Statin Use and the Risk of Prostate-Specific Antigen Recurrence After Radiation Therapy With or Without Hormone Therapy for Prostate Cancer
Authors: Anthony V. D'Amico
Journal: Journal of Clinical Oncology (2010)

Statin use has been shown to be associated with a reduction in the risk of being diagnosed with prostate cancer (PC) overall as well as presenting with advanced disease. In addition, for men diagnosed with PC, statin use has been associated with a lower prostate-specific antigen (PSA) level at diagnosis and a lower burden of disease at radical prostatectomy (RP). Although basic science reports provide evidence to support statin use and a reduction in cancer progression in cell lines and animal experiments, retrospective studies differ on whether statin use is associated with a decreased risk of PSA progression for men undergoing primary therapy with RP or radiation therapy (RT). Moreover, to date, a definitive prospective randomized study is lacking to establish whether statins can reduce PC recurrence after RT or RP. In this issue of Journal of Clinical Oncology, Gutt et al evaluate 691 men with clinically localized (652; 94%) or locally advanced (39; 6%) PC who were treated using external-beam RT to a median dose between 72 and 74 Gy or prostate brachytherapy primarily or as a boost after external-beam RT. In addition, 286 men (41%) received hormone therapy (HT). Similar to prior reports, men taking statins in their study presented with a lower PSA level and with less advanced clinical tumor (T) category. Competing risk regression analysis disclosed a significant association between statin use and decreased PSA recurrence defined using the Phoenix or nadir 2 definition for PSA recurrence (adjusted hazard ratio [AHR], 0.47; 95% CI, 0.36 to 0.86; P .03). Although relapse-free survival was also improved with statin use, it is more difficult to ascertain its clinical significance, given that relapse-free survival also included death from non-PC causes such as cardiovascular death, which can be reduced with statin use. In addition, given the median follow-up of 50 months, there was inadequate power to assess the end point of PC-specific mortality. Despite these considerations, this study raises an interesting hypothesis regarding statin use and a possible decrease in the risk of PSA recurrence in men undergoing RT that requires prospective validation given the retrospective nature of the study as well as alternative explanations for the findings. Specifically, it is well-established that prevalent cancers (ie, those diagnosed after a single PSA test) as compared with incident cancers diagnosed after serial PSA testing present with higher PSA levels and more advanced clinical stage and, as a result, have a worse prognosis. Given that statin users may be more health conscious or have increased access to care as compared with nonusers, this raises the possibility that these men may also be more likely to undergo serial screening with PSA as compared with nonstatin users, explaining why they presented with less advanced disease in the current and prior studies. Inclusion of a covariate that describes whether the patient was diagnosed after a single or serial PSA measurements could aid in adjusting for the potential confounding that prevalent versus incident cancer can have on the end point of the risk of PSA recurrence. Second, although the authors adjusted the analysis for several established prognostic factors (RT dose, HT use, PSA level, Gleason score, and T category), adjustment for other known adverse prognostic factors such as increasing percent positive biopsies, pre-RT PSA velocity more than 2 ng/mL/year, perineural invasion in men with Gleason score 6 cancer, and the presence of tertiary grade 5 in men with Gleason score 7 cancers would be recommended in the multivariable competing risks model to reduce the likelihood that the selection bias could explain the results. That is, if nonstatin users were more likely to have these unfavorable prognostic factors as compared with statin users, then the reduction in the risk of PSA recurrence in statin users may simply reflect an imbalance in distribution of the adverse prognostic factors favoring statin users and not a true therapeutic benefit of statin use on PC progression. Future studies are needed to address this concern. In contrast, it is noteworthy that in this study statin users presented with lower PSA levels and less advanced T category, yet higher RT dose and more HT use was used. The selection of more aggressive treatment in statin users as compared with nonusers despite less advanced disease could have resulted if statin users were younger or had better overall health compared with nonusers. If true, then statin users would be expected to live longer and, therefore, be more likely to have PSA failure observed should it occur as compared with nonstatin users, who may die from non-PC causes before PSA failure. This effect, if present, would strengthen the association between statin use and reduced PSA recurrence noted in this study. Therefore, inclusion of age and a validated measure of comorbidity such as the Adult Comorbidity Evaluation-27 score as covariates in the competing risks regression would also be advised in future studies. Therefore, we wish to congratulate the authors on a novel observation. We also wish to encourage additional retrospective analyses JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 28 NUMBER 16 JUNE 1 2010