ADT and risk for cardiovascular complications of therapy

Not so long ago, we addressed the question of whether first-line androgen deprivation therapy (ADT) was really an appropriate form of care for any man with localized prostate cancer. A new paper by Haque et al. has now re-raised the same issue in the British Journal of Cancer — but in a somewhat different context.

What Haque et al. have done is conduct a prospective, cohort study of data from > 7,000 patients with relatively early-stage prostate cancer, all managed within the Kaiser Permanente health network between 1998 and 2008 and followed through 2010. Their goal was

to examine the association between ADT and the risk of cardiovascular disease (CVD).

According to the abstract of the paper,

The study included men with newly diagnosed localised prostate cancer … who initially underwent active surveillance (N  = 7637)

and the research team looked for 10 individual cardiovascular outcomes. However, it is not clear from the abstract whether the term “active surveillance” is inclusive of man who were being managed on “watchful waiting”. Nor is it clear what the criteria were for initiation of ADT in management of these patients, so we are going to need to be cautious in our interpretation of the following results:

  • Nearly 30 percent of the 7,637 patients received treatment with ADT at some point after their diagnosis.
  • Treatment with ADT was associated with increased risk of heart failure (adjusted hazard ratio [aHR] = 1.81) in men without any pre-existing signs or symptoms of CVD.
  • Elevated risks of arrhythmia (aHR = 1.44) and conduction disorder (aHR = 3.11) were only observed among patients with pre-existing signs and symptoms of CVD.

The authors conclude that:

In men with clinically localised prostate cancer who were initially under active surveillance, ADT was associated with a greater risk of heart failure in men without any preexisting CVD. We also found an increased risk of arrhythmia and conduction disorder in men with preexisting CVD. This study provides the basis for identifying high-risk men treated with ADT who might benefit from regular cardiac monitoring and lifestyle modification recommendations.

However, it is arguable that there is a whole other issue here, which is why many of these men, who appear to have had localized prostate cancer (albeit not necessarily of low risk) were being started so early on ADT.

Quite apart from the risk for cardiovascular problems that are well known to be associated with ADT, there is the fact that early initiation of ADT would have been doing two other things:

  • Potentially accelerating the risk for early onset of castration-resistant prostate cancer
  • Reducing the potential for initiation of effective palliative care when ADT actually became necessary as a means to prevent bone pain and other symptoms of advanced and metastatic prostate cancer

Now, as indicated above, we have only seen the abstract of this study, so there is a distinct limit to what we could actually say about the “meaning” of the results of this study. However, what we can say is this:

  • The abstract of the paper gives us no idea of the absolute risk for cardiovascular disease among the men in this study. If, for example, there were 20 men out of  roughly 1,700 men who had no history of cardiovascular disease and who were given ADT who had heart failure (an absolute risk of 1.18 percent) and about 26 men out of the 4,000 who had no history of cardiovascular disease and who didn’t get ADT who had heart failure (an absolute risk of about 0.65 percent), then this is a pretty low level of absolute risk, even though the hazard ratio is about 1.8.
  • For any man who has a history of cardiovascular disease, any form of ADT is potentially problematic, and the doctor and the patient need to have a serious conversation about the risk involved before such a man is started on ADT. That conversation should usually include the patient’s primary care physician and his cardiologist (if he has one).
  • For any man who is starting on ADT, there are known cardiovascular risks associated with this type of treatment. The use of early ADT as a primary treatment for localized prostate cancer is controversial as a consequence, because the proven survival benefits are small (as compared to delayed ADT) and the known risks are significant.
  • ADT is not a potentially curative treatment for localized prostate cancer except when it is used in combination with radiation therapy in carefully selected patients.
  • ADT on its own can, in general, only delay the biochemical progression of prostate cancer and ameliorate some of the symptoms of advanced prostate cancer (such as the pain associated with metastasis to the bones); it may also extend survival for some patients (but it is impossible to project which patients will gain such a benefit in advance).

Last but by no means least, there may be an inherent problem with this study in that initiation of ADT may have been associated with other factors that would predispose patients for risk of cardiovascular disease. We can’t tell anything about this without having seen the full text of the full paper.

9 Responses

  1. ADT, Cardiovascular Risk, and Countermeasures

    As a veteran of ADT as sole therapy for a high-risk, life-threatening case between 1999 and 2013, cardiovascular risk was prominent on my own radar screen. Therefore this article caught my attention, especially the following sentence: “For any man who is starting on ADT, there are known cardiovascular risks associated with this type of treatment. The use of early ADT as a primary treatment for localized prostate cancer is controversial as a consequence, because the proven survival benefits are small (as compared to delayed ADT) and the known risks are significant.“

    Pertinent risks include such problems as a tendency toward increased cholesterol, a likelihood of increased weight, a tendency toward higher blood pressure, and a greater likelihood of metabolic syndrome. My own experience was that I had a high cholesterol of around 250 at the start (but a very good ratio), no blood pressure problem ever, weight gain of 10 to 15 lb (intermittent therapy, so varying amounts over four rounds of ADT), and no metabolic syndrome.

