and (3) any intravesical therapy. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using generalized linear mixed models with a binary outcome and urologist as a random effect. RESULTS: From 2001 to 2015, 41% of newly diagnosed NMIBC patients were treated with intravesical therapy. Postoperative chemotherapy use increased significantly over this period (OR per-year = 1.16, 95% CI: 1.07-1.25). BCG use was strongly associated with tumor characteristics: patients with high-grade or carcinoma in situ tumors were more likely to receive BCG (OR = 10.10, 95% CI: 8.39-12.16). Few treatment differences were found by sex or race/ethnicity, but were observed by age. Wide treatment variability across urologists was observed, with some urologists never using intravesical therapy as part of initial treatment while others almost always used it. Differences across urologists accounted for more variability in postoperative chemotherapy (intraclass correlation coefficient = 0.52) than BCG immunotherapy (intraclass correlation coefficient = 0.11) use. CONCLUSION: Substantial variability in initial treatment of NMIBC was observed across urologists, accounting for tumor, patient, and provider characteristics. Results suggest a considerable opportunity for quality improvement programs to reduce unwanted treatment variability and improve care for patients.

Factors That Influence Selectionof Urinary Diversion Among Bladder Cancer Patients in 3 Community-based Integrated Health Care Systems.

OBJECTIVE: To assess the relative contributions of patient and surgeon factors for predicting selection of ileal conduit (IC), neobladder (NB), or continent pouch (CP) urinary diversions (UD) for patients diagnosed with muscle-invasive/high-risk nonmuscle invasive bladder cancer. This information is needed to enhance research comparing cancer survivors' outcomes across different surgical treatment options. METHODS: Bladder cancer patients' age ≥21 years with cystectomy/UD performed from January 2010 to June 2015 in 3 Kaiser Permanente regions were included. All patient and surgeon data were obtained from electronic health records. A mixed effects logistic regression model was used treating surgeon as a random effect and region as a fixed effect. RESULTS: Of 991 eligible patients, 794 (80%) received IC. One hundred sixty-nine surgeons performed the surgeries and accounted for a sizeable proportion of the variability in patient receipt of UD (intraclass correlation coefficient = 0.26). The multilevel model with only patient factors showed good fit (area under the curve = 0.93, Hosmer-Lemeshow test P = .44), and older age, female sex, estimated glomerular filtration rate <45, 4+ comorbidity index score, and stage III/IV tumors were associated with higher odds of receiving an IC vs neobladder/continent pouch. However, including surgeon factors (annual cystectomy volume, specialty training, clinical tenure) had no association (P = .29). CONCLUSION: In this community setting, patient factors were major predictors of UD received. Surgeons also played a substantial role, yet clinical training and experience were not major predictors. Surgeon factors such as beliefs about UD options and outcomes should be explored.

Achieving proficiency with robot-assisted radical prostatectomy: Laparoscopic-trained versus robotics-trained surgeons.

BACKGROUND: Initiating a robotics program is complex, in regards to achieving favourable outcomes, effectively utilizing an expensive surgical tool, and granting console privileges to surgeons. We report the implementation of a community-based robotics program among minimally-invasive surgery (MIS) urologists with and without formal robotics training. METHODS: From August 2008 to December 2010 at Kaiser Permanente Southern California, 2 groups of urologists performing robot-assisted radical prostatectomy (RARP) were followed since the time of robot acquisition at a single institution. The robotics group included 4 surgeons with formal robotics training and the laparoscopic group with another 4 surgeons who were robot-naïve, but skilled in laparoscopy. The laparoscopic group underwent an initial 7-day mentorship period. Surgical proficiency was measured by various operative and pathological outcome variables. Data were evaluated using comparative statistics and multivariate analysis. RESULTS: A total of 420 and 549 RARPs were performed by the robotics and laparoscopic groups, respectively. Operative times were longer in the laparoscopic group (p = 0.002), but estimated blood loss was similar. The robotics group had a significantly better overall positive surgical margin rate of 19.9% compared to the laparoscopic group (27.8%) (p = 0.005). Both groups showed improvements in operative and pathological parameters as they accrued experience, and achieved similar results towards the end of the study. CONCLUSIONS: Robot-naïve laparoscopic surgeons may achieve similar outcomes to robotic surgeons relatively early after a graduated mentorship period. This study may apply to a community-based practice in which multiple urologists with varied training backgrounds are granted robot privileges.

