Surgical orchiectomy vs. medical castration in treatment of metastatic prostate cancer

A new study in JAMA Oncology has suggested that surgical orchiectomy may have lower risk for complications and side effects than medical castration with LHRH agonists (also known as GnRH agonists) like leuprolide acetate (Lupron) and others in treatment of men newly diagnosed with metastatic prostate cancer. This is a complex issue!

The new paper by Sun et al. is based on a careful retrospective analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database encompassing 3,295 men, all aged 66 years or older and all diagnosed with metastatic prostate cancer between January 1995 and December 2009. The study has both strengths (because of the numbers of patients) and weaknesses (because it is a retrospective analysis based largely on diagnostic coding as opposed to actual clinical data). These strengths and weaknesses are discussed in an editorial by Kolinsky et al. that also appears in JAMA Oncology. In addition, the topic and the new data are discussed in an article on the Medscape web site.

What is clear at this stage, however, is that this is the first-ever, really large scale study that has attempted to compare the adverse effect profiles of the two most established methods for minimizing testosterone levels as a primary form of treatment to prevent the pain and suffering long associated with metastatic prostate cancer. Older and smaller studies have reached conflicting conclusions about the relative merits of the two primary types of castration in use around the world today. So here is what the authors claim to have established:

  • All 3,295 patients included had a primary diagnosis of metastatic prostate cancer (i.e., these were not men whose cancer was diagnosed at an earlier stage and then progressed over time).
  • Compared to patients treated with LHRH agonists, the patients treated by surgical orchiectomy had
    • Lower risk for bone fractures (hazard ratio [HR] = 0.77; P = 0.01)
    • Lower risk for peripheral arterial disease (HR = 0.65; P = 0.004)
    • Lower risk for cardiac-related complications (HR = 0.74; P = 0.01)
    • Similar risk for diabetes
    • Similar risk for cognitive disorders
  • Compared to patients treated by surgical orchiectomy, the patients treated with LHRH agonists for ≥ 35 months had
    • Higher risk for fractures (HR = 1.80; P ≤  0.01)
    • Higher risk for peripheral arterial disease (HR = 2.25; P ≤  0.01)
    • Higher risk for venous thromboembolism (HR = 1.52; P ≤  0.01)
    • Higher risk for cardiac-related complications (HR = 1.69; P ≤  0.01)
    • Higher risk for diabetes (HR = 1.88; P ≤  0.01)
  • Average (median) management costs for the first 12 months after prostate cancer diagnosis were similar for the two sets of patients.

The authors conclude that

[LHRH] agonist therapy is associated with higher risks of several clinically relevant adverse effects compared with orchiectomy.

Now it would be inappropriate to immediately conclude that we should start treating all men initially diagnosed with metastatic prostate  cancer with an orchiectomy (and docetaxel-based chemotherapy) based on these data alone. However, as Kolinsky et al. note in their editorial, the really key question is “Can we do less harm?” in the treatment of men with metastatic prostate cancer. There is no doubt that there can be significant psychological harms associated with a surgical orchiectomy for many men (above and beyond the loss of “maleness” caused by a massive reduction in serum testosterone). There is also the question of whether a patient wants to retain the potential for intermittent androgen deprivation therapy (which may depend on a whole range of factors).

The truth is that it would be impossible to reach any firm conclusions about the relative merits of orchiectomy as opposed to medical castration without conducting a large, careful, detailed, randomized, prospective clinical trial … and the chances that such a trial could be conducted today are pretty much zero, because of the cost of such a study and also because many patients simply wouldn’t be willing to be randomized to a surgical orchiectomy.

To quote Dr. Kolinsky from the above-mentioned Medscape article:

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.

11 Responses

  1. Could anyone speculate as to the reason why, since both stop the production of testosterone by the testes?

    Also Sitemaster, I am unclear how the incidence of diabetes can be both higher for the LHRH group and also similar for both groups.

    Happy New Year to you and all — may 2016 bring much health and happiness.

  2. Dear Rick:

    There are all sorts of possible reasons why the two form of therapy have different effects, starting with the fact that LHRH agonists are produced in the hypothalamus but act primarily on cells that control luteinizing hormone releasing hormone (LHRH) in the pituitary gland (which then has effects on a whole range of other biochemical pathways and not only on production of testosterone), whereas orchiectomy eliminates the majority of cells in the testes that normally produce testosterone.

    With regard to the effects on diabetes, the first set of data showing no difference included all patients in the study, whereas the second set included only patients who had been on androgen deprivation (by one method or the other) for a minimum of just under 3 years (i.e., a longer average period of time).