    Almost from the outset I learned from doctors practicing a lot of advanced ADT that these effects were fairly frequent unless countered, but that countermeasures were often quite effective, and so I followed their advice on countermeasures. That included starting a statin (for other reasons related to prostate cancer as well), maintaining exercise to minimize weight gain (and achieve other benefits), improving my diet and nutrition (generally a Mediterranean diet but also very specifically several fish oil capsules daily for the cardiovascular benefit), avoiding increased stress, and striving to go on intermittent therapy instead of continuous ADT, which I was able to do eventually. This all worked quite well except for the weight gain, where I was a bit slow on the uptake of what to do; eventually I reduced grain in my breakfast, substituting more fruit while eliminating orange juice, which helped a lot, finally adding branch chain amino acids with morning fasting to my gym workouts, which enabled me to bring my weight down to any level I wished, even while on ADT. I achieved and remain at ideal weight (though a few fewer pounds lower is my goal). The regimen worked so well for cholesterol that my primary care doctor is always surprised I have such a high HDL, which hovers around 100.

    The point of this anecdotal evidence is that countermeasures to cardiovascular risk while on ADT can be powerfully effective. That markedly reduces the risk level from ADT. However, a major practical problem I have seen, based on knowing many patients on ADT, is that a large proportion of ADT patients do not employ these countermeasures sufficiently. Unfortunately, for instance, substantial obesity is an obvious problem, and many of us do not achieve compliance with ideal diet and nutrition; I am always somewhat amazed that the food selections you see even at prostate cancer conventions are often well short of ideal. Perhaps studies paint a more favorable landscape of countermeasures for ADT’s cardiovacular risk, but I haven’t felt the need to check as the first-hand evidence is so negatively impressive. Unfortunately, it also appears that many doctors treating prostate cancer do not advise their patients about these countermeasures.

    The bottom line: a motivated, informed patient is likely to be able to minimize cardiovascular risk that appears to be associated with ADT.

  2. Webmaster,

    Sometimes you use the phrase “problems that are well known” as you did on this message — “Quite apart from the risk for cardiovascular problems that are well known to be associated with ADT.” They may be well known to you, but generally not to the patients … because the urologists don’t tell them. I started on ADT (here’s another problem… what kind, there’s a broad range of ADT) with Lupron and within 2 weeks developed heart problems. My cardiologist checked me out just before I started ADT and I was OK. After my problem surfaced the urologist denied that my ADT caused any problems. Since then I have avoided the injections, just Avodart and Casodex, although other urologist keep trying to push it. The Mayo Clinic website gave me the first warning about the heart problems. Doctors here have never mentioned it to me the ” cardiovascular problems that are well known to be associated with ADT,”

  3. Canary in the Mine — ADT Association with Cardio Events Versus Cause

    As a veteran of long-time ADT, my impression also is that this issue is not settled. Sitemaster expressed it as follows:

    “Last but by no means least, there may be an inherent problem with this study in that initiation of ADT may have been associated with other factors that would predispose patients for risk of cardiovascular disease.”

    For many years, some well-known doctors treating prostate cancer have thought that the occurrence of cardiovascular problems while on ADT is at least in part due to other factors experienced simultaneously with ADT. For example, Dr. Charles “Snuffy” Myers has long used the analogy to the canaries used by miners to alert them that the air in the mine was unfit; in other words, prostate cancer may be a sign, like the canary, that other health challenges are occurring.

    That may be especially true in the US, where ADT has historically tended to be used for less able patients such as those not considered good candidates for surgery, as contrasted with Japan, for instance, where ADT and even primary ADT have been more common. In other words, being on ADT may be in large measure a proxy for age and other health challenges.

  4. Dear George:

    The fact that your doctors didn’t mention cardiovascular risk to you doesn’t mean that these cardiovascular risk are not well known. It means your doctors didn’t fully advise you of the risks.

    This also doesn’t mean that all urologists don’t tell their patients about these risks.

    Maybe I’m compulsive, but whenever I am told I may need to take a drug that I am not familiar with, I look it up on the internet using words “side effect” and the name of the drug. I then decide whether I need to have another conversation with the prescribing physician before I take the drug.

    You should be aware that antiandrogens such as Casodex have also been associated with cardiovascular side effects in some patients (although apparently this isn’t a problem in your case).

  5. Dear Jim:

    Yes. You are correct. However, once again I would point out that you were given ADT because your had a progressive, metastatic, non-localized form of prostate cancer.

    A key part of the whole question here is why anyone gets treated with ADT as a first-line therapy for localized prostate cancer. Countermeasures to address side effects of inappropriate therapy are in and of themselves inappropriate (although many patients might well benefit from taking serious steps to address other co-morbid conditions such as high cholesterol levels, diabetes or pre-diabetic conditions, obesity, etc.).

  6. “… why anyone gets treated with ADT as a first-line therapy[?]”

