Bertrand Tombal

Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antagonist

BACKGROUND Androgen deprivation therapy (ADT) is associated with increased cardiovascular morbidity. OBJECTIVE To determine whether cardiovascular morbidity differs following initiation of gonadotropin-releasing hormone (GnRH) agonists compared with an antagonist. DESIGN, SETTING, AND PARTICIPANTS Pooled data from six phase 3 prospective randomized trials that recruited 2328 men between 2005 and 2012 to compare the efficacy of GnRH agonists against an antagonist. Men recruited had pathologically confirmed prostate cancer, an Eastern Cooperative Oncology Group score <2, a minimum life expectancy of 12 mo, and were naïve to ADT. Men were excluded if they had a prolonged baseline QT/corrected QT interval, other risk factors for heart failure, hypokalemia or a family history of long QT syndrome, or had another cancer diagnosed within 5 yr. INTERVENTION Men were randomized to receive a GnRH agonist or an antagonist for either 3-7 mo (n=642) or 12 mo (n=1686). Treatment groups were balanced for common baseline characteristics. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Event analysis was based on death from any cause or cardiac events. Data documenting adverse experiences were classified based on the Medical Dictionary for Regulatory Activities. The following conditions defined a cardiac event: arterial embolic or thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction, and other ischemic heart disease. Kaplan-Meier curves and log-rank tests were used to compare time to a cardiovascular event or death. RESULTS AND LIMITATIONS Among men with preexisting cardiovascular disease, the risk of cardiac events within 1 yr of initiating therapy was significantly lower among men treated with a GnRH antagonist compared with GnRH agonists (hazard ratio: 0.44; 95% confidence interval, 0.26-0.74; p=0.002). Since our analysis is post hoc, our findings should only be interpreted as hypothesis generating. CONCLUSIONS GnRH antagonists appear to halve the number of cardiac events experienced by men with preexisting cardiovascular disease during the first year of ADT when compared to GnRH agonists.

Exercise for Men with Prostate Cancer: A Systematic Review and Meta-analysis

CONTEXT Exercise could be beneficial for prostate cancer survivors. However, no systematic review across cancer stages and treatment types addressing potential benefits and harms exists to date. OBJECTIVE To assess the effects of exercise on cancer-specific quality of life and adverse events in prostate cancer trials. EVIDENCE ACQUISITION We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, SPORTDiscus, and PEDro. We also searched grey literature databases, including trial registers. Searches were from database inception to March 2015. Standardised mean differences (SMDs) were calculated for meta-analysis. EVIDENCE SYNTHESIS We included 16 randomised controlled trials (RCTs) involving 1574 men with prostate cancer. Follow-up varied from 8 wk to 12 mo. RCTs involved men with stage I-IV cancers. A high risk of bias was frequently due to problematic intervention adherence. Seven trials involving 912 men measured cancer-specific quality of life. Pooling of the data from these seven trials revealed no significant effect on this outcome (SMD 0.13, 95% confidence interval [CI] -0.08 to 0.34, median follow-up 12 wk). Sensitivity analysis of studies that were judged to be of high quality indicated a moderate positive effect estimate (SMD 0.33, 95% CI 0.08-0.58; median follow-up 12 wk). Similar beneficial effects were seen for cancer-specific fatigue, submaximal fitness, and lower body strength. We found no evidence of benefit for disease progression, cardiovascular health, or sexual function. There were no deaths attributable to exercise interventions. Other serious adverse events (eg, myocardial infarction) were equivalent to those seen in controls. CONCLUSIONS These results support the hypothesis that exercise interventions improve cancer-specific quality of life, cancer-specific fatigue, submaximal fitness, and lower body strength. PATIENT SUMMARY This review shows that exercise/physical activity interventions can improve quality of life, fatigue, fitness, and function for men with prostate cancer.

