Risks of Androgen Suppression Therapy for Prostate Cancer: The Importance of Comorbidities

Abstract & commentary

Synopsis: In a post hoc analysis of patients entered on a prostate cancer clinical trial, among those receiving androgen suppression therapy, those with higher levels of comorbidity were more likely to suffer adverse consequences, and this was particularly evident for those who had lower risk for prostate cancer specific mortality.

Source: D'Amico AV, et al. Causes of death in men undergoing androgen suppression therapy for newly diagnosed localized or recurrent prostate cancer. Cancer. 2008;113:3290-3297.

Androgen suppression therapy (ast) is demonstrably of value in the treatment of metastatic prostate cancer1 and in the prevention of recurrence, when used in the neoadjuvant2 or adjuvant settings.3 Yet, there is a developing literature regarding adverse outcomes associated with AST, particularly with regard to metabolic syndrome and coronary artery disease.4,5 In fact, recently it was suggested that overall survival may even be shortened for those receiving AST plus external beam radiation compared with those receiving external beam radiation alone. D'Amico et al from the Dana Farber Cancer Institute have approached the issue of AST-associated mortality in the context of existing comorbidities by examining outcomes of 148 men who received AST treatment as part of a randomized clinical trial for prostate cancer. Of these, 102 were randomized to receive radiation therapy (RT) and AST and 46 men received salvage AST for recurrence. Detailed information on pre-existing medical conditions and comorbidities were collected at baseline, and a comorbidity score was assigned using ACE-27, a 27-item validated comorbidity index.6 Cox regression multivariable analyses were performed to estimate the mortality hazard ratio (HR) in men with moderate-to-severe, as compared with no or minimal comorbidity, adjusting for age and known prostate cancer prognostic factors.

After a median follow-up of 8.4 years (interquartile range: 7.2-9.6 years), prostate cancer-specific mortality (PCSM) comprised 13% and 75% of all mortality in men with newly diagnosed localized and recurrent prostate cancer, respectively. There was an increased risk of death in men with moderate-to-severe as compared with no or minimal comorbidity (adjusted HR [AHR], 11.5; 95% confidence interval [CI], 5.2-25.6; p < .001) in men with newly diagnosed localized prostate cancer, but not in men with recurrent prostate cancer (AHR, 2.5; 95% CI, 0.2-37.8; p = .51).

Commentary

Thus, it appears that the increased risk of death associated with AST is observed primarily in men with lower risk of prostate cancer death (eg, low risk factors, early treatment) and higher levels of comorbidity. In this group, the metabolic consequences of AST are likely to occur over sufficient duration to exacerbate the underlying comorbidities. In contrast, in situations where the risk of prostate-cancer specific mortality is greater (eg, higher number of risk factors or more advanced disease), the comorbidity issue is less of a factor; AST remains of benefit across the board with regard to survival.

In the accompanying editorial,7 Oefelein provides a thoughtful review of the benefits and risks of AST, and offers insight with regard to the relevance of these findings. He also raises certain methodological issues, particularly the omission of data regarding cardiovascular risk factors (eg, tobacco use, body weight, blood pressure, etc.) that suggest that over interpretation of the findings would be ill-advised.

Nonetheless, it is fair to conclude that AST administered to prostate cancer patients is not as safe as it was once thought to be, and that patients with existing comorbidities are likely to be at higher risk for catastrophic consequence. Thus, patients with low risk for prostate cancer mortality, but with significant comorbidities may be better served by a treatment strategy that employs active surveillance and more conservative utilization of AST.

References

1. Wirth MP, et al. Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median follow-up of 5.4 years. J Urol. 2004;172:1865-1870.

2. D'Amico AV, et al. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008;299:289-295.

3. Messing EM, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006;7:472-479.

4. Braga-Basaria M, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol. 2006;24:3979-3983.

5. Smith MR, et al. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91:1305-1308.

6. Piccirillo JF, et al. Prognostic importance of comorbidity in a hospital-based cancer registry. JAMA. 2004;291: 2441-2447.

7. Oefelein MG. Androgen suppression therapy and prostate cancer: balancing the harms and the benefits. Cancer. 2008;113:3275-3278.