Impact of ADT on all-cause mortality in men treated with brachytherapy-based radiation therapy

The addition of androgen deprivation therapy (ADT) to radiation therapy for men with localized prostate cancer is common. It may be used to reduce the size of the prostate prior to brachytherapy or for longer periods in men with higher risk disease to extend survival (which has been demonstrated in large-scale, randomized, multi-center clinical trials).

What has been less clear is whether the addition of ADT to radiation is appropriate for men with localized prostate cancer and a history of heart disease (e.g., myocardial infarction and/or congestive heart failure). In particular it is not known whether such neoadjuvant or adjuvant ADT should be used for men with high-risk, localized prostate cancer and a history of heart disease.

Nguyen et al. carried out a retrospective analysis of data from a cohort of 14,594 patients diagnosed with localized or locally advanced prostate cancer (clinical stages T1c-T3aN0M0), all of whom were treated with brachytherapy-based radiation between 1991 and 2006. Within this total cohort, they identified 1,378 patients (9.4 percent) with a prior history of congestive heart failure or myocardial infarction.  These 1,378 patients comprised the actual study cohort:

  • The average (median) age of the patients was 71.8 years.
  • The average (median) follow-up was 4.3 years.
  • 311/1,378 (22.6 percent) were treated with brachytherapy + supplemental external beam radiation therapy.
  • 591/1,378 (42.9 percent) were treated with brachytherapy-based radiation and received a median of 4 months of neoadjuvant ADT.

Here are the key findings from the analysis:

  • Overall, the patients treated with ADT had a significantly increased risk for all-cause mortality compared to those who did not receive ADT (adjusted hazard ratio [AHR] = 1.76; p = 0.0001).
  • The 5-year estimates of all-cause mortality were
    • 22.71 percent for men treated with ADT
    • 11.62 for men not treated with ADT
  • When the impact of ADT on all-cause mortality was evaluated in terms of D’Amico risk group,
    • Men with high-risk disease had an AHR = 2.57; p = 0.019.
    • Men with intermediate-risk disease had an AHR = 1.75; p = 0.012.
    • Men with low-risk disease had an AHR = 1.52; p = 0.075.

Ngyuen et al. conclude that, among prostate cancer patients with a prior history of  congestive heart failure or myocardial infarction being treated with brachytherapy-based radiation therapy, neoadjuvant or adjuvant ADT is associated with increased all-cause mortality, “even for patients with high-risk disease.” They argue that even though ADT has been clearly shown to improve overall survival in patients with high-risk disease in randomized, Phase III clinical trials, the small subgroup of high-risk patients with a prior history of serious cardiovascular disease may be harmed by neoadjuvant or adjuvant ADT.

In attempting to determine the clinical significance of these data, it would be interesting to know to what extent the combination of patient age and time on ADT might be influential in these patients. What is very clear from this study is that the use of neoadjuvant and adjuvant ADT in combination with radiation therapy for the treatment of all men with a prior history of cardiovascular disease needs to be considered with caution, and that careful clinical decisions need to be made in the best interests of the individual patients.

From an individual patient perspective, men who have a significant history of cardiovascular disease, and who are considering radiation therapy + neoadjuvant and/or adjuvant ADT for treatment of localized prostate cancer,  may want to have a discussion with their cardiologist (and perhaps a thorough cardiovascular check-up) before actually proceeding with such treatment.

4 Responses

  1. Thank you as always for finding and presenting these important studies! That marked difference in survival is striking, especially considering the relatively short duration of median follow-up. The study certainly waves the caution flag!

    I have a few comments from my viewpoint as an 11.5-year veteran of intermittent androgen deprivation therapy, fortunately free of heart disease.

    Firstly, there has been some disagreement about the impact of androgen deprivation therapy (ADT) on heart disease among doctors who use ADT extensively in practices dedicated to prostate cancer. While the concern is recognized generally, some research suggests there may be a cardioprotective effect, perhaps due to ADT resulting in a decrease in red blood cells, making the blood thinner and thereby reducing strain on the cardiovascular system. It seems to me that this issue is unresolved, but the research you report should help illuminate what is happening.

    Secondly, the doctors who appear to me to be savvy proponents of hormonal therapy vigorously advocate a number of measures to decrease cardiovascular risk of ADT. One of the main elements is to put men on intermittent ADT when possible, keying on achievement of a PSA of < 0.05 ng/ml (or lower for some) as a criterion for going off the heavier duty drugs (the LHRH agonists and antiandrogens). A second method is to use lifestyle tactics, especially nutrition, exercise, and stress reduction, with heart-healthy components. The Mediterranean diet is one widely used tactic. Consumption of fish and fish oil supplements is another, with the established sharp reduction in sudden death from heart attack due to fish/fish oil consumption well established as I see it. A third tactic is to take a statin drug. This class of drugs not only improves lipid profiles but is also associated with a substantial reduction in the incidence of lethal prostate cancer. I am personally employing all these tactics, and I am pleased to say that my cardiovascular-related test results are outstanding.

    Considering the time frame of the research, I suspect that not many of the patients who died were employing such countermeasures. That's conjecture of course, but it's based on the fact that knowledge of these countermeasures and their effectiveness and knowledge of the cardiovascular effects of ADT have both increased greatly since the time that most of the men in the study would have been treated. (On the other hand, perhaps, as heart disease patients, they may already have been more aware of such tactics than their peers who were free of heart disease.)

  2. The problem appears to be more the reduction of testosterone brought about by prescribing either an LHRH agonist or the LHRH antagonist degarelix — or, for that matter, transdermal estradiol (TDE) patches or gel — that have been found hazardous to patients experiencing cardiovascular, diabetes issues or prone to having a stroke. I recognize that sequential androgen blockade (SAB) without an LHRH agonist or an LHRH antagonist but with an antiandrogen can be prescribed. This option serves to block androgen receptors from testosterone access to the cancer cell nucleus and contact with 5-alpha-reductase (5-AR) enzymes where it can be converted to the more powerful stimulant to prostate cancer cell growth, dihydrotestosterone (DHT). Should this option be employed, rather than the antiandrogen as monotherapy, it is my opinion that a 5-AR inhibitor (either dutasteride/Avodart [preferred] or finasteride/Proscar) should be prescribed to accompany the antiandrogen in order to prevent T conversion to DHT should any testosterone gain access via faulty androgen receptors. In any event, it has been my observation over several years of monitoring prostate cancer support lists that SAB has a short-lived effectiveness of only a year or two before androgen receptor mutation and antiandrogen failure.

  3. Mike,

    Do you have data on the same approach for RP patients. I would think we would see a similar affect using adjuvant ADT regardless of the chosen primary therapy.

  4. Tony:

    I am not aware of a similar study in men treated with RP. The vast majority of men with localized, high-risk prostate cancer who are treated surgically do not get a short course of neoadjuvant or adjuvant hormone therapy (although this was done for a brief period back in the 1990s by some surgeons). Patients who receive first-line surgical treatment are much more likely to get hormone therapy only as part of their second-line care, if their surgery is followed by adjuvant or salvage radiation therapy.

    By contrast, a short course (3 to 4 months) of neoadjuvant hormone therapy is very common among men treated with first-line brachytherapy, because it is often necessary to reduce the prostate volume down below about 45 cm3 prior to radioactive seed implantation.

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