Long-term Tolerability and Efficacy of Degarelix: 5-Year Results From a Phase III Extension Trial With a 1-Arm Crossover From Leuprolide to Degarelix

OBJECTIVE To demonstrate the safety and efficacy of up to 5 years of degarelix treatment and the effects of crossing over from leuprolide to degarelix in the extension phase of a phase III pivotal 1-year trial. METHODS Patients receiving degarelix who completed the 1-year trial continued on 80 mg (n = 125) or 160 mg (n = 126) maintenance doses. Patients who received leuprolide were rerandomized to degarelix 240/80 mg (n = 69) or 240/160 mg (n = 65). Safety and tolerability were assessed (primary end point), as well as testosterone and prostate-specific antigen levels and prostate-specific antigen progression-free survival (secondary end points). RESULTS Adverse event frequency was similar between both the groups. Adverse events included initial injection site reactions, hot flushes, and increased weight. Testosterone and prostate-specific antigen values during the extension study were similar to those seen during the 1-year trial in patients who continued on degarelix or crossed over from leuprolide. The prostate-specific antigen progression-free survival hazard rate was decreased significantly after the crossover in the leuprolide to degarelix group (from 0.20 to 0.09; P = .002), whereas in patients who continued on degarelix, the rate did not change significantly. In patients with baseline prostate-specific antigen >20 ng/mL, the same hazard rate change pattern was observed on crossover (from 0.38 to 0.19; P = .019). CONCLUSION Degarelix was well tolerated; no safety concerns were identified. The significant prostate-specific antigen progression-free survival benefit established for degarelix over leuprolide during year 1 remained consistent at 5 years.

Inhibition of caspase activity does not prevent the signaling phase of apoptosis in prostate cancer cells.

Caspases are a family of cysteine proteases capable of characteristically cleaving after an aspartic acid residue. Various members of the caspase family (e.g., caspases 8 and 9) have been implicated as critical initiators in the signaling phase, while others (e.g., caspases 3, 6,and 7) have been implicated in the effector or execution phase of apoptosis. Thapsigargin (TG) is capable of inducing cell proliferation‐independent apoptosis of prostate cancer cells. This study was undertaken to determine if caspase inhibition can prevent TG‐ or 5‐fluorodeoxyuridine (5‐FrdU)‐induced apoptosis in prostate cancer cells.

Radiation Therapy Versus Radical Prostatectomy: A Never-ending Discussion

The management of nonmetastatic prostate cancer (PC) continues to stir discussion and debate. A number of population-based studies have concluded that survival rates are better after radical prostatectomy (RP) than after radiation therapy (RT). The article published by Wallis et al [1] in this issue of European Urology used several of these reports in a meta-analysis. These studies have many common features [2]. First, the authors assume a cause and effect relationship between survival difference and treatment. Second, they claim that they used high-quality data from large populations and that they corrected for several confounders using different methodologies to exclude bias (eg, propensity score matching, NewcastleOttawa scale). Third, the authors acknowledge several limitations including the inclusion criteria, patient age, and selection. Fourth, they accept that the type of surgery (eg, extent of lymphadenectomy) and the type of radiation therapy delivered (eg, radiation technique and total dose) were not consistent. Fifth, they admit that they could not secure the recommended combination of androgen deprivation therapy (ADT) and RT. Sixth, they usually present inconsistent and/or poorly documented rates of adjuvant therapies (eg, postoperative RT, ADT). Finally, in their conclusion, and despite all the evident limitations, the authors imply that their data represent the truth and should be used by physicians and patients to guide treatment. In their paper, the authors state that ‘‘... the majority of included studies were felt to have low to moderate risk of bias’’. Further on, they state that ‘‘... patients treated with radiotherapy experienced an increased risk of overall mortality compared with those treated with radical

Charlson score to predict overall survival and cancer-related death in elderly patients featuring high-risk prostate cancer.

84 Background: In elderly patients, Charlson score among other features, might allow clinicians to limit the use of aggressive adjuvant treatment strategies or even primary surgical treatment to those who might not achieve benefit during their lifetime. Methods: Retrospective analysis, 7,650 case multicenter high-risk prostate cancer (Pca) radical prostatectomy database selecting >= 70 years old cases. We predicted death from all causes (DAC) and cancer related death (CRD) including all clinical and pathological data. Multivariable analysis were performed to identify independent predictors of DAC and CRD with binary logistic regression, using STATA® software, version 13.1. Results: 2,106 patients from 14 high-volume centers were included. Mean age was 72.8 years (SD 2.46). 206 (9.78%) patients were classified as ASA 3-4 and 497 (23.6%) as CS >=1. Mean PSA was 21.7 ng/ml (SD 50.5). At final histopathology, 800 (38%) had pT3b-T4 disease, GS was 8-10 in 589 (28%), LNI was found in 518 (24.6%) and 822 (39%) P...