Statin therapy is not associated with prostate cancer recurrence among patients who underwent radiation therapy.

We investigated whether statin use is associated with reduced risk of recurrence in prostate cancer patients who undergo radiotherapy. A retrospective cohort of 774 patients from a California health plan was followed for 5 years. Statin use prior to, during and after radiotherapy was not associated with prostate cancer recurrence [hazard ratio=0.99 (0.70-1.39), 0.87 (0.62-1.22) and 0.78 (0.55-1.09), respectively] in multivariable Cox models. No clear dose-response relationship was observed for average daily statin dose or duration of statin use. Our findings do not support a preventive benefit of statins in prostate cancer recurrence after radiotherapy.

Black men have lower rates than white men of biochemical failure with primary androgen-deprivation therapy.

INTRODUCTION: Black men have a higher incidence of advanced stage at diagnosis and mortality from prostate cancer than do men in other racial groups. Given that androgen-deprivation therapy (ADT) is one of the mainstays of treatment for advanced prostate cancer, we investigated the development of biochemical failure, or recurrence of elevated prostate-specific antigen (PSA) levels, among different races in men receiving ADT. METHODS: Patients with prostate cancer who received ADT in the Kaiser Permanente Southern California Cancer Registry between January 2003 and December 2006 were eligible for inclusion in our study. Patients who had prior treatment for their cancer with surgery or radiation were excluded. Treatment failure was defined as an increase in PSA of >2 ng/mL from PSA nadir, with no subsequent decrease in PSA. We compared the biochemical failure rate in white patients to those in black, Hispanic, and Asian/other patients. The Cox proportional hazards regression model was used to estimate hazards ratios. RESULTS: Our study population consisted of 681 patients: 416 (61%) were white; 107 (16%) were black; 107 (16%) were Hispanic; and 51 (7%) were Asian or another race. After we controlled for all demographic variables and for variables related to prostate cancer, blacks were the only group with a lower risk of treatment failure compared with whites. The hazard ratios for treatment failure were as follows: black versus white, 0.66 (p = 0.03); Hispanic versus white, 1.00 (p = 0.8); Asian/other race versus white, 1.5 (p = 0.1). In this multivariate analysis, pretreatment PSA level and cancer stage were the only other variables associated with a higher risk of treatment failure. CONCLUSION: Among patients receiving ADT as primary monotherapy for prostate cancer, blacks may have a lower rate of biochemical failure compared with whites. Although the etiology of this finding is unclear, it suggests the possibility that prostate cancer in black men may be more androgen sensitive than it is in white men.

Early development of castrate resistance varies with different dosing regimens of luteinizing hormone releasing hormone agonist in primary hormonal therapy for prostate cancer.

OBJECTIVES: Luteinizing hormone releasing hormone (LHRH) agonist therapy is one of the mainstays of prostate cancer treatment. Three dosing regimens currently exist: calendar-based, intermittent, and a testosterone (T)-based (T-based) regimen. We investigated the differences in development of early castrate resistance rates between these different regimens. METHODS: We evaluated 1617 patients with prostate cancer who received LHRH-agonist monotherapy in the Kaiser Permanente Southern California Cancer Registry between January 2003 and December 2006. Patients who had undergone surgery and/or radiation were excluded. Patients were grouped according to their dosing regimen: calendar-based, intermittent dosing, and T-based. Cox proportional hazard-regression analysis was used to estimate the hazards ratio (HR) for treatment failure. RESULTS: A total of 692 patients who received an LHRH agonist as primary monotherapy for prostate cancer fit our criteria. Calendar-based dosing was used in 325 patients; 252 received T-based dosing and 115 received intermittent dosing. On multivariate analysis controlling for demographic and prostate cancer-related variables, the T-based dosing group showed a significantly lower relative risk of treatment failure (HR = 0.65, P = .02). The intermittent-dosing group trended toward a lower risk treatment failure (HR = 0.80, P = .3). Among the variables analyzed, only a Gleason score >8 (HR = 2.05, P = .01) and a pretreatment prostate-specific antigen >20 (HR = 2.00, P <.01) were associated with a higher risk of treatment failure. CONCLUSIONS: During the time period studied, T-based and intermittent dosing regimen of LHRH agonist had lower rates of early castrate resistance compared with standard calendar dosing, based on measurements for early androgen resistance.

