Roberto L. Muller

Serum Testosterone and Dihydrotestosterone and Prostate Cancer Risk in the Placebo Arm of the Reduction by Dutasteride of Prostate Cancer Events Trial

BACKGROUND Findings of studies on the association between androgens and prostate cancer (PCa) are mixed. Androgens may affect prostate-specific antigen (PSA) levels, thereby influencing biopsy recommendations. Also, androgens may stimulate prostate growth at very low levels with no additional effects at higher levels (saturation model). OBJECTIVE To test whether androgens were associated with PCa risk in the placebo arm of a prospective study in which biopsies were performed regardless of PSA level. DESIGN, SETTING, AND PARTICIPANTS Of 8122 men in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, 4073 men (50.1%) received placebo. Key entry criteria were PSA 2.5-10 ng/ml and one prior negative biopsy. INTERVENTION Per-protocol biopsies at 2 and 4 yr; for-cause biopsies at physician discretion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariable logistic regression was used to test the association between baseline log-transformed testosterone and dihydrotestosterone (DHT) levels and the risk of detecting either PCa or low-grade PCa (Gleason score <6) compared with high-grade PCa (Gleason score >7). In secondary analysis, we stratified the analysis by low baseline androgen levels (testosterone <10 nmol/l; DHT <0.76 nmol/l) compared with normal baseline androgen levels. RESULTS AND LIMITATIONS Of 4073 men, 3255 (79.9%) had at least one biopsy after randomization and were analyzed. Androgen levels tested continuously or by quintiles were generally unrelated to PCa detection or grade. PCa detection was similar among men with low compared with normal baseline testosterone levels (25.5% and 25.1%; p=0.831). In secondary analysis, higher testosterone levels at baseline were associated with higher PCa detection (odds ratio: 1.23; 95% confidence interval, 1.06-1.43; p=0.006) only if men had low baseline testosterone (<10nmol/l). For men with normal baseline testosterone (≥10 nmol/l), higher testosterone levels at baseline were unrelated to PCa risk (p=0.33). No association was found for DHT and PCa (all p>0.85). CONCLUSIONS Baseline serum testosterone and DHT levels were unrelated to PCa detection or grade. Our findings of the lowest testosterone levels being associated with the lowest PCa risk with no further changes with higher testosterone support a saturation model but must be confirmed in future studies using an a priori defined hypothesis. CLINICALTRIALS.GOV IDENTIFIER: NCT00056407.

Baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: Results from the REDUCE study

The current study was performed to evaluate whether baseline acute and chronic prostate inflammation among men with an initial negative biopsy for prostate cancer (PCa) increased the risk of subsequent PCa detection in a clinical trial with systematic biopsies.

Obesity Is Associated with Increased Prostate Growth and Attenuated Prostate Volume Reduction by Dutasteride

BACKGROUND Although obesity has been associated with larger prostate volumes (PV), few studies have actually investigated whether obesity enhances PV growth, especially among men using 5α-reductase inhibitors. OBJECTIVE To examine whether obesity is associated with enhanced PV growth measured by serial transrectal ultrasound (TRUS) measurements. DESIGN, SETTING, AND PARTICIPANTS We conducted a secondary analysis of the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, which was originally aimed at cancer risk reduction among high-risk men with a single negative prestudy biopsy. INTERVENTION Per-protocol randomization to placebo or dutasteride and mandatory TRUS-guided biopsies at 2 yr and 4 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Percentage change in PV at 2 yr and 4 yr from baseline. We tested its association with baseline body mass index (BMI) groups of <25, 25-29.9, and ≥ 30 kg/m(2) using multivariable linear regression. Secondarily, we tested whether BMI was associated with the likelihood of having no PV reduction among men randomized to dutasteride using multivariable logistic regression. RESULTS AND LIMITATIONS Of 8122 participants, we analyzed 71.8% and 54.5% with complete 2-yr and 4-yr PV data, respectively. In multivariable analysis, men on placebo with BMI ≥ 30 versus < 25 kg/m(2) had enhanced PV growth from baseline (at 2 yr: 17.0% vs 10.7%, p<0.001; at 4 yr: 29.4% vs 20.1%; p=0.001). Men on dutasteride with BMI ≥ 30 versus < 25 kg/m(2) had attenuated PV reduction from baseline (at 2 yr: -14.3% vs -18.5%; p=0.002; at 4 yr: -13.2% vs -19.3%; p=0.001) and higher likelihood of having no PV reduction (at 2 yr: odds ratio [OR]: 1.44; 95% confidence interval [CI], 1.08-1.93; p=0.014; at 4 yr: OR: 1.62; 95% CI, 1.18-2.22; p=0.003). We found no significant interactions between BMI and dutasteride on PV change at 2 yr and 4 yr (p interaction ≥ 0.36). No clinical outcomes or effects of weight change were assessed. CONCLUSIONS Obesity enhanced PV growth and attenuated PV reduction by dutasteride. The null interaction between obesity and dutasteride for PV change implies that the effect of obesity on dutasteride-treated men is likely a combination of dutasteride-driven PV reduction with obesity-driven PV growth rather than decreased dutasteride efficacy.

