Androgen Depletion and Increased Cardiac Risk in Prostate Cancer Patients

Abstract & Commentary

By William B. Ershler, MD, Editor

Synopsis: In a retrospective review of a primarily community-based registry of prostate cancer patients, a heightened risk of cardiovascular mortality was found for patients with localized disease treated with either adjuvant or neoadjuvant androgen deprivation.

Source: Tsai HK, et al. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst. 2007;99:1516-1524.

Currently, primary treatments for localized prostate cancer include watchful waiting, active surveillance, interstitial brachytherapy, external beam radiotherapy, cryotherapy, radical prostatectomy, and primary hormonal therapy.1 Oftentimes, treatment is guided by the experience of the attending physician coupled with an assessment of the risk for progressive cancer and dying of this disease in the context of the patient's age and comorbidities. As an adjunct to prostatectomy or radiation therapy, some patients are offered androgen deprivation therapy (ADT) either by a neoadjuvant or adjuvant approach. Indeed, ADT use has increased substantially in this setting over the past few years,2 and there has been recent evidence linking it with increased risk for both diabetes and cardiovascular disease.3 ADT can lead to elevated body mass index, increased fat deposition, and decreased insulin sensitivity, all of which characterized the metabolic syndrome.4 Accordingly, the influence of ADT on the development or progression of cardiovascular disease has become an important issue.

In a retrospective review, Tsai and colleagues examined data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) dataset that included 3262 prostatectomy patients and 1630 patients treated with external beam radiotherapy, brachytherapy, or cryotherapy for localized prostate cancer. The overall CaPSURE registry included 13,124 patients from 31 urology practices (25 community-based, 3 university practices, and 3 US Department of Veterans Administration Hospitals). Men with localized disease were identified and of these there were 4892 for whom data was available for this analysis. ADT was defined as treatment with gonadotropin releasing hormone agonist and/or an antiandrogen either neoadjuvantly (initiated before the start of local therapy) or adjuvantly (initiated up to six months after the start of local therapy). Overall, 1015 patients were treated with ADT in conjunction with local therapy, and 3877 patients were not treated with ADT. Among the patients who underwent radical prostatectomy, 266 were treated with ADT, and among those who received nonsurgical treatment, 749 were treated with ADT. The median follow-up time was 3.8 years (range equals 0.1 to 11.3 years).

The outcome examined was cardiovascular death, and competing risk methods were utilized to determine time of cardiovascular death while accounting for those competing risks (ie, death from prostate cancer or other non-cardiovascular causes). Additionally, regression analysis for age and known risk factors for cardiovascular disease were included.

The results indicated that ADT statistically significantly shortened time to cardiovascular death and was associated with an increased cumulative incidence of cardiovascular death at five years among prostatectomy patients regardless of age. Also noted was a greater incidence of cardiovascular death among patients 65 years old and older who were treated with ADT and managed with external beam radiotherapy, brachytherapy, or cryotherapy, but the difference from those not given ADT did not reach statistical significance.

Thus, in this series, the use of adjuvant (or neoadjuvant) ADT was associated with increased risk of death from cardiovascular disease, and this was particularly noticeable for those treated surgically.

Commentary

In this careful review of the CaPSURE data set, ADT was apparently associated with cardiovascular mortality. In fact, more patients treated for localized prostate cancer died of cardiovascular disease than died of prostate cancer. It also appeared from their analysis that those treated by surgical approach were at greater risk for the ADT-enhanced cardiovascular mortality than those treated by non-surgical approaches that included adjuvant ADT. However, the numbers were relatively small for those receiving ADT after surgery compared to after radiotherapy, and any conclusion regarding the difference between primary approach (surgery vs radiation) and the risk of ADT would be premature. However, as for the use of adjuvant (or neo-adjuvant) ADT in general, the association with increased cardiovascular risk seems valid.

But, even this finding requires confirmation as the analysis was retrospective. Patients offered adjuvant ADT are likely not quite the same as those who were not offered the additional treatment. Indeed, in this series they had higher prostate-specific antigen (PSA) levels, larger primary tumors and higher Gleason scores. Even though these factors were considered in the regression analysis and by the competing risk methods adjusting for known cardiovascular risk factors, the association of ADT and cardiovascular mortality remained significant. Yet, in a retrospective analysis such as this, other factors that were not included may define differences between those treated and those not, and to the extent that these factors may be associated with cardiovascular risk, the findings are made less definitive.

Nonetheless, it is quite likely that ADT increases risk for cardiovascular death both in the prostatectomy (as demonstrated here) and radiotherapy-treated, and the mechanism may well relate to the metabolic alterations noted above. It is notable that a pooled analysis of three trials that randomly assigned patients to radiation therapy, either with or without short course ADT, showed statistically significant shorter times to fatal myocardial infarction among patients 65 and older treated with ADT and radiation when compared to those treated with radiation alone.5 Although data from a prospective randomized trial is not currently available, the authors recommend that patients with localized prostate cancer considering adjuvant ADT after primary therapy be carefully screened for other cardiovascular risk factors and observed very closely in that regard during therapy. This makes good sense.

References

1. Thompson I, et al. 2007 update. J Urol. 2007;177(6):2106-2131.

2. Shahinian VB, et al. Cancer. 2005;103(8):1615-1624.

3. Keating, NL, et al. J Clin Oncol. 2006;24(27):4448-4456.

4. Braga-Basaria M, et al. J Clin Oncol. 2006;24(24):3979-3983.

5. Smith MR, et al. J Clin Endocrinol Metab. 2002;87(2):599-603.