Two articles in the July 24 issue of The Cancer Letter referenced a April 1 Journal of Urology manuscript (doi:10.1097/JU.0000000000000577) describing frequent delays in administration of LHRH agonists and the potential clinical impact as assessed through recovery of testosterone.
The interview with Jason Hafron further emphasized that this issue has the potential for becoming even worse during the COVID-19 pandemic, given patients’ reluctance to come to clinic or physician offices for routine care.
Given the well-known association of adherence with socioeconomic status, it is further interesting to speculate on the differential impact of late LHRH agonist administration in socioeconomically deprived communities, a factor that was not investigated by Hafron and colleagues, but is almost certainly relevant, based on our anecdotal observations.
The clinical relevance of the modest observed impacts on testosterone is debatable, but the randomized Level 1 data of intermittent versus continuous androgen ablation strongly argues that this is important. Dr. Hafron, and other commentators, also discuss potential causes for delays in treatment and focus on reimbursement schedules that place institutions and practices at financial risk with these very expensive medications.
That in itself is an interesting claim for those of us old enough to recall the illegal, sponsor-supported, schemes of providing discounted leuprolide to practitioners who then sold them to patients (and their insurance carriers) at a handsome profit.
While one can certainly consider multiple policy, business, and health system approaches to better financially support appropriate medical therapy, the authors and commentators seem to have forgotten a far cheaper, permanent, and potentially more effective approach to androgen ablation; namely, surgical orchiectomy.
The economic impacts of LHRH agonists, in an era with increasing attention to medical costs, are staggering. A 2001 article estimated an orchiectomy cost per case of $2,479, compared to an annual cost of depot leuprolide of $7,136 (doi:10.1097/00005392-200101000-00026). Not only do patients with advanced disease receive these treatments for many years, drug prices have continued to escalate, despite the availability of several medically equivalent LHRH agonists.
The clinical relevance of the modest observed impacts on testosterone is debatable, but the randomized Level 1 data of intermittent versus continuous androgen ablation strongly argues that this is important.
Perhaps most relevant is that in 2018 Medicare alone spent over $358 million for leuprolide and goserelin under Medicare parts B and D. When private insurance and patient out-of-pocket costs are additionally considered, an annual United States expenditure of a billion dollars is at least the correct order of magnitude.
Is there any true value to this expenditure?
From an economic and medical perspective, it is hard to justify. Surgical orchiectomy is a rapid, permanent, and highly effective method for decreasing testosterone levels; nevertheless, its use is low and has been decreasing over the last two decades (doi:10.1097/JU.0000000000000684).
There have been arguments that LHRH agonists may have additional beneficial impacts; however, this is not borne out in randomized studies (doi:10.1016/S0090-4295(99)80197-6). In fact, comparative studies suggest that adverse effects of LHRH agonists may actually be higher than orchiectomy (doi:10.1001/jamaoncol.2015.4917).
Similarly, a recent study of a novel LHRH antagonist suggested a higher risk of cardiovascular morbidity with a LHRH agonist, compared to the antagonist (doi:10.1056/NEJMoa2004325). A review of the event curves in this study suggests that this increased risk occurs early, raising the hypothesis that it is associated with the testosterone flair that occurs with initial LHRH agonist therapy.
We are thus using an expensive drug that is no more effective, and potentially more lethal, than a simple surgical procedure.
Clearly, there are body image and patient-related issues with surgical orchiectomy. Many of these are associated with the physiologic effects of androgen ablation in general rather than orchiectomy specifically; however, the absence of palpable and notable testicles is noteworthy.
Interestingly, subcapsular orchiectomy has an equivalent impact on testosterone, compared to simple orchiectomy, but leaves residual tissue, and is associated with potentially less psychologic stress and less of the so-called postoperative empty scrotum feeling (doi: 10.1016/S0090-4295(99)80460-9), (doi: 10.4274/uob.925).
Here, it is perhaps important to point out that medical castration also leads to involution and marked shrinkage of the testicles to approximately half the pretreatment size (doi: 10.1097/01.ju.0000135831.19857.5c).
Based on our experience, patients seem more willing to consider surgical orchiectomy after a period of exposure to medical castration. Therefore, to more carefully study these issues, we are opening a clinical trial assessing feasibility and acceptance of performing subcapsular orchiectomy in patients on long-term medical castration.
In this trial, eligible patients will be approached to participate in a short education session about orchiectomy, and the fraction of patients who eventually undergo the procedure will be the primary endpoint.
Other important endpoints include change in body image perception, sexual function and satisfaction, and decision regret. The total institutional and out-of-pocket costs of one year of therapy with medical versus surgical castration will be compared.
The cost of medical care in general and oncologic care specifically continues to dominate the headlines, and in oncology the cost of drugs is becoming an increasing component of medical expenditures.
While it is not politically expedient to discuss appropriate maximum healthcare spending, at least in the United States, there is little doubt that tradeoffs are necessary. Fundamentally, money spent on a specific treatment will likely preclude alternative spending.
In a field that continues to be dominated by men, one might ask if scrotal cosmesis is worth a billion dollars.