Radical Prostatectomy for Locally Advanced Prostate Cancer: Current Status.

In the past, prostate cancer (PC) could only be detected clinically, and delayed diagnosis of locally advanced or metastatic disease at presentation was common. Prostate-specific antigen testing and magnetic resonance imaging led to PC detection in a much earlier stage. However, controversy about the best treatment for locally advanced PC remains. Recent refinements in surgery and radiation therapy have improved outcomes, but no comparative study has yet conclusively determined superiority of one option over the other. In this review, we present the most recent evidence about the role of radical prostatectomy for locally advanced PC treatment from a surgeons perspective.

Smoking Is Associated with Acute and Chronic Prostatic Inflammation: Results from the REDUCE Study

Both anti- and proinflammatory effects of cigarette smoking have been described. As prostate inflammation is common, we hypothesized smoking could contribute to prostate inflammation. Thus, we evaluated the association of smoking status with acute and chronic inflammation within the prostate of men undergoing prostate biopsy. We retrospectively analyzed 8,190 men ages 50 to 75 years with PSA levels between 2.5 and 10 ng/mL enrolled in the Reduction by Dutasteride of Prostate Cancer Events study. Smoking status was self-defined as never, former, or current. Prostate inflammation was assessed by systematic central review blinded to smoking status. The association of smoking with inflammation in the baseline, 2-year, and 4-year biopsies was evaluated with univariable and multivariable logistic regressions. At study enrollment, 1,233 (15%), 3,203 (39%), and 3,754 (46%) men were current, former, and never smokers, respectively. Current smokers were significantly younger and had smaller prostates than former and never smokers (all P < 0.05). Former smokers were significantly heavier than current and never smokers (P < 0.001). Acute and chronic prostate inflammations were identified in 1,261 (15%) and 6,352 (78%) baseline biopsies, respectively. In univariable analysis, current smokers were more likely to have acute inflammation than former (OR, 1.35; P, 0.001) and never smokers (OR, 1.36; P, 0.001). The results were unchanged at 2- and 4-year biopsies. In contrast, current smoking was linked with chronic inflammation in the baseline biopsy, but not at 2- and 4-year biopsies. In conclusion, among men undergoing prostate biopsy, current smoking was independently associated with acute and possibly chronic prostate inflammations. Cancer Prev Res; 8(4); 312–7. ©2015 AACR.