Impact of robotic training on surgical and pathologic outcomes during robot-assisted laparoscopic radical prostatectomy.

OBJECTIVES: To prospectively compare outcomes during robotic prostatectomy between surgeons with formal training in either robotic prostatectomy (RALP) or laparoscopic prostatectomy (LRP). METHODS: A total of 286 robotic prostatectomies were performed by 12 urologists between August 2008 and March 2009 as part of a new robotic surgery program at one of the largest health maintenance organizations in the United States. Four surgeons had formal training in RALP and 8 had formal training in LRP. We prospectively compared surgical and pathologic outcomes between these 2 groups of surgeons. RESULTS: The 4 RALP surgeons performed 121 RALPs and the 8 LRP surgeons performed 165 RALPs. Patient demographics were similar between groups. The robot-naive group had significantly more clinical stage T1c than the robot-trained group (87.9% vs 74.4%, P = .003). Prostatectomy parameters were similar between the 2 groups of surgeons in terms of prostate size, Gleason score, pathologic stage, and estimated blood loss. The robot-trained surgeons had significantly lower overall positive margin rates (24% vs 34.6%, P = .05) and lower margin rates in T3 tumors (38.5% vs 61.8%, P = .07), which were approximately statistically significant. There was no difference in margin rates in T2 tumors. The robot-trained surgeons had significantly lower apical margin rates (8.3% vs 21.2%, P = .003) and lateral margin rates (1.7% vs 7.3%, P = .05). The robot-trained surgeons had 10%-15% shorter procedure times. There was no difference in complication rates. CONCLUSIONS: Formal RALP training may be beneficial for surgical and pathologic outcomes of RALP compared with formal LRP training during the initial implementation of a new robotics program.

Rapid implementation of a robot-assisted prostatectomy program in a large health maintenance organization setting.

PURPOSE: We present the rapid implementation of a robot-assisted surgery program by one of the largest health maintenance organizations (HMOs) in the United States. MATERIALS AND METHODS: A core group of 10 urologists were offered access to a new da Vinci S surgical system. A core group of five ancillary staff was assembled and trained at an Intuitive Surgical-designated training site. An experienced robotic surgeon acted as a proctor. Data regarding patient demographics, preoperative parameters, operative times, pathologic outcomes, and EPIC-26 quality-of-life questionnaires were collected prospectively and reviewed. All procedures were recorded on digital video disc as part of a quality assurance protocol. The core group reviewed complications monthly and received feedback on surgical techniques and pathologic outcomes. RESULTS: A total of 100 robot-assisted laparoscopic radical prostatectomies were performed from August to October 2008. The patient demographics, preoperative parameters, operative times, and pathologic outcomes of these first 100 procedures are outlined. CONCLUSIONS: We demonstrate the rapid implementation of an efficient multisurgeon HMO-based robot-assisted prostatectomy program with promising initial outcomes.

Decision tree for laparoscopic partial nephrectomy versus laparoscopic renal cryoablation for small renal masses.

PURPOSE: We propose an algorithm to help guide surgeons' decisions between laparoscopic partial nephrectomy (LPN) and renal laparoscopic cryoablation (LCA) based on preoperative parameters and outcomes defined in the literature. PATIENTS AND METHODS: From July 2004 to December of 2007, we performed 51 LPNs and 22 LCAs. We formulated an algorithm between LPN and LCA based on outcomes from published series. Candidates for LPN are younger than 70 years; have few comorbidities; masses < or = 7 cm; and solitary, solid, and or cystic masses with an exophytic or mesophytic location. Candidates for LCA are 70 years old or older, with multiple comorbidities, masses < or = 3.5 cm, multiple masses, solid masses only, and include endophytic or hilar tumors. We then applied this decision tree to our series. RESULTS: Our results for LPN are statistically similar to the published series except there was a higher positive margin rate in our series (11.8 v 3.5%). Our LCA series had older patients (71 v 65 y), larger masses (3.2 v 2.5 cm), and a higher rate of bleeding necessitating transfusion (18%). We applied the algorithm to all 73 patients in our series. It estimated that 45 patients should undergo LPN and 28 should undergo LCA. A correlation between the predicted surgery and the surgery performed was seen, but approximately one in five patients would have a change in the surgery performed. CONCLUSIONS: This algorithm validates decisions surgeons are already making between LPN and LCA. While not a perfect model, it can be used to help simplify decisions between these two minimally invasive procedures to achieve optimal outcomes.

