Surgical Castration Instead of Drugs in Prostate Cancer

Veronica Hackethal, MD

December 29, 2015

For some men with metastatic prostate cancer, surgical castration to remove the testicles (orchiectomy) could be a better option than "chemical castration" achieved by long-term use of prostate gonadotropin-releasing hormone (GnRH) agonist products, as it may carry less risk for adverse events, suggests a new study published online December 23 in JAMA Oncology.

"The paradigms of treatment for advanced prostate cancer are ever changing, but there remains a group of men who require permanent castration. For those men, orchiectomy is a reasonable alternative that is associated, according to our study, with lower risks of fractures, peripheral arterial disease, and cardiac-related complications than GnRH agonists," commented lead author Quoc-Dien Trinh, MD, from Harvard Medical School in Boston, Massachusetts.

"Unfortunately, for a multitude of reasons, most of which are unjustified, urologists and medical oncologists no longer offer the option of orchiectomy," he continued. "This is in spite of guidelines continuing to recommend orchiectomy as a first-line treatment for men presenting with metastatic prostate cancer."

I find it disconcerting that a perfectly reasonable, cost-effective surgical treatment...has disappeared from medical practice for nonscientific reasons. Dr Quoc-Dien Trinh

"I find it disconcerting that a perfectly reasonable, cost-effective surgical treatment with potentially less adverse effects and compliance issues than its pharmacologic equivalent has disappeared from medical practice for nonscientific reasons," Dr Trinh emphasized.

CV Risk With Androgen Deprivation

For the last 50 years, androgen-deprivation therapy has been the cornerstone of treatment of metastatic prostate cancer, the authors write.

However, achieving androgen deprivation by bilateral orchiectomy has basically been eliminated from clinical practice, mainly because of aesthetic and psychological issues, but also because medical therapy is reversible and easy to administer, the authors write.

The current standard of care is long-term use of GnRH agonist products such as goserelin (Zoladex, AstraZeneca) and leuprolide (Lupron, AbbVie).

However, there is mounting evidence that androgen-deprivation therapy is linked to significant adverse effects, such as cardiovascular events, diabetes, acute kidney injury, and bone loss, the authors write. The US Food and Drug Administration requires that GnRH agonist product labeling include a warning about the increased risk for diabetes and cardiovascular disease.

Past research looking at adverse cardiac events associated with GnRH agonist products has suggested there is a lower cardiac risk in patients with orchiectomies. That led to the hypothesis that cardiac adverse effects may be related to GnRH agonist products, rather than androgen deprivation per se.

The authors set out to compare directly the adverse events seen with androgen deprivation achieved by surgery vs those achieved by GnRH agonist use.

Fewer Adverse Events After Orchiectomy

In the current study, researchers used the Surveillance, Epidemiology, and End Results database linked to Medicare records to identify participants. The study included 3295 Medicare recipients aged 66 years and older with metastatic prostate cancer diagnosed between January 1995 and December 2009 and treated with a GnRH agonist or orchiectomy within 12 months of diagnosis. Eighty-seven percent of men received a GnRH agonist, and 13.0% had orchiectomies.

Results showed that compared with men who received GnRH agonist products, those who underwent bilateral orchiectomies had:

  • 23% lower risk for any fracture (hazard ratio [HR], 0.77; P = .01);

  • 35% lower risk for peripheral arterial disease (HR, 0.65; P = .004); and

  • 26% lower risk for cardiac-related complications (HR, 0.74; P = .01).

Men who received GnRH agonist for 35 months or more had substantially increased risk for fractures (HR, 1.80), peripheral arterial disease (HR, 2.25), venous thromboembolism (HR, 1.52), cardiac-related complications (HR, 1.69), and diabetes (HR, 1.88) (P ≤ .001 for all).

No statistically significant differences existed between orchiectomy and GnRH agonists for patients with diabetes and cognitive disorders.

Patients Asking About Surgery

GnRH agonists have largely replaced orchiectomy because of their ease of administration, reversibility, the avoidance of disfiguring surgery, and likely (at least in part) the financial incentive afforded to prescribing physicians, write the authors of an accompanying editorial. The authors are Michael P. Kolinsky, BSc, MD, Pasquale Rescigno, MD, and Johann de Bono, MB, ChB, FRCP, PhD, FMedSci, all from the Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.

"Patients we are seeing in clinic are raising concerns about the cardiovascular safety of GnRH agonists, and some in fact have questioned whether they would have been better off having had a bilateral orchiectomy," Dr Kolinsky commented to Medscape Medical News.

Providing a direct answer is difficult, however, because the topic is "controversial," and studies have shown "contradictory results," he explained.

The current article "adds fuel to an already controversial debate and the discredit brought by the reimbursement issues," the editorialists write.

However, although it adds to the important debate, the study has several limitations. Although the researchers adjusted for potential confounders, its retrospective design still carries the risk for bias. The results will need verification in a randomized prospective study "before any firm conclusions can be made," Dr Kolinsky pointed out.

"Unfortunately a study of this type is unlikely to occur because many, if not most, patients would find the prospect of being randomized to orchiectomy unpalatable," he concluded. "For the time being, the only conclusion that can be made is that both options should be presented to patients in an unbiased fashion, with a frank discussion of the potential advantages and disadvantages of both forms of androgen-deprivation therapy, and to allow patient preference to guide the final decision."

"In the absence of clear evidence to the contrary, patients are likely to continue to overwhelmingly favor [GnRH agonists] over orchiectomy, " the editorialists conclude.

Two coauthors report relationships with industry. The other coauthors and the editorialists have disclosed no relevant financial relationships.

JAMA Oncol. Published online December 23, 2015. Article abstract, Editorial extract


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