PROSTATE CANCER INCREASES THROMBOEMBOLIC RISK

April 15, 2010 — All men with prostate cancer have a higher risk for thromboembolic disease, compared with the general population, and the risk for deep vein thrombosis (DVT) and pulmonary embolism (PE) is "especially high" in those undergoing hormonal therapy.

These results come from a new analysis of data from the Swedish National Prostate Cancer Register, published online in The Lancet Oncology.

Lead author Miekle van Hemelrijck, MSc, at the Cancer Epidemiology Group at King's College Hospital, London, United Kingdom, who is a doctoral candidate, said she has just been asked to present these data at a late-breaking session at the European Association for Urology meeting taking place this weekend.

This same team has recently reported, from the same database, that the risk for cardiovascular disease is increased by hormonal therapies used in prostate cancer. Similar findings have been reported from several other studies, and earlier this year the increased risk for cardiovascular disease in men with prostate cancer treated with hormonal therapies was highlighted in an advisory in February 2010 issued jointly by the American Heart Association, the American Cancer Society, and the American Urological Association.

Suppression of Testosterone Detrimental?

This new study focused on thromboembolic disease, but some of the findings are similar to the group's previous study on cardiovascular disease, Ms. Van Hemelrijck commented in an interview with Medscape Oncology.

For instance, the highest risk for both was seen in men undergoing gonadotrophin-releasing hormone (GnRH) agonist therapy or those who had undergone orchidectomy, whereas men who were treated with antiandrogens were at the lowest risk among those who were treated with hormonal therapies. This ties in with research suggesting that testosterone is important both in the functioning of the heart and in thromboembolism and that suppressing it completely is detrimental to both, Ms van Hemelrijck explained. With antiandrogens, there is still testosterone circulating, but it is prevented from acting on the prostate by androgen receptor blockade, she added.

However, an accompanying editorial points out that several factors limit the observation that antiandrogens were associated with a more modest increase in the risk of thromboembolism compared with GnRH agonist or orchidectomy.

Editorialists Philip Saylor, MD, and Annmarie Fogerty, MD, from the Massachusetts General Hospital Cancer Center in Boston, note that the antiandrogen subset was small. These patients were also less likely to have metastatic disease than patients in the other treatment groups. In addition, antiandrogen monotherapy "is not currently the standard of care in any setting," they point out.

Main Message: Monitor Patients

The most important point from these studies, Ms. van Hemelrijck says, is that men with prostate cancer who are being treated with hormonal therapies should be monitored for cardiovascular disease (as suggested by the first study) and also for thromboembolic disease (as suggested by this present study), because they are at increased risk of both.

"But we are not saying that these hormonal therapies should not be used," she emphasized, pointing out that hormonal therapy is often the only option in locally advanced and metastatic prostate cancer.

The accompany editorial concurs. These new data "should increase clinical suspicion for venous thromboembolism in men with prostate cancer," the editorialists write, but the data "do not support withholding GnRH agonists or orchidectomy in clinical situations where they are known to be beneficial."

Highest Risk Is for DVT

The new study analyzed data collected in Sweden from 1997 to 2007 on 76,600 men with prostate cancer. Of these, 30,642 were treated with hormonal therapies, specifically, 9066 with a GNRH agonist, 5340 with orchidectomy, 3391 with antiandrogens, and 1199 with a combination of other drugs. The remaining men received either curative treatment, such as prostatectomy (n = 26,432) or active surveillance (n = 19,526).

Thromboembolic disease developed in 1881 of these men: 767 had a DVT, 873 had a PE, and 241 had an arterial embolism (AE).

This incidence of thromboembolic disease is higher than is seen among men in the general population, and this is "not surprising," commented Ms. van Hemelrijck, "as cancer is known to increase the risk of thromboembolism."

The risk was increased (nearly doubled) for DVT and PE but not for AE (although the AE numbers were small, the researchers point out).

The results are expressed as a standardized incidence ratio (SIR), defined as the ratio of the observed number of a particular thromboembolic disease to the expected number of that disease.

The SIRs for all men with prostate cancer were 1.9 for DVT, 1.85 for PE, and 1.02 for AE.

The increase in risk was seen regardless of the treatment received, but the magnitude of this increased risk varied. The largest absolute risk (more than doubled) was seen for DVT for men receiving endocrine treatment.

The SIRs for men with prostate cancer undergoing endocrine therapy were 2.48 for DVT, 1.95 for PE, and 1.0 for AE.

For men who had undergone curative treatment, the SIRs were 1.73 for DVT, 2.03 for PE, and 0.95 for AE, whereas for men undergoing surveillance the SIRs were 1.27 for DVT, 1.57 for PE, and 1.08 for AE.

However, this study "cannot directly quantify how much the observed differences in thromboembolic disease risk between treatments groups are due to the treatments themselves," the researchers write.

Cancer itself, increased age, and hormonal treatments all increase the risk of thromboembolic disease, but "we cannot tease out the contribution made by each of these factors," Ms. Hemelrijck added.

Causation Cannot Be Inferred

Although an increase risk in both DVT and PE was seen with endocrine therapy, "causation cannot be inferred from these observations," the editorialists emphasize.

They point out that men treated with endocrine therapy had a greater proportion of metastatic or otherwise poor-risk disease, and advanced cancer is a known risk factor for venous thromboembolism. This group of patients also included the highest proportion of men older than 75 years, and advanced age is also a known risk factor for venous thromboembolism in patients with cancer, they add.

Nevertheless, these latest data raise the question of whether endocrine therapy increases the risk of venous thromboembolism, they concede. They hope that the new findings will "stimulate further study of potential interactions between androgen deprivation and blood coagulability."

Ms. Hemelrijck has disclosed no relevant financial relationships, but 2 coauthors do: one has served on the data monitoring committee for AstraZeneca, and another has received consultancy fees from Ferring Pharmaceuticals (which markets a GnRH agonist). The editorialists have disclosed no relevant financial relationships.

Lancet Oncol. Published online April 14.