Prostate cancer survival among statin users after prostatectomy in a Finnish nationwide cohort

Abstract

Background: Improved prostate cancer (PCa) survival by statin use has been reported among PCa patients managed with radiation or androgen deprivation therapy (ADT), while results are controversial for men managed surgically. We evaluate the association between cholesterol-lowering medication with initiation of ADT and disease-specific death among PCa cases who underwent radical prostatectomy in Finland between 1995 and 2013. Methods:The study cohort included 14 424 men with PCa who underwent radical prostatectomy in Finland between 1995 and 2013. Cases were identified from national hospital discharge registry. Clinical data were amended from patient files of the treating hospitals. Information on co-morbidities, additional radiation-or chemotherapy, and causes of deaths were collected from national registries. Personal-level data on medication use during 1995-2014 were gathered from national prescription database. Registry linkages were carried out using personal identification number. Lipid-lowering drugs were categorized into statins and non-statin drugs. Risk of PCa death and initiation of ADT was analyzed using Cox-regression model with adjustment for age, radiation therapy, chemotherapy, co-morbidities and other drug use. Statin use was analyzed as time-dependent variable. Delayed risk associations were evaluated in lag-time analysis. Results: Compared to non-users the risk of PCa death was significantly lower among statin users before PCa diagnosis (HR 0.70, 95%CIs 0.52-0.95). For statin use after PCa diagnosis the risk was lowered in age-adjusted analysis (HR 0.76 95%CIs 0.62-0.93) but not after multivariable-adjustment. Post-diagnostic statin use was associated with improved PCa-specific survival in 1, 3 and 5 years lag-time analyses. The risk reduction was clearest for statin use initiated 5 years earlier (HR 0.71 95%CIs 0.55-0.92). Use of statins both before and after PCa diagnosis was associated with reduced risk of ADT use (HR 0.72 95%CIs 0.65-0.80 and HR 0.73, 95%CI 0.67-0.80, respectively). The risk of ADT decreased by increasing intensity of statin use before diagnosis. Conclusion: Statin use among surgically treated PCa patients has significant association with decreased risk of starting ADT and PCa death. The risk is lowered especially among men with statin use before PCa diagnosis and in men who used statins at high-dose. Our results are hypothesis generating due to retrospective study design. K E Y W O R D S cohort, prostate cancer, prostatectomy, statin, survival

Access and concentrations of atorvastatin in the prostate in men with prostate cancer

“…Further, it has been unknown whether statins can even access prostatic tissue from the plasma. 12 We show for the first time that ATV can access the prostate, as the drug concentrations are measurable from the tissue. Further, we demonstrate that these tissue concentrations are in the nanomolar range, thus somewhat below those used in most in vitro studies.…”

“…In vivo, it is uncertain whether ATV could have a direct effect on the prostate as the concentrations used in the in vitro experiments (micromolar range) outreach those reached in the plasma within standard clinical dosing (nanomolar range). Further, it has been unknown whether statins can even access prostatic tissue from the plasma . We show for the first time that ATV can access the prostate, as the drug concentrations are measurable from the tissue.…”

“…7,8 Statin users have also been reported to have improved prostate cancer-specific survival compared to nonusers, especially in the context of androgen deprivation therapy. [9][10][11] Improved progression-free and disease-specific survival among statin users have also been reported after radical prostatectomy, 12 although not all studies agree. 13 Survival benefits are likely to depend on treatment compliance, as lowered risk of disease recurrence has been observed only in men whose serum cholesterol decreases after statin intervention.…”

Reply to: Calcium channel blockers therapy and the risk of prostate cancer death

“…For example, the use of statins has been associated with better PCa survival and therefore is a potent confounding subject. 4 It is also very general knowledge that many groups of anti-HT drugs are used to treat hypertension at the same time as targeting recommended blood pressure levels. So, if not considered in earlier studies, it may even be possible that reduced risk of PCa diagnosis among calcium channel blocker users is caused by, for example, angiotensinreceptor blockers (ATR-blockers) used together with calcium channel blocker therapy.…”

“…To minimize confounding bias, it is important to study the use of all groups of anti‐HT drugs at the same time and, if possible, other drugs commonly used together with anti‐HT drugs as well (such as statins and antidiabetic medication). For example, the use of statins has been associated with better PCa survival and therefore is a potent confounding subject . It is also very general knowledge that many groups of anti‐HT drugs are used to treat hypertension at the same time as targeting recommended blood pressure levels.…”