    Dear Sitemaster,

    Your point at the end of your comment of 10:36 pm (thanks) asking the subject question reflects the great improvements in technology that have occurred over the past two decades. A good case for primary ADT could have been made for many men back around 2000, but that group is now far smaller, perhaps limited to patients with inability to have one of various modern therapies. My hunch is that I myself could have moved to radiation fairly soon instead of after 13 years of IADT3, perhaps with just initial preparatory ADT and then radiation, had the imaging, radiation and other technologies now available been available then, instead of waiting until 2013 for technologies to improve.

    Back in 2000, some of the problem areas that favored primary ADT were that:

    — Active surveillance was a low-confidence approach in the early investigatory stage at a number of centers. Today it is, of course, a highly credible, well-established approach for men with low-risk prostate cancer and even favorable intermediate-risk cancer. Primary, one-time ADT was achieving attractive looking results in these groups back then, though we now know that they probably would have done very well without treatment.

    — Radiation at many centers was not adequate due to either insufficient dosage or insufficient targeting (including cold spots for brachytherapy). Now these are no longer problems where care is competent, and radiation can give greater odds of cure when there is likely spread beyond the prostate, where surgery cannot reach.

    — Imaging was much poorer in quality, both for bone spread and for soft tissue spread. Now imaging, though not yet perfect, is excellent in a high proportion of cases, indicating that the cancer is often not distantly or widely spread.

    — Similarly, it was not certain whether high-risk disease and extracapsular disease was often wide-spread or generally limited to areas near the prostate, especially within the range of effective radiation. We now know, thanks to research, that disease that has spread is often not widely spread and is fairly close to the prostate, within range of radiation.

    — Similarly, it was believed that metastatic cancer was difficult if not impossible to cure by surgery or radiation. It now appears that oligometastatic disease, especially if there are three or fewer spots in accessible locations, can be cured with radiation or surgery. Dr. Eugene Kwon, MD, of the Mayo Clinic in Rochester, Minnesota is one of those who believes that a large proportion of men with metastatic disease had oligometastatic disease early on, and he believes those men likely to have metastatic disease can, in effect, be screened to catch the disease early.

    So I see your main point the same way you do. However, it is valuable to get different views, and I would be interested to get a Japanese perspective on the use of primary ADT in our current era as they have used it a lot more than it has been used in the US.

  7. Dear Jim:

    (1) I’m glad to hear that you see my main point the same way that I do — particularly since I would dispute some of the premises that you stated to have been key to what was going on in about 2000.

    (2) However, assuming that we are both correct, then why is the use of ADT as a primary therapy for localized prostate cancer increasing? This has nothing to do with Japan. It is happening here in America! And it makes no sense at all from a clinical point of view.

  8. ADT possibly lowering cardio risk?

    Thanks for highlighting this issue and your follow-up thread of today, which confirms the concerns you and I had about a likely association rather than a cause.

    Just one more thought relevant to that point: while most oncologists I follow closely are concerned about cardiovascular risk and ADT, at least one, Dr. Mark Scholz, MD, has made an argument backed by some evidence that ADT actually improves the cardiovascular profile in a fair proportion of instances. I can go into that if you wish, but it is expressed in his book The Invasion of the Prostate Snatchers, with the late Ralph Blum, page 101. In essence his view is that ADT lowers testosterone, which thins the blood into the female range, and that makes it easier on the blood vessels, etc., thereby resulting in an “overall REDUCTION in heart attacks by about 10%,” with some studies cited to back that up. He uses the awkward and arguably misleading term TIP (testosterone inactivating pharmaceuticals) for ADT, and I know the quirky backstory on that).

    Along the same line, in a recent review Dr. E. David Crawford and colleagues reviewed a more favorable cardiovascular risk profile for the LHRH antagonist, which I think must have been Firmagon®/degarelix.

    It is likely not worth discussing the merits of the premises I mentioned in my earlier comment, but I do have support for them if anyone wishes to see it.

  9. “why is the use of ADT as a primary therapy for localized prostate cancer increasing?”

    As someone who has tracked ADT developments for years in the context of other developments in prostate cancer, I don’t understand that either. I’m curious about the current state of affairs and trend.

    However, at least one researcher stated (in 2014) that the trend for primary ADT (implying overall — not just local) is decreasing, though from a “relatively high” level, with 2009 mentioned as the benchmark starting point.

    One possibility is that primary ADT for localized disease is decreasing and offsetting an increase in primary ADT for non-localized disease that is trending upward in incidence, probably as a result of the US Preventive Services Task Force’s prior misguidance about the net benefit of screening. My impression is that non-localized disease suspected of being systemic is often treated with primary ADT as sole therapy, though that is arguably not the best approach these days.

    Possibly primary ADT counts the 5-alpha-reductase inhibitors (5-ARI) finasteride and dutasteride, which are used by some doctors as part of a basically active surveillance approach, but that is not the case in one large study I checked, which was mentioned by Dr. Trinh, above. That study defined ADT as an LHRH agonist or orchiectomy, not including a 5-ARI drug.

    Another possibility is that LHRH agonist manufacturers are again aggressively marketing their product. Back in the day, they paid out substantial checks (Thank you!) as part of a class action settlement for what might be kindly described as price coordination.

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