  3. Thanks for posting your article on this study. Here are a few initial thoughts as a veteran of IADT for 14 of the past 16 years. (I had no proven metastases at any time.)

    It is well established that bilateral orchiectomy works considerably faster and more reliably in reducing testosterone, and that corresponds to more rapid relief from pain due to pressure of the cancer in bone.

    The relatively new drug Firmagon, an LHRH-antagonist, is much faster acting and much more effective in lowering testosterone than the old LHRH-agonists. It probably functions much the same as orchiectomy.

    Apparently, per experts, about 10% of men do not benefit fully from medical ADT due to drug delivery issues or to unusually rapid clearance of the drug by the patient. Many doctors apparently do not check testosterone levels, so the problem is not detected. This almost surely impacted the study results. This problem can be solved if the doctor monitors testosterone.

    A Japanese study of various types of androgen deprivation therapy suggested that orchiectomy was somewhat more effective than medical ADT.

  4. Jim:

    Men in whom LHRH agonists aren’t working to their full capacity for the reasons you mention would probably also be less likely to experience the side effects referred to in this study, so I am not sure how your comments are actually pertinent to the study’s findings. Also, men who are treated by orchiectomy are (like men treated with LHRH agonists) still capable of producing testosterone via secondary androgen pathways, and there is considerable individual variability in the ability to generate testosterone via such pathways.

  5. The UPI report on this study also noted a difference in life expectancy, favoring medical over surgical castration:

    “Of the men included in the study, 87 percent were treated with GnRHa and 13 percent were treated with orchiectomy. The three-year survival rate for patients was 46 percent for those treated chemically and 39 percent who had their testicles removed.”

    It’s not clear from the context whether it’s prostate cancer-specific mortality or overall mortality, or whether those who opted for surgical castration were older and/or sicker.

  6. The JAMA Oncology study considers the survival differences as insignificant and I understand why. Most oncologists that would recommend orchiectomy are doing so for financial reasons or for, in their opinion, a patient that is expressing more advanced indications that he will not benefit from or be able to consider intermittent hormonal therapy. Certainly, there is no doubt from the study, that there were more skeletal-related events and other morbidities associated with chemical castration. What effect that has on overall survival is unclear.

    What would be best is a Level 1 clinical trial that appropriately randomizes patients into the two categories as opposed to this being a cognizant decision from a data pool. And a clear comparison between prostate cancer-specific versus overall survival can be more accurately assessed.

  7. Tony:

    Yes, … but as I stated in the commentary, the chances that anyone will be able to do such a study now are effectively zero.

  8. There is still some chatter out there for such a trial. But yes, funding is an issue, as is the case for all trials where financial benefits and/or profitability is not a consideration. Sad but true.

  9. David,

    Another issue is that some men choose orchiectomy because it is less expensive and is a one-time event. This suggests that men choosing medical treatment are better off financially.

  10. Another Factor Making a Trial Unlikely

    Hi Tony and Sitemaster,

    Another factor making a trial unlikely is that superior medications are likely moving toward use for men with less advanced disease. For instance, the antiandrogen drug Xtandi (enzalutamide) binds to androgen receptor much more strongly than the earlier generation antiandrogens, and that is probably a primary factor that makes it much more effective. As another example, Zytiga/abiraterone is far more effective than the LHRH agonists in reducing — indeed minimizing — testosterone. Those who might considering sponsoring and managing a trial of medical versus surgical ADT would likely be discouraged by the fair prospect that these advanced agents would crowd out the older agents sometime during the trial, which would disturb the results. There is some likelihood that the older agents will become obsolete within the next decade, a development that would limit the value of results to academic but not clinical audiences.

  11. Good observation, Jim.

    I think that all need to remember that abiraterone acetate and enzalutamide both come with even more toxicity than an LHRH agonist with bicalutamide, thus further gapping the morbidities between those methods of treatment over orchiectomy. The more definitively we suppress androgens through chemical ways, the more we call into question the use of chemicals over physical castration.

    For men with advanced disease with metastatic lesions (4 or visceral) we have an even bigger issue in comparison — CHAARTED. Many trials had to be altered because the standard of care at the time was an LHRH plus bicatutamide. And not starting those patients on six cycles of docetaxel is put to the question.

    Some day, not in the near future, we have to continue to search for what is right for an individual and not a cohort. And so it is we continue to look at translational medicine using the genomics and outcomes and the targeting options. And I have a feeling that “obsolete” will come back into question based on the individualized approach.

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