PCa castration study fuels surgery vs. GnRHA debate

While the use of orchiectomy for androgen deprivation therapy (ADT) has been almost entirely replaced by medical castration with a gonadotropin-releasing hormone agonist (GnRHA), guidelines continue to recommend orchiectomy as a first-line treatment for men with metastatic prostate cancer.

Now, results of a recently published, population-based study examining the safety of the two approaches (JAMA Oncol epub ahead of print, Dec. 23, 2015: 1-8) support stronger consideration for orchiectomy, according to its authors.

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The investigation, using the Surveillance, Epidemiology, and End Results Medicare-linked database, identified 3,295 men aged 66 years and older who were treated from 1995 to 2009 with ADT as primary cancer therapy within 12 months of metastatic prostate cancer diagnosis.

Results of analyses using competing risk regression models and adjusting for all-cause mortality showed the surgical castration group (429 patients) had significantly lower risks of any fractures (–23%), peripheral arterial disease (–36%), and cardiac-related complications (–26%) when compared to their counterparts receiving GnRHA treatment (2,866 patients).

Additional analyses showed orchiectomy was associated with a significantly higher 3-year overall survival rate versus GnRHa treatment (46% vs. 39%) and similar total expenditures at 1 year after prostate cancer diagnosis in an analysis adjusting for treatment propensity scores.

Next: Orchiectomy "a perfectly reasonable, cost-effective treatment"

Corresponding author Quoc-Dien Trinh, MD, told Urology Times, “The adverse effects of orchiectomy and GnRHAs have been compared previously, but this is the first comprehensive, head-to-head assessment of six major risks. Based on our study, orchiectomy is a perfectly reasonable, cost-effective treatment with potentially less adverse effects than its pharmacologic equivalent, and it mitigates compliance issues.

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“While they may be more limited today than before, indications for permanent castration still exist. We find it disconcerting that for a multitude of reasons that are non-scientific and mostly unjustified, urologists and medical oncologists no longer offer the option of orchiectomy when appropriate,” added Dr. Trinh, of Brigham and Women’s Hospital, Boston, who worked on the study with first author Maxine Sun, MPH, and colleagues.

The primary endpoint analyses in the study also evaluated the risks of diabetes mellitus, venous thromboembolism, and cognitive disorders, but found no significant treatment-related differences. However, subgroup analyses stratifying men by duration of GnRHA exposure found that men who received GnRHA treatment for at least 35 months remained at significantly higher risk of experiencing fractures, peripheral arterial disease, and cardiac-related complications relative to their surgical castration counterparts. In addition, the medical castration group had significantly increased risks of developing diabetes mellitus and venous thromboembolism.

Dr. Trinh acknowledged that the study has limitations; the fact that it is a retrospective observational study leads to the possibility of confounding.

“Our statistical methods were designed to account for potential treatment selection biases that could occur because the patients were not randomly assigned to the two ADT groups. Nevertheless, there may be some confounding that cannot be accounted for, including that related to body mass index, tobacco use, and genetic predisposition,” he said.

In addition, because the outcomes were identified using diagnosis codes, it is possible that men receiving GnRHA treatment might have been more likely to be diagnosed and treated for the adverse events as a result of having more frequent doctor visits.

Dr. Trinh also noted that because the study included only Medicare beneficiaries, the findings might not be applicable to men of all ages or those with other insurance coverage.

Dr. Trinh and colleagues noted that a prospective study would be needed to more definitively determine the relative risks of medical and surgical castration.

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“However, the paradigms of treatment for advanced prostate cancer are ever changing, and I do not think such a study will ever be conducted,” he said.

Next: Dr. de Bono, colleagues comment on study in editorial

An editorial relating to the study (JAMA Oncol epub ahead of print, Dec. 23, 2015: 1-2) written by Johann S. de Bono, MB, ChB, MSc, PhD, and colleagues from the Institute of Cancer Research and the Royal Marsden National Health Service Foundation Trust, London, discussed potential weaknesses of the study and recognized its strengths and the biologic plausibility of the findings.

“Despite their retrospective nature, studies such as this are critically important, because they increase awareness of these concerns,” Dr. de Bono and colleagues stated in their conclusion. “Because men with metastatic prostate cancer are living longer than ever, it is imperative that we minimize the risk of harm from therapies. Physicians treating patients with prostate cancer must familiarize themselves with how to prevent and treat these complications.

“The current article by Sun et al. adds fuel to an already controversial debate and the discredit brought by the reimbursement issues. When there is more than one reasonable option, clinical decisions must be guided by the patient’s values and preferences. In the absence of clear evidence to the contrary, patients are likely to continue to overwhelmingly favor GnRHA over orchiectomy,” they wrote.

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