Statins and Prostate Cancer Recurrence: RCT Now Needed, Say Experts

June 30, 2010 — It's time for a randomized trial to evaluate the effect of statins on outcomes in men with prostate cancer undergoing treatment, say experts in the field.

The calls for a prospective trial have been prompted by retrospective observational trials that have shown a significant reduction in the risk for biochemical recurrence in men treated for the disease who were also taking statins. Two such studies have been published recently.

The first trial, published online June 28 in Cancer, showed that 1319 men who underwent radical prostatectomy and took statins at the time of surgery had a 30% lower risk for biochemical recurrence (P = .03) than men not taking statins.

Median follow-up was 24 months for men taking statins and 38 months for those who were not.

This trial was first reported at the 2009 annual meeting of the American Urological Association(AUA), where AUA spokesperson J. Brantley Thrasher, MD, from the University of Kansas School of Medicine in Kansas City, said: "From here forward, we have to put more emphasis on well-designed clinical trials. . . These will need to be at least 10 to 15 years in duration . . . before we know whether statins should be prescribed for prevention of prostate cancer recurrence."

The second trial, published in the June 1 issue of the Journal of Clinical Oncology, of 691 men who underwent radiotherapy, showed a significant association between statin use and decreased biochemical recurrence (adjusted hazard ratio, 0.47; 95% confidence interval [CI], 0.36 - 0.86; P < .03). The median follow-up was 50 months.

A definitive prospective randomized study is lacking.

The authors of that study and Anthony V. D'Amico, MD, from Brigham and Women's Hospital in Boston, Massachusetts, who wrote an editorial that accompanied it, say that a prospective randomized study is needed to evaluate whether statin use reduces the risk for biochemical recurrence and prostate-cancer-specific mortality.

"To date, a definitive prospective randomized study is lacking to establish whether statins can reduce prostate cancer recurrence after radiotherapy or radical prostatectomy," observes Dr. D'Amico.

Surgery Study Results.

The authors of the Cancer study reviewed data on 1319 men treated with radical prostatectomy from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.

Time to biochemical recurrence was compared between 236 (18%) men who were taking statins at the time of surgery and the remaining men who were not, report the authors, led by Robert Hamilton, MD, who was at Duke University in Durham, North Carolina, at the time of the study. Dr. Hamilton is now at the University of Toronto in Ontario.

To be considered a statin user, a man had to have been taking the therapy for at least 1 day before surgery. Recurrence is defined as a single PSA value above 0.2 ng/mL, 2 concentrations at 0.2 ng/mL, or secondary treatment for detectable postoperative PSA.

Among the statins used were simvastatin (171 men; 72%), lovastatin (35 men; 15%), and atorvastatin (12 men; 5%).

Simvastatin dose-equivalents were calculated by the investigators to provide a uniform measure for the various statins and were found to be fairly evenly distributed: a simvastatin dose-equivalent below 20 mg was used by 74 men (33%), of 20 mg was used by 80 men (35%), and above 20 mg was used by 73 men (32%).

Using Cox proportional hazards models adjusted for multiple clinical and pathological features, the investigators found that statin use was associated with a 30% lower risk for PSA recurrence (hazard ratio [HR], 0.70; 95% CI, 0.50 - 0.97).

Statin users differed significantly from nonusers at presentation.

The authors explain the need for the statistical adjustment: "In our cohort, statin users differed significantly from nonusers at presentation. Statin users had lower PSA [levels] and clinical stages, but were older and had higher BMI [body mass index] and higher biopsy Gleason scores."

The reduced risk was dose dependent, with no reduction in men who took the simvastatin dose-equivalent of 20 mg or less and a 46% reduction in men who took the dose-equivalent of 20 mg or more (P = .005)

Notably, although age and race did not affect the association between the use of statins and risk for biochemical recurrence, BMI did.

Among the men in the highest BMI category (>35 kg/m²), statins were associated with an increased recurrence risk, say the authors. However, this was a small number of men (n = 22), and the authors believe this finding needs more study.

The study was not powered to examine mortality because too few men met end points related to disease-specific or overall survival.

Dr. Hamilton and his coauthors, although calling for a randomized trial to study statins, admit that the literature on the effect of statins on biochemical recurrence after surgery or radiotherapy has been mixed.

However, they also note that only 1 previous study found no change in the risk for biochemical recurrence in statin users undergoing radical prostatectomy. That study had a number of limitations, they point out; namely, "statin dose, duration of therapy, and other important potential confounding variables were not controlled for."

Radiotherapy Study Results.

The authors of the study appearing in the Journal of Clinical Oncology evaluated 691 men with clinically localized (94%) or locally advanced (6%) prostate cancer who were treated with external-beam radiotherapy to a median dose between 72 and 74 Gy or prostate brachytherapy (primarily or as a boost after external-beam radiotherapy).

Also, 286 of the men in the study (41%) received hormone therapy.

Freedom from biochemical failure was the primary end point and was defined using the Phoenix equation (PSA nadir + 2 ng/mL), report the authors of this single-center study, led by Ruchika Gutt, MD, from the University of Chicago in Illinois. This end point was compared between the 189 (27%) men who were taking statins and the remainder who were not. Statin users included those who took statins during radiotherapy (n = 150) or during follow-up (n = 39).

As was the case in the above-mentioned surgery study, the men taking statins in this radiotherapy study presented with lower PSA levels and with less advanced clinical tumor categories.

A competing risk-regression analysis revealed that there was a significant association between statin use and decreased biochemical recurrence. As was the case in the newly published surgery study, there were inadequate data to assess disease-specific mortality in this study.

The improvement in freedom from biochemical failure was also independent of hormone therapy and radiation dose, the authors report.

Selection Bias?

As noted above, in both studies, statin users differed from nonusers. As a result, both sets of investigators controlled for multiple clinical and pathologic variables. However, both sets of investigators also admit that "residual confounding" could explain the reduced recurrence risk and cannot be ruled out.

With regard to the surgery study, Dr. Hamilton and his colleagues at Duke say that statin users might have had different diet, exercise, smoking, and screening behaviors.

After considering these theoretic possibilities, the authors conclude that more data on lifestyle "would only have further strengthened the inverse association between statins and recurrence."

The surgery study authors do not discuss the subject of access to care and how it might differ between users and nonusers of statins.

Dr. D'Amico, in his editorial accompanying the radiotherapy study, thinks this might be very important. Statin users might have better access to care than nonusers or be more health conscious, he suggests.

The significance of this lies in the possibility that more affluent and more health conscious men are likely to have their prostate cancer detected by serial screening — not just a single screening. It is "well established" that men who have their prostate cancer detected from a single screening have a worse prognosis, writes Dr. D'Amico.

In addition to calling for a randomized trial of statins in this setting, Dr. D'Amico calls for future investigators of retrospective data to include a covariate that describes whether or not a man was diagnosed with a single or serial PSA measurement.

The surgery study was supported by the Department of Defense, the Department of Veterans Affairs, the National Institutes of Health, the Georgia Cancer Coalition, and the American Urological Association Foundation/Astellas Rising Star in Urology Award. The radiotherapy study was supported by a Young Investigator Award from the Prostate Cancer Foundation.

Cancer. 2010;116:3389-3398.

J Clin Oncol. 2010;28:2651-2652, 2653-2659. Abstract, Abstract