Determining dosing intervals for luteinizing hormone releasing hormone agonists based on serum testosterone levels: a prospective study.

PURPOSE: Long acting luteinizing hormone releasing hormone agonists are the predominant form of androgen suppression in the treatment of prostate cancer with the goal of maintaining castrate levels of testosterone. Current dosing of luteinizing hormone releasing hormone agonists does not include monitoring the end organ response of serum testosterone. Recent evidence suggests standard dosing regimens fail to achieve castrate levels of testosterone in some patients while in other patients testosterone can remain at castrate levels longer than the manufacturer recommended dosing interval. We prospectively evaluated patients with prostate cancer receiving luteinizing hormone releasing hormone agonist hormonal therapy to determine the length of time that serum testosterone remains at or below castrate levels. MATERIALS AND METHODS: A 3-month dose of 22.5 mg leuprolide was administered to all patients as a first dose followed by a second dose 3 months later. Serum testosterone and prostate specific antigen were measured prospectively before starting hormonal therapy, after the first dose (12 weeks) and again following the second dose (24 weeks) to assess if castrate levels of testosterone (50 ng/dl or less) had been reached. At 24 weeks if patient serum testosterone was 50 ng/dl or less, then 22.5 mg leuprolide were not administered, and serum testosterone and prostate specific antigen were checked monthly. When serum testosterone was greater than 50 ng/dl a subsequent dose of 22.5 mg leuprolide was given. Serum testosterone and prostate specific antigen were then checked 3 months later and monthly thereafter until testosterone was greater than 50 ng/dl. Thus, the time that testosterone remained at castrate levels could be accurately established. RESULTS: From February 2003 to August 2005, 42 patients were treated in this manner with a median followup of 18 months (range 10 to 30). Average patient age was 77 years. Median Gleason grade was 7 (range 6 to 9). Median pretreatment prostate specific antigen was 15.1 ng/ml (range 0.6 to 433) and median posttreatment prostate specific antigen was 0.74 (less than 0.1 to 120). The median dosing interval was 6 months (range 5 to 12). Three patients had an increase in prostate specific antigen while receiving treatment despite castrate levels of testosterone. No patient required more frequent dosing than every 5 months. CONCLUSIONS: Testosterone based luteinizing hormone releasing hormone agonist therapy makes empirical sense. It represents continuous androgen ablation based on the patient physiological end point, namely testosterone. Early data suggest that using serum testosterone to guide luteinizing hormone releasing hormone dosing is safe, efficacious and cost-effective. By following end organ response, patients receive individualized care and more accurate androgen suppression therapy.

Molecular pathways in bladder cancer.

The aim of this review is to provide a contemporary outline of our current understanding of the molecular and genetic events associated with tumorigenesis and the progression of bladder cancer. A comprehensive review of the literature was performed on the molecular alterations associated with transitional cell carcinoma (TCC) of the bladder. Intense research efforts are being made to better identify and characterize various bladder cancers and their true biologic potential. The need to predict which superficial tumors will recur or progress, and which invasive tumors will metastasize has led to a much better understanding of the molecular pathways associated with bladder cancer. The molecular changes that occur in TCC of the bladder are numerous and can be categorized into: (1) chromosomal alterations leading to carcinogenesis, (2) loss of cell cycle regulation accounting for cellular proliferation, and (3) metastasis, guided by events such as angiogenesis. It is becoming apparent that the accumulation of genetic and molecular changes ultimately determines a tumors phenotype and subsequent clinical behavior. At the present time, conventional histopathologic evaluation of bladder cancer (tumor grade and stage) is inadequate to accurately predict the behavior of most bladder tumors. While new laboratory techniques have allowed us to better understand how bladder cancer develops and ultimately progresses, few of these techniques are currently available for use in the clinical setting. The ultimate goal is to develop reliable prognostic markers which will accurately predict not only the expected clinical course of an individual bladder tumor but also the response of that tumor to currently available therapies. More importantly, this information may be employed in the future to dictate altogether new treatments for the prevention and/or stabilization of the early molecular events that lead to the development of bladder cancer.