Parenteral estrogen may reduce hormone agonist toxicity in prostate cancer

Issue: June 10, 2013

Parenteral estrogen patches were associated with encouraging reductions in fasting glucose and cholesterol in a cohort of men with advanced prostate cancer, according to results of a multicenter phase 2 trial.

Ruth E. Langley, MRCP, of the Medical Research Council’s clinical trials unit, and colleagues from several other sites in the United Kingdom conducted the open-label, randomized trial to determine whether parenteral estrogen could reduce the toxic effects of luteinizing hormone-releasing hormone agonists in prostate cancer therapy.

Men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy were eligible for analysis.

Study protocols dictated a 2:1 randomization ratio. The analysis included 169 patients assigned to four self-administered estrogen patches at a dose of 100 mcg per 24 hours to be changed twice weekly, and 85 patients assigned to luteinizing hormone-releasing hormone agonists administered according to local practice. Castrate testosterone concentrations were defined as 1.7 nmol/L or lower. When this point was reached, men were assigned three estrogen patches to be changed twice weekly.

Cardiovascular morbidity or mortality served as the primary endpoint.

Three-month results indicated that 92% of the 121 patients in the estrogen cohort and 93% of 75 patients in the hormone agonist cohort had reached castrate testosterone concentrations.

The median follow-up duration was 19 months (interquartile range, 12-31 months). At this time point, 24 cardiovascular events occurred. There were 18 events among 17 men (10.1%; 95% CI, 6.0-15.6) in the estrogen group and six events among six men (7.1%; 95% CI, 2.7-14.9) in the hormone agonist group. Half of the 18 events in the estrogen group occurred before crossing over to hormone agonists.

At 12 months, men in the estrogen group experienced a mean change in fasting glucose concentrations of –0.16 mmol/L (–2.4%) compared with a change of 0.33 mmol/L (5.5%) in the luteinizing hormone-releasing hormone agonists group (P=.004). The mean changes for fasting cholesterol were –0.23 mmol/L (–3.3%) for estrogen and 0.2 mmol/L (4.1%) for hormone agonists (P<.0001).

The 6-month adverse event analysis results indicated that gynecomastia occurred in 75% of 138 patients in the estrogen arm and 19% of 78 patients in the hormone agonist arm. Hot flushes occurred in 25% of estrogen patients and 56% of hormone agonist patients, whereas dermatological problems were reported in 42% of the estrogen group and 13% of the hormone agonist group.

Fred Saad

“The study, although small and with short follow-up, does provide reassuring data in terms of cardiovascular risk, but efficacy needs to be confirmed,” Fred Saad, MD, FRCS, professor of surgery/urology, chairman of the division of urology and director of urologic oncology at the University of Montreal Health Center, wrote in accompanying editorial.

“Normally, efficacy of [androgen deprivation therapy] is classified as patients achieving castrate levels of testosterone. Nevertheless, a reduction of testosterone concentrations to lower than the historical castrate threshold of 1.7 nmol/L alone should no longer be viewed as sufficient,” Saad wrote. “Just how low testosterone concentrations go with [estrogen] patches needs to be investigated.”

The optimal dose of estrogen to maintain testosterone suppression remains unclear, Saad said. However, the approach may be safe, effective and cheap, and enthusiasm for this approach should not wane, he wrote.

For more information:

Langley RE. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70025-1.

Saad F. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70057-3 .