Smoking and prostate cancer survival and recurrence

Smoking is associated with several major benign and malignant diseases, representing one of the most important modifiable risk factors. Among urothelial neoplasms, smoking is pivotal in tumor carcinogenesis, but its role in prostate cancer is still controversial. Many authors have failed to demonstrate an association between smoking and prostate cancer.1, 2, 3 However, large epidemiological studies have shown that smoking is associated with higher risk of developing and dying of prostate cancer.4 Thus, large sample sizes and long follow-ups are important when studying prostate cancer given that its natural history can be quite long. In selected clinical scenarios, smoking has been reported to be related to worse disease after diagnosis. For example, prostate cancer was associated with more aggressive disease at diagnosis5 and after surgical treatment,6 higher recurrence rates after surgery7, 8 and radiotherapy,9 increased risk of metastatic disease after radiotherapy10 and worst overall survival.1, 11 However, large epidemiological studies are still required to confirm these findings and elucidate the role of cigarette smoking on prostate cancer progression after diagnosis. Recently, Kenfield et al.,12 using data from the Health Professionals Follow-Up Study, published a paper investigating the association of prostate cancer with overall, disease-specific and disease-free survival. In that study, they evaluated a cohort of 5366 prostate cancer cases over a follow-up of 22 years. All patients provided detailed information on smoking status before cancer diagnosis. Smoking exposure such as cumulative tobacco exposure (pack-years), smoking status (current, former, never) and time since quitting and prostate cancer outcomes including biochemical recurrence, overall survival, prostate cancer-specific mortality (PCSM) and cardiovascular mortality were analyzed. At cancer diagnosis, current smokers had higher clinical stage and grade compared with non-smokers (P<0.001). In addition, they found that smokers exercise less, drink more coffee, consume more saturated fat and less calcium and tend to have less previous screening for prostate cancer. Smokers had higher risk of biochemical recurrence (HR=1.61), PCSM (HR=1.61), cardiovascular mortality (HR=2.13) and all-cause mortality (HR=2.28). At 5 years of follow-up, a higher disease-specific mortality among smokers was already noted and persisted throughout the study interval. Non-smokers and former smokers who had quit for more than 10 years before cancer diagnosis had a better prognosis than current smokers or more recent quitters. The absolute crude mortality rates per 1000 person-years were 9.6 and 10.3 respectively for non-smokers and long-term former smokers, and 13.8 and 15.3 respectively for more short-term former smokers and current smokers. A dose–effect relationship between smoking and disease-specific mortality was observed. Interestingly, former smokers who quit less than 10 years before cancer diagnosis and smoked less than 20 pack-years had similar risks to current smokers for biochemical recurrence, but their risks of dying from prostate cancer were comparable to never smokers. The authors hypothesize that the deleterious effects of smoking on prostate cancer mortality are due to worst stage and grade at diagnosis. Given that prostate cancer stage is altered by screening,13 it is conceivable that smokers present with more advanced disease in part due to the lower screening rate observed in the study. This suggests that smokers may be less attentive to preventive measures than non-smokers which may have deleterious consequences later, given that patients with locally advanced disease are known to have worst survival14 and screening practices for prostate cancer have impact on mortality.15, 16 This is also supported by the fact that no differences in PCSM between smokers and non-smokers were observed after adjustment for cancer stage and grade and screening. Moreover, the authors speculate that the biological effects of smoking on cancer progression may be mediated by direct action of carcinogens, modulation of sexual hormones, epigenetic gene expression changes, nicotine-induced angiogenesis or the interplay among them. Although all these hypotheses are plausible, their data do not favor any specific pathway. Thus, it will be interesting to see further studies looking at these mechanisms by which smoking affects prostate cancer. The study is not without limitations. One of the caveats is that, being a cohort of health professionals, the prevalence of smoking is only 5.2%—three times lower than many other series. Thus, it is possible that in populations with higher prevalence of smoking the differences in PCSM between groups may be diluted or attenuated, given that the strength of the association found was much higher for cardiovascular mortality and all-cause mortality. In those populations, patients might die of other smoking-related diseases before developing end-stage prostate cancer, reducing the effect of smoking on PCSM. Another limitation is that primary therapies for prostate cancer were not explored in detail. Given that smoking is associated with comorbidities which, in turn, may be correlated with treatment option, it is important to take into consideration that treatments may vary among smoking groups and that may modify the disease course. Finally, no information about smoking habits changes after diagnosis was available. Given the long natural history of prostate cancer, changes in smoking habits such as quitting smoking may also affect disease progression and ideally should be accounted for. In conclusion, this is one of the largest studies that demonstrated an association between smoking at the time of diagnosis and adverse prostate cancer events. Its strengths include the large sample size, long follow-up, consistency of findings and dose–effect relationship of their results. The authors found that smoking was associated with worst overall and PCSM mainly due to its effect on tumor differences at diagnosis in this population of low prevalence of current smokers. The effect of smoking on PCSM seems to be reversible after 10 years of cessation of cigarette consumption before a prostate cancer diagnosis. Their conclusions reinforce the benefits of counseling patients for smoking cessation, especially before diagnosis of prostate cancer, but in the current era of highly screened populations and stage migration to better clinical profiles at diagnosis, its role in this type of contemporary setting of early screening-detected cancers remains to be determined in present prospective cohorts.

Laparoscopic Retroperitoneal Lymph Node Dissection as a Safe Procedure for Postchemotherapy Residual Mass in Testicular Cancer

BACKGROUND To evaluate the feasibility, clinical and perioperative outcomes of laparoscopic retroperitoneal lymph node dissection (L-RPLND) in the management of patients with germ cell tumors (GCT) and residual post-chemotherapy mass. METHODS We report our experience of 25 patients treated with L-RPLND between 2008 and 2015. All 25 patients were diagnosed with GCT by primary pathological evaluation of the specimens after orchiectomy. All patients received cisplatin-based chemotherapy. The technique consisted of L-RPLND excision of the residual mass using unilateral template dissection. We assessed perioperative data and histological findings. RESULTS Surgery was successfully completed in 24 (96%) patients, 1 patient required an open surgery due to intense adhesions of the mass to the inferior vena cava. Mean operation time was 213 minutes. Mean blood loss was 260 mL. Postoperative complications were upper limb osteomuscular pain in 2 patients and chylous ascites in 1 patient. Mean postoperative hospital stay was 2 days. The median residual mass diameter was 3.3 cm (range 1.1-6.6 cm). Histopathological findings were necrotic tissue in 9 patients, teratoma in 9 patients, viable tumor in 6 patients, and Castleman disease in 1 patient. The median follow-up was 30 months. Normal antegrade ejaculation was preserved in all patients. CONCLUSIONS Laparoscopic postchemotherapy RPLND is a feasible, safe, and highly oncologically efficient procedure, which has the benefits of minimally invasive surgery.

