Aspirin and Statin Nonuse Associated With Early Biochemical Failure After Prostate Radiation Therapy

Abstract & Commentary

By Samir P. Kanani, MD, Associate Clinical Professor of Neurosurgery and Radiation Oncology, George Washington University; Radiation Oncology, Inova Fairfax Hospital, Falls Church, VA. Dr. Kanani reports no financial relationships relevant to this field of study.

Synopsis: In a large retrospective series, 2051 men with clinically localized prostate cancer received definitive radiation therapy (RT) alone. The rates of aspirin use and statin use were 36% and 34%, respectively. The primary endpoint was IBF (interval to biochemical failure) of < 18 months. With a median follow-up of 75 months, univariate analysis demonstrated that an IBF of < 18 months was associated with aspirin nonuse, statin nonuse, anticoagulant nonuse, cardiovascular disease, and PSA, but not Gleason score, age, RT dose, or T stage. On multivariate analysis, only aspirin nonuse and statin nonuse were associated with an IBF of < 18 months.

Source: Zaorsky NG, et al. Aspirin and statin nonuse associated with early biochemical failure after prostate radiation therapy. Int J Radiation Biol Phys 2012; [Epub ahead of print].

Between 1989 and 2006, 2051 men with localized prostate cancer received definitive RT (median dose = 76 Gy) without androgen deprivation therapy. 3DCRT was used to treat 64% of the patients and the remainders were treated with intensity-modulated radiotherapy. Approximately 90% of the patients were low- and intermediate-risk patients, according to the National Comprehensive Cancer Network criteria. Thirty-six percent reported aspirin use either at the time of radiotherapy or during follow-up and 34% reported statin use. Cardiovascular disease was present in 35% of patients.

The primary objective of this study was to retrospectively analyze this cohort of men to evaluate whether the use of statins and/or aspirin could prolong the interval to biochemical failure to > 18 months. The authors chose the surrogate endpoint of interval to biochemical failure (IBF) < 18 months as a cutoff, as this has been shown to be the single strongest predictor of distant metastasis, prostate cancer survival, and overall survival after radiation therapy (RT). On univariate analysis, an IBF of < 18 months was associated with aspirin nonuse (P < 0.0001), statin nonuse (P < 0.0001), anticoagulant nonuse (P = 0.0006), cardiovascular disease (P = 0.0008), and initial PSA level (continuous variable) (P = 0.008). Gleason score (2-6 vs 7 vs 8-10), age, RT dose, and T stage were not significant in predicting an IBF < 18 months.

On multivariate analysis, aspirin nonuse (P = 0.0012) and statin nonuse (P = 0.0002) were associated with an IBF < 18 months. Aspirin nonuse had an odds ratio (OR) of 2.052 (95% confidence interval [CI], 1.3-3.1) for an IBF < 18 months, and statin nonuse had an OR of 2.47 (95% CI, 1.53-3.97). The authors conclude that in men receiving RT for prostate cancer, aspirin and statin nonuse were associated with the early development of biochemical failure.

Commentary

The above summarized study definitely adds some clinical validity to the vast in vitro data regarding the antineoplastic effects of aspirin and statins. Aspirin is well known for its properties of inhibiting cyclooxygenase 2 (COX-2), which is upregulated in prostate cancer, and overexpression correlates with higher grade tumor.1 Aspirin has been shown to promote apoptosis through a variety of cellular mechanisms, including the upregulation of the Par-4 gene2 and inducing the expression of proapoptotic proteins Bax and Bak.3 Statins have demonstrated antineoplastic effects and have immunomodulatory effects via the effect on fatty acid synthesis.

The series by Zaorsky et al confirms a number of previously reported series that show a benefit in delaying biochemical failure patients with prostate cancer on anticoagulant therapy and/or statins. To date, no series has demonstrated on overall survival advantage.4-6 Certainly the population at risk for prostate cancer has a number of competing risk factors for mortality and it is easy to understand why no clear survival advantage could be found. It will be important to prospectively study the use of these drugs in the management of prostate cancer in respect to other clinically important endpoints such as metastasis-free survival. Also, it is crucial to point out that these retrospective series confirm an association between statins, aspirin, and biochemical failure, but by no means demonstrate causation between drug use and risk of biochemical failure. Drugs such as aspirin and statins have their own side effect profile that must be weighed carefully against any potential benefit in delay/prevention of biochemical failure in robust prospective trials. Optimal dosing schedules need to be determined as well. In my opinion, the strong association seen in this trial needs further investigation and the use of statins and aspirin should not be recommended until prospective trials validate that there is a causation between statin and aspirin use and biochemical outcomes.

References

1. Madaan S, et al. Cytoplasmic induction and over-expression of cyclooxygenase-2 in human prostate cancer: Implications for prevention and treatment. BJU Int 2000;86:736-741.

2. Zhang Z, DuBois RN. Par-4, a proapoptotic gene, is regulated by NSAIDs in human colon carcinoma cells. Gastroenterology 2000;118:1012-1017.

3. Zhou XM, et al. Non-steroidal anti-inflammatory drugs induce apoptosis in gastric cancer cells through up-regulation of bax and bak. Carcinogenesis 2001;22:1393-1397.

4. Rothwell PM, et al. Effect of daily aspirin on long-term risk of death due to cancer: Analysis of individual patient data from randomised trials. Lancet 2011;377:31-41.

5. Choe KS, et al. The use of anticoagulants improves biochemical control of localized prostate cancer treated with radiotherapy. Cancer 2010;116:1820-1826.

6. Marcella SW, et al. Statin use and fatal prostate cancer: A matched case-control study. Cancer 2011; Epub ahead of print.