Statin Use and Clinical Outcomes after High-Dose Radiotherapy for Prostate Cancer

Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 31 de octubre del 2007

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Presenter: M. Zelefsky
Presenter's Affiliation: Memorial Sloan Kettering Cancer Center, New York, NY
Type of Session: Scientific

Background

  • Clinical and laboratory work has suggested that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly known as statins, may have anti-cancer activity. These drugs have been demonstrated to decrease risk of malignancy, most notably colorectal cancer, in some studies [Platz, 2006; Poynter, 2005].
  • Statins have been demonstrated to interact with anti-apoptotic pathways and act as radiosensitizers in other studies [Shafer, 1989; Goldstein, 1990; Miller, 1995].
  • Prostate cancer is the most common malignany to affect men, many of whom have co-morbidities that require statin treatment.
  • This study was carried out in order to assess the effect of statin use concurrent with high-dose radiotherapy in patients undergoing treatment for adenocarcinoma of the prostate. Clinical outcomes examined included PSA-relapse free survival (PSA-RFS), distant metastasis free survival (DMFS), and overall survival (OS).

Materials and Methods

  • The records of 871 men treated for prostate cancer at Memorial Sloan Kettering Cancer Center between 1/ 1995 and 7/ 2000 were retrospectively reviewed.
  • All patients had biopsy-proven, clinical stage T1-T3 prostate adenocarcinoma, and were treated with conformal radiotherapy or intensity modulated radiation therapy to a median dose of 81 Gray (Gy) (range 75.6 – 86.4 Gy).
  • Statin use at the time of diagnosis was documented in 19% of patients (n = 168), and was not discontinued during radiotherapy in any patients.
  • Androgen ablation was employed in the treatment of 54% of patients analyzed in this study. This treatment consisted of androgen ablation delivered for 3 months prior to radiotherapy and during radiotherapy. Androgen ablation was discontinued at the completion of radiotherapy.
  • PSA relapse was defined according to the Phoenix definition (nadir + 2).
  • Mean follow-up was 85 months. 
  • Statin use was evaluated with known tumor-related and treatment-related predictors of clinical outcomes after radiotherapy, including Gleason score, disease risk stratification, and use of androgen ablation treatments.

Results

  • The 5 and 10 year PSA-RFS for patients on a statin drug were 91% and 76%, respectively, versus 81% and 66%, respectively, for those not taking a statin (p = 0.01 at 10 years).
    • On subset analysis, PSA-RFS risk modification was found to be most notable for patients with high-risk disease (hazard ratio 3.27, p = 0.005 at 10 years).
    • Decreased risk of PSA-RFS trended towards significance for intermediate-risk patients (hazard ratio 1.87, p = 0.07), and was not statistically significant for low-risk patients (hazard ratio 0.49, p = 0.078).
    • On multivariate analysis, statin use, in addition to androgen ablation, was found to be an independent predictor of PSA-RFS in patients with high-risk disease, resulting in a 3-fold improvement in PSA-RFS.
    • Cox-regression analysis demonstrated Gleason score < 7 (hazard ratio 2.01, p < 0.001), clinical stage T1 – T2 (hazard ratio 2.41, p < 0.001), and statin use (hazard ratio 1.58, p = 0.03) to be associated with improved PSA-RFS for the entire patient population.
  • For high-risk patients, a trend towards improved DMFS was also observed (hazard ratio 3.07, p = 0.04). No significant change in DMFS was observed intermediate or low-risk patients.
  • No apparent difference in OS was observed for patients taking a statin versus those not on a statin (p = 0.28).
  • No apparent difference in cause-specific survival was observed between the two groups (p = 0.77).

Author's Conclusions

  • The authors conclude that statin drugs are associated with improved PSA-RFS in patients treated with radiotherapy for adenocarcinoma of the prostate.
  • They note that, in addition to androgen ablation therapy, statin use may impose up to a 3-fold improvement in PSA-RFS in patients with high-risk disease.
  • An improvement in DMFS was also observed in patients with high-risk disease on statin therapy.
  • The authors recognize the limitations of this study, including its retrospective nature which prevents analysis of statin dose used, duration of statin use, type of statin drug, and fasting cholesterol levels.

Clinical/Scientific Implications

  • The data presented in this study represents an exciting contribution to the prostate-cancer oriented body of literature. 
  • Although the use of statins improved PSA-RFS for intermediate and high-risk patients examined in this study, this was not reflected in OS for any subset of the population.
  • As the authors point out, significant limitations exist to this study, mainly due to its retrospective nature. Because patients who were taking statin medications were not doing so as part of their treatment for prostate cancer, the majority of details of statin therapy employed by this cohort are unknown. 
  • A phase III, randomized, prospective trial, potentially with an element of statin dose-variation or escalation would serve to answer the question of the role of statins in prostate cancer more completely, and is certainly warranted. The current study, however, serves an important role as a well-designed, observational, retrospective first attempt to examine this question.

Partially funded by an unrestricted educational grant from Bristol-Myers Squibb.



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