Managing the side effects of ADT — a new review


According to a new analysis and review of recent, published data, the “numerous well recognized adverse effects” of androgen deprivation therapy (ADT) include “vasomotor flushing, loss of libido and impotence, fatigue, gynecomastia, anemia, osteoporosis and metabolic complications, as well as effects on cardiovascular health and bone density.”

Conversely, of course, ADT has many well-recognized benefits when used in appropriate patients, and numerous trials have documented the benefits of ADT — alone and in combination with other forms of treatment.

Ahmadi and Daneshmand (of the USC Institute of Urology, USC/Norris Comprehensive Cancer Center at the University of Southern California) carried out a PubMed database search of all prospective clinical studies published between 2000 and 2012, including randomized and non-randomized clinical trials and meta-analysis studies concerning preventive and therapeutic interventions for the various side effects of ADT. They then used the highly regarded Oxford 2011 Levels of Evidence classification system to categorize selected studies according to the projected treatment benefits of the different possible interventions.

Here are their core findings:

  • The drug gabapentin appears to have moderate efficacy for the long-term treatment of hot flashes.
  • Combined resistance/aerobic exercise programs can lead to significant improvement in fatigue, sexual function and cognitive function.
  • Home-based and/or group exercise programs  can also improve fatigue and unfavorable metabolic changes.
  • The drug denosumab can
    • Increase bone mass density in the lumbar spine, hip, and radius
    • Reduce risk for vertebral fractures in men receiving ADT for non-metastatic prostate cancer.
  • The drug metformin, when used in conjunction with lifestyle interventions is a safe, well-tolerated intervention for adverse metabolic changes.
  • The drug toremifene can be used to improve patients’ lipid profiles.
  • Intermittent ADT improves early side effects, such as hot flashes, sexual activity, fatigue, and quality of life, although its effect on long-term side effects remains inconclusive.

The authors are, however, careful to add the following statement, with which The “New” Prostate Cancer InfoLink is in complete concurrence:

Despite significant improvement in management strategies for the side effects of ADT, the best way of preventing side effects is to use ADT only when it is absolutely indicated.

We have long felt that the greatest risk associated with the clinical application of ADT is when it is used too early — i.e., to manage PSA levels as opposed to actually managing real clinical issues — or for longer than it is actually needed.

6 Responses

  1. I am pleased to say that I fairly comprehensively covered all these issues some time ago in my paper regarding ADT side effects.

  2. Mike,

    Your article is well written but I do have some concerns. For example, it does not take into provisioning for adjuvant or neoadjuvant hormonal therapies. We do have studies that support that such treatments can deliver biochemical and prostate cancer-specific survival benefits.

    I am a 6-year survivor of advanced prostate cancer and have been riding excellent results since initial therapies that included adjuvant choices. I took this path after extensive research on the possible benefits of such options and there is Level I data that supported that route. The article seems to imply that side effects of hormonal therapy can be managed but it should only be given as a therapy only when absolutely necessary and that’s ambiguous to me. Clearly there needs to be more research on the benefits of adjuvant and neoadjuvant HT but for now I have no regrets. And if anyone is on such therapies, this is a great article to help you manage those pesky side effects. Thank you for this one, it’s a great one for a prostate cancer advocate to share…

  3. Dear Tony:

    The authors of the review article are suggesting, and I entirely concur with them, that ADT is appropriately used when supported by good data showing a real benefit to the patient. This is very definitely the case for the use of neoadjuvant and aduvant hormonal therapy (most especially when used in combination with radiation therapy alone or as a follow-up to first-line surgery).

    What the reviewers were most certainly drawing attention to, however, was the overly early use of ADT in men with progressive disease after first and second-line therapies who are completely symptom free and may have PSA levels as low as 0.1 ng/ml without any data on their PSA doubling times. In such cases we have no good data that supports either a progression-free or an overall survival benefit from the early as opposed to the delayed use of ADT. We don’t even have data from a large, randomized trial that had ever tested this hypothesis in such patients.

    We do have data from two old trials that tested the hypothesis that early ADT (orchiectomy) was better that delayed ADT in men diagnosed back in the 1980s with truly advanced, metastatic disease … but then most of those men had been initially diagnosed with evident metastatic disease, so the situation is hardly parallel. The two trials showed conflicting results, with the larger, MRC trial showing survival benefits.

    At base, we really have no useful indicators (that I am aware of ) — other than a short PSA doubling time — as to when it is best to start ADT in a man with a rising PSA after first- and second-line therapy. What we do know is that the longer one is on ADT the more the severe the side effects become for many men. This is another case where the potential harms of overly aggressive treatment may outweigh any benefits of that treatment.

  4. Tony,

    You may want to re-think your “those pesky side effects” comment. For some folks like me, who can’t really get off ADT for any significant period of time, and who have very significant side effects from ADT, your comment is seems unfair.

    Bill Manning

  5. WELCOME EMPHASIS ON AEROBIC AND RESISTANCE EXERCISE

    Thanks once again for keeping us up to date on important studies.

    This study does a good job in helping publicize major side effects of ADT and selected countermeasures. As a now savvy veteran of intermittent triple ADT for the past 13 years and counting as my sole therapy (until next Tuesday — radiation to try to cure) for a challenging case, I am quite familiar with many of the issues and the state of play regarding ADT, its side effects, and countermeasures. I was very glad to see the emphasis on the combination of aerobic and resistance exercise in the abstract, which is so important for countering “fatigue, sexual function and cognitive function. A home-based/group exercise programme also improves fatigue and unfavourable metabolic changes.”

