Is Problem X really a side effect of ADT, or not …?


We have long been bedeviled by questions about some of the short- and the long-term side effects and complications of androgen deprivation therapy (ADT) in the treatment of prostate cancer. Frankly, the distinctly muddy water doesn’t seem to be getting much clearer (based on two recent publications).

In an article in The Journal of Clinical Pharmacology, Kao et al. have now conducted a retrospective analysis of data from the Taiwan Longitudinal Health Insurance Database 2005, and shown that:

  • They could identify 1,244 prostate cancer patients who had received ADT (the study cohort) and 1,806 prostate cancer patients who did not receive ADT (the comparison cohort).
  • In the full cohort study, incidence rates of heart failure per 100 person‐years within a 1‐year follow‐up period were
    • 4.00 for the ADT users
    • 1.89 for the non-users
  • Also based on the full study cohort, and compared to the non-users, the hazard ratio (HR) for heart failure among ADT users was 1.72.
  • Based on a propensity score‐matched cohort study, and compared to propensity score‐matched set of non-users, the adjusted HR for heart failure among ADT users was 1.92.

The authors concluded that:

… this study found that androgen deprivation therapy users had a higher risk of heart failure than non-users among prostate cancer patients in both the full cohort study and the propensity score‐matched study.

It does, however, need to be emphasized that this 72 percent increase in risk for heart failure was being observed in a predominantly Asian set of patients.

Conversely, in a study just published on line in JAMA Oncology, Deka et al. report that they were unable to observe any increase in risk for dementia or Alzheimer’s disease in a cohort of prostate cancer patients being treated within the VA medical system here in the US. All the patients were diagnosed with prostate cancer between January 1, 2001, and October 31, 2015, and received definitive radiotherapy with or without ADT.

It is perhaps unsurprising that there was no apparent increase in the risk for dementia or Alzheimer’s disease in this group of men, who would have largely received a short course of ADT (perhaps 6 to 18 months) as opposed to continuous ADT for 3 years or longer.

What we are suffering from here is an excess of information on the fact that serious, long- and short-term side effects of ADT do occur and can be readily observed and a shortage of accurate information about the incidence and severity of these side effects from well-planned clinical trials in carefully monitored patients.

Retrospective data from registry studies and clinical databases like these are all very well, but these databases were never intended to be used for the purpose of gaining accurate knowledge about the risk for complications and side effects of ADT. If we are ever to get to the bottom of the real risks for side effects of ADT, we are going to need data from a registry study in which patients are followed for 5 or more years; are regularly asked to complete appropriate questionnaires; and are clinically followed (at least annually) with regard to the patients actual health status.

The chances on a registry study like that happening in the current environment for research funding have to be pretty low.

2 Responses

  1. A Quick Way to Get Your Study Published: Focus on a Problem Associated with ADT Patients (but Ignore Seriousness of Disease and Older Age as Likely Causes)

    I really appreciate your skepticism, Sitemaster.

    My background; Study Confounders.

    As a patient once on long-term intermittent ADT prior to a curative attempt with radiation in 2013, I know this territory pretty well. The indisputable fact is that long-term ADT is typically used, in the United States, for more serious cases of prostate cancer, and such cases are predominantly in older men. Right there you have two additional circumstances — seriousness and older age — that almost certainly explain some of the effects seen in studies of ADT and certain hypothesized side effects, and that possibly account for many — if not nearly all — of these side effects.

    Prostate cancer as the canary in the mine; Cardiovascular Disease, Etc.

    Dr. Charles “Snuffy” Myers is known to many of us as a prolific researcher and prominent medical oncologist who had a large practice devoted solely to prostate cancer patients before his recent retirement; this gave him experience with thousands of prostate cancer patients, many of whom had serious cases and were elderly, whom he monitored closely from both prostate cancer and internal medicine perspectives. Dr. Myers emphasized that a diagnosis of prostate cancer is like the canary that dies in the coal mine: it signals that the patient likely has serious health challenges in addition to just prostate cancer. Prominent among those is cardiovascular disease, the subject of the first study. Diabetes and metabolic syndrome are other somewhat likely health challenges for prostate cancer patients, especially for older patients and arguably those with serious prostate cancer, or even more so for both. All of these are affected by diet and lifestyle choices and practices over the years. Therefore, a study looking at just ADT and cardiovascular disease, with no filter for preexisting cardiovascular disease, runs a significant risk of documenting a false association.

    The dementia study.

    Regarding the second study, dementia and Alzheimer’s are two conditions that are closely linked with age. As prostate cancer, and especially more serious prostate cancers, are linked closely with age, a sound study of dementia/Alzheimer’s and ADT must have an effective method of filtering out the effects of age. There have been several observational studies analyzed at this site that suggest a link between ADT and dementia but lack that critical filter for the independent effect of age. My own approach is to ignore them except as indicators of what the general interested public and the medical community may have uncritically accepted, which is important to know for those of us who help others navigate prostate cancer.

    Countermeasures.

    Another key aspect of this is the use of countermeasures to side effects. There are a lot of studies that document side effects of ADT, real possible side effects (e.g., control of weight and body mass index), but without addressing the impact of countermeasures known to be effective against those side effects (e.g., diet and exercise for weight and BMI). But that’s another story.

    Again, thanks for your skepticism and emphasis on rigor in studies.

  2. Apparently I have been truly blessed since all the adverse side effects reported regarding ADT have not occurred to me over my current 22 years of near continuous ADT that inluded Lupron, Casodex, generic of Casodex, dutasteride/Avodart, abiraterone acetate/Zytiga, and enzalutamide/Xtandi — oh, and denosumab as Prolia. Only break was just short of 6 years several years back, but during that time I continued/maintained dutasteride/Avodart to prohibit any testosterone/androgen from converting to dihydrotestosterone/DHT if transiting towards my androgen receptors.

    My mind has remained what I consider very functional over that time, and the only adverse effect I can determine is tiring/fatigue from the lack of testosterone (< 3.0 each time tested). Of course at 86 years of age the aging process also contributed as well.

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