MP92-09 IMPLICATIONS OF REGIONALIZING CARE IN THE DEVELOPING WORLD: IMPACT OF DISTANCE TO REFERRAL CENTER ON COMPLIANCE TO BIOPSY RECOMMENDATIONS IN A BRAZILIAN PROSTATE CANCER SCREENING COHORT

NOTES pathway. Precipitating events for these deviations were recorded by abstractors. RESULTS: A total of 4710 RPs were performed by 209 surgeons in 41 participating MUSIC practices. Thirty day readmission rates were 4.1% overall, 3.8% for those with LOS 0-2 days and 7.1% for those with LOS 3 days. The most frequent events driving readmission were gastrointestinal (GI) events such as ileus or bowel injury (24.5%), infection (19.8%), urine leaks (13.0%) and pulmonary embolism (PE)/ deep vein thrombosis (DVT) (12.5%) (Table 1). GI events resulted in 56.3% of readmissions within 3 days of discharge (Figure 1). Infection, urine leaks and PE/DVT remained persistent drivers beyond this period (Figure 1). CONCLUSIONS: GI and urine complications represent the majority of drivers resulting in 30 day readmission. Measures to specifically reduce these by appropriate patient education and close postdischarge surveillance may represent a high impact opportunity for quality improvement efforts after RP.

Impact of Comorbidity, Race, and Marital Status in Men Referred for Prostate Biopsy with PSA >20 ng/mL: A Pilot Study in High-Risk Patients

Objective. To assess the impact of comorbidity, race, and marital status on overall survival (OS) among men presenting for prostate biopsy with PSA >20 ng/mL. Methods. Data were reviewed from 2000 to 2012 and 78 patients were included in the cohort. We analyzed predictors of OS using a Cox proportional hazards model and the association between Charlson Comorbidity Index (CCI) score and PCa diagnosis or high-grade cancer using logistic regression and multinomial regression models, respectively. Results. The median age of patients was 62.5 (IQR 57–73) years. Median CCI was 3 (IQR 2–4), 69% of patients were African American men, 56% of patients were married, and 85% of patients had a positive biopsy. CCI (HR 1.52, 95% CI 1.19, 1.94), PSA (HR 1.62, 95% CI 1.09, 2.42), and Gleason sum (HR 2.04, 95% CI 1.17, 3.56) were associated with OS. CCI was associated with Gleason sum 7 (OR 4.06, 95% CI 1.04, 15.89) and Gleason sum 8–10 (OR 4.52, 95% CI 1.16, 17.54) PCa. Conclusions. CCI is an independent predictor of high-grade disease and worse OS among men with PCa. Race and marital status were not significantly associated with survival in this cohort. Patient comorbidity is an important component of determining the optimal approach to management of prostate cancer.

Does salvage radiation therapy (SRT) change the biology of recurrent prostate cancer (PCa) based on PSA doubling times (PSADT)? Results from the SEARCH database.

203 Background: SRT offers a second opportunity for PCa control after biochemical recurrence in men treated with radical prostatectomy. Although some retrospective data suggest an overall survival benefit, we hypothesized that in men with radio-resistant tumors, SRT may indeed promote transformation to a more aggressive cancer due to radiation-induced mutations. To test this, we used PSADT as a surrogate for cancer aggressiveness and compared PSADT before and after SRT in men who failed SRT. METHODS Of 288 men who underwent SRT in the Shared Equal Access Regional Cancer Hospital (SEARCH) database since 1988, we detected 78 with SRT failure defined as PSA ≥ 0.2 ng/mL above the post-SRT nadir. Of these, 44 had PSADT available before and after SRT, which was compared using Wilcoxons paired test with men serving as their own controls. We also tested predictors of PSADT change using multivariable logistic regression. RESULTS There were no differences in PSADT before and after SRT (10.6 vs. 12.2 months; P=0.85). However, in some individual cases large changes were observed. Only seminal vesicle invasion showed a trend towards an association with a shorter post-SRT PSADT relative to the pre-SRT PSADT (P=0.067). CONCLUSIONS Overall, the PSADT after and before SRT were statistically similar suggesting that after SRT failure, PCa does not emerge with more aggressive biologic features. Further studies are needed to identify predictors and the clinical relevance of individual PSADT changes noted in our study. (Note: Authors R. L. Muller and S. J. Freedland received support from DoD Award Number W81XWH-10-1-0155).