    However, my impression from many contacts with survivors is that far too few of us get adequate exercise, and that many of us therefore do not experience the benefits. An unfortunate consequence is that many doctors do not realize that their patients CAN substantially achieve weight control and fitness – with all their benefits – while on ADT. Completing a vicious circle, the doctors do not inform or encourage their patients adequately about countermeasures. This study will help doctors underscore the importance of exercise, as well as suggesting selected other tactics, though far from being comprehensive.

    My own experience bears out the importance of exercise and diet, which for me is basically Mediterranean. I have lost between 25 to 30 pounds from my peak weight on ADT, and now, at the end of my fourth month of my fourth cycle of ADT3, I am maintaining a steady weight within a few pounds above my ideal target – 136 pounds, for my height of 5′ 6″. My BMI is now hovering around a desirable level of 22.5 thanks to my combined diet and exercise program. My lipids are fine, aerobic stress test indicating good heart function, and my fasting glucose score is fine. I normally cruise on the treadmill with a racewalking speed of a little faster than 15 minutes per mile (that’s a worthy speed, especially at age 69), but I can go considerably faster. With resistance weights, my legs and core are in fine shape – I’m doing leg extensions of more than 400 pounds with twelve slow reps for instance, and my upper body is in adequate shape.

    While my experience is obviously not a study, it does demonstrate what is possible. I’m convinced that the vast majority of us could achieve similar success while on ADT. Before that happens, more of us will need to understand three things: that keeping weight down and fitness up are IMPORTANT; HOW TO do it; and that it REALLY IS POSSIBLE.

    It is important to minimize extra weight, especially around the abdomen. Research indicates that fat measured by such extra weight generates its own unfavorable hormones. No doubt the study above includes many references that indicate the importance of achieving weight control and fitness while on ADT.

    There are several good sources of information about how to achieve success. I’m thinking especially of Drs. Mark Scholz (medical co-author of Invasion of the Prostate Snatchers) and his current and former colleagues Richard Lam and Stephen Strum, and Charles (Snuffy) Myers, author of his own books on prostate cancer. Dr. Mark Moyad has also published books that provide easily understandable information.

    I have put this advice to work. Even though I would love to chomp into a nice thick hamburger or steak, or devour a pork barbecue feast – things I never do now, I enjoy the treats of well prepared vegetables and seafood, plus chicken. I enjoy red wine and dark chocolate daily. In short, I like my diet. I really don’t miss the red meat, egg yolks, hefty servings, etc. that typify the Western diet associated with higher risk. As for exercise, I’m far from being a gym rat, but I strive for more than 20,000 steps a day, though during these recent cold weather months I’ve actually averaged between 10,000 and 20,000 steps. I get resistance exercise from household chores and two trips to the gym a week for a weights workout of about a half hour, plus stretching and fast walking – about an hour and a half to two hours total per session.

    Also, before many of us achieve success with weight, more of us will need to believe that it IS possible to control weight on ADT with reasonable effort. I did not achieve excellent weight control during previous rounds of ADT, though I did fairly well with fitness. Talking to other survivors who had achieved success with weight as well as fitness, and being encouraged by experts, enabled me to become a believer, and now I have achieved my fitness and weight goals (mostly).

    However, I’m concerned that some patients and doctors reading the study abstract or the fine report above may lay too much emphasis on the word “absolutely” in the phrase from the abstract “use ADT only when it is absolutely indicated.” Instead, a key take-home point from this research should be that proper exercise and diet greatly enhance the feasibility and value of earlier and much longer effective ADT. That has definitely been my own experience. It is a perspective that has been hammered home for years by some of the experts in ADT. I’ll post about that separately.

  6. AMBIGUITY OF “USE ADT ONLY WHEN IT IS ABSOLUTELY INDICATED”

    Dear Tony and Sitemaster,

    Thanks Tony for pointing out this ambiguity in your comment of 2/27 10:52 PM. The ambiguity bothered me too. Unfortunately, as many of us are aware, at least one of the most prominent pioneers of surgery for prostate cancer, practicing in the mid-Atlantic coast area, has emphatically advocated his view that ADT should be more or less a last resort, to be used only when a patient experiences the symptoms that are typical of late stage disease. In sharp contrast, my sense is that ADT experts concur that ADT is limited in its usefulness at that stage. (Though, hopefully, recent advances with new drugs will improve that prospect, as suggested in a number of Sitemaster’s reports here.) It is important to make sure that “only when absolutely indicated” does NOT imply such late use.

    Thanks Sitemaster for clarifying in your reply of 2/28 9:58 AM that “only when absolutely indicated” was not meant to apply to timely neoadjuvant or adjuvant ADT but rather to early use upon detection of a recurrence after primary therapy. The physicians I follow and regard as leading experts would concur, as I see it, that many recurrences are too mild to warrant any intervention but deserve monitoring instead. I believe that most of them would also be in favor of lifestyle nutrition, exercise, stress reduction, and perhaps mild medication programs (such as a statin and/or a 5-alpha-reductase inhibitor) to slow, stabilize, reverse or even eliminate evidence of the recurrence. They would resort to ADT, tailoring it to the patients circumstances, if those specific circumstances suggested the cancer would become a real problem for the patient in the context of his goals, his life expectancy, and specific co-morbidity issues.

    There is one other use for ADT that is still controversial: ADT as primary therapy, including such use in men with low-risk disease. The best paper on this that I know about is “Primary androgen deprivation (AD) followed by active surveillance (AS) for newly diagnosed prostate cancer (PC): A retrospective study
    by Scholz et al. (published in the January 2013 issue of The Prostate). While the results are from a single practice, it is intriguing that a substantial portion of patients were able to enjoy an indefinitely long period off-therapy after a single, relatively short round of two-drug therapy.

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