Prostate Cancer ADT May Up Risk for Thromboembolism

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Androgen-deprivation therapy without estrogen is associated with a significant 43% increased risk of thromboembolic events, meta-analysis shows.
Androgen-deprivation therapy without estrogen is associated with a significant 43% increased risk of thromboembolic events, meta-analysis shows.

Androgen deprivation therapy (ADT) may increase the risk for thromboembolic events such as deep vein thrombosis and pulmonary embolus in men with prostate cancer (PCa), Kevin T. Nead, MD, MPhil, of the Hospital of the University of Pennsylvania in Philadelphia, and colleagues reported in Urology.

ADT (e.g. gonadotropin-releasing hormone agonists, antiandrogens) without estrogen increased the risk for thromboembolic events by a significant 43% in exposed versus unexposed patients, according to a meta-analysis of 10 studies including more than 250,000 men. The researchers found 10% and 58% greater risks among patients with localized and metastatic PCa, respectively. Nonsignificant results suggested that men who received ADT for more than a year were the most at risk. Investigators found no significant differences in risk between recipients of continuous and intermittent ADT.

In addition, other findings confirmed substantial risks from estrogen therapy alone. Estrogens were associated with a more than 3-fold increased risk for thromboembolic events, based on data from more than 1250 men in 9 studies. According to a meta-regression analysis, the risk for thromboembolic events was 53% greater with estrogen therapy than with ADT without estrogen.

“In conclusion, we provide evidence to support an association between ADT in the treatment of prostate cancer and the risk of thromboembolic events even in the absence of estrogen therapy,” Dr Nead and colleagues wrote. “Adverse thromboembolic events should be considered when selecting patients for and treating patients with ADT, particularly in settings where it is unknown whether the use of ADT will provide a survival benefit. This finding further contributes to the body of evidence identifying potential harms of ADT and underscores the importance of appropriate patient selection.”

The investigators urged careful consideration of ADT in patients where the benefit is less clear, such as in low-risk disease. The risks and benefits need to be weighed particularly in patients with multiple risk factors for thromboembolic events.

With regard to potential mechanisms, ADT might increase the risk for thromboembolism via androgens, Dr Nead and his peers explained. Testosterone correlates with antithrombin, and suppression of testosterone can lead to a hypercoagulable state.

The team could not evaluate thromboembolic event risk by specific type of ADT, which is a limitation. They also recommended that future randomized trials evaluate thromboembolic prophylaxis in patients receiving ADT.

With regard to the findings that support an association between ADT and thromboembolic risk,  Nirmish Singla, MD, of the University of Texas Southwestern Medical Center in Dallas, in an accompanying editorial, questioned what should be done with this information. “Is there a role for thromboembolic prophylaxis in patients receiving ADT? Secondly, should baseline thromboembolic risk be factored into the candidacy and contraindications for ADT?”

Although no definitive guidelines directly addressing these questions exist, “physicians should undoubtedly be aware of this association and counsel prostate cancer patients accordingly prior to the initiation of ADT.”

Additionally, other factors that raise the risk for thromboembolism, including baseline malignancy status and disease burden, advanced age, immobilization, fractures, cardiovascular disease, and prior thromboembolic events, must be taken into account when prescribing ADT, Dr Singla wrote.

“The decision to administer ADT and the type of ADT should follow an informed discussion between provider and patient that incorporates this data,” he said.

References

Nead KT, Boldbaatar N, Yang DD, Sinha S, Nguyen PL. Association of androgen deprivation therapy and thromboembolic events: a systematic review and meta-analysis.  Urol. 2018. doi: 10.1016/j.urology.2017.11.055

Singla N. [Editorial comment] Association of androgen deprivation therapy and thromboembolic events: a systematic review and meta-analysis. Urol. 2018. 

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