Adverse effects of ADT in men with non-metastatic prostate cancer


Two new studies just posted on line in the Journal of Clinical Oncology specifically address some of the adverse effects associated with 12 months of continuous androgen deprivation therapy (ADT) in men with non-metastatic prostate cancer. It is unclear whether these studies are based on the same groups of patients, but it does seem highly likely.

In the first study, Alibhai et al. examined the impact of ADT on physical functioning in a total of 259 men in three groups: 87 patients on ADT (Group A), 86 other prostate cancer patients (group B), and 86 healthy controls (Group C). The groups were all similar in age (mean, 69.1 years; range, 50 to 87 years) and physical function at study initiation.

They report the following results:

  • Distance walked during a 6-minute walk test was stable over time in Group A (the ADT group) but improved significantly in Groups B and C.
  • Grip strength declined in Group A, but remained stable in Group B, and improved significantly in Group C.
  • TUG scores (“timed up-and-go” scores) were stable over time across all three groups.
  • SF-36 physical function summary score declined significantly in Group A, but increased significantly in Groups B and C.
  • Negative effects on outcomes were observed within 3 months of starting ADT and were generally independent of age.

In their second study, Alibhai et al. examined the impact of ADT for up to 12 months on cognitive function on a total of 241 men in three groups: 77 patients on ADT (Group D), 82 other prostate cancer patients (group E), and 82 healthy controls (Group F). The groups were all similar in education (mean 15.4 years; range, 8 to 24 years) and age (mean, 68.9 years; range, 50 to 87 years) at study initiation. All patients received a predetermined set of 14 neuropsychological tests, examining eight cognitive domains, at baseline, 6 months, and 12 months.

Here are the results of this second study:

  • After adjustment for age and education level, all three patient groups had similar cognitive scores at baseline (with the exception of one test of working memory).
  • There was no apparent association of use of ADT with significant changes in attention/processing speed, verbal fluency, verbal memory, visual memory, or cognitive flexibility at 6 or 12 months after the start of treatment in for patients in Group D compared to those in Groups E and F.
  • For patients in Group D, one test each of immediate memory, working memory, and visuospatial ability demonstrated significantly poorer results at 12 months that for patients in Groups E and F, but these findings were not confirmed by other testing techniques.

For the first of these two studies, the authors conclude that, “Endurance, upper extremity strength, and physical components of [quality of life] are affected within 3 months of starting ADT.” They go on to suggest that exercise interventions to counteract these losses may be warranted. For the second study, they conclude only that, “There is no consistent evidence that 12 months of ADT use has an adverse effect on cognitive function in elderly men with [prostate cancer].”

The “New” Prostate Cancer InfoLink suggests that the first conclusion is what might be expected and the second is accurate but based on a flawed study. Basically, we suspect that neither study population was really either large enough or continued for long enough. Although some men do report relatively rapid changes in cognitive function when treated with ADT, this adverse effect appears to be much more likely in men treated for significantly longer than 12 months. It would be helpful to know if this was a continuing study that might report additional data after 2 years of follow-up, when we might expect to see some more significant impact on cognitive function among a subset of the patients in Group D.

9 Responses

  1. These studies are consistent with my own experience on intermittent androgen deprivation therapy, mostly IADT3, over nearly 11 years, including three complete on-therapy phases and two-complete, one pending off-therapy phases.

    For the first phase, starting in December 2000, I was not aware that strength exercise was an important countermeasure to side effects, and I lost some upper body muscle strength. I maintained lower body strength, perhaps due to regular aerobic exercise. For the second and third on-therapy cycles I was aware of the need for strength exercise and followed a program using resistance exercise plus some free weights. I maintained or bettered upper body strength during the second 19-month cycle, and I bettered upper body strength during the third cycle. During the third cycle my testosterone measured less than 10, proving to me that it is possible to increase muscle strength, including upper body extremity muscle strength, despite having virtually no testosterone.

    Dr. Mark Scholz (in the forefront) and some other leaders in intermittent androgen deprivation therapy have been preaching about the importance of aerobic and especially strength exercise for years. I’m delighted to see that the first paper makes this point. I’m convinced that most of the side effects of ADT can be eliminated or at least minimized if proper countermeasures are employed by the patient.

  2. The studies cover a population of men 50 to 87 years old in age. This is quite a large spread. I believe it is necessary to have a follow-up study with a larger population more uniform in age.

    For statistical reasons it is important to analyze the effect of ADT on quality of life — physical and mental — for different age cohorts. The natural decline at an advanced age may be more pronounced than at a younger age.

  3. These studies don’t address psychosocial, emotional, sexual, or gender identity issues.

    They don’t address cognitive functioning in any meaningful, day-in-day-out, how-to-make-life-really-work way. If you’re 87, perhaps it’s not such a problem. If you’re 50 and trying to try court cases, help your kids with their homework, do engineering, drive a combine, preach a sermon, or, perhaps, … do surgery on some other guy’s prostate — you pretty need and deserve your fully cognitive capacity.

    These studies have been done to rationalize an existing treatment of arguable ethics and efficacy, rather than as speculative studies done to see if a treatment meets the standard of “do no harm.”

    There probably is a place in prostate cancer treatment for the use of ADT, but physicians who choose to ignore (and fail to frankly and explicitly inform their patients about) the extraordinary risk to their patients of a treatment that has the capacity to meaningfully change their personalities, body type, body image, to measurably reduce cognitive function, and to eradicate all vestiges of human sexuality are cruel.

    This idea that you can destroy everything that makes a person who they are and call it a “cure” is heartbreakingly misguided. If you’ve taken someone’s strength, personality, intelligence, and ability to feel and experience normal adult physical love, how can you possibly construe that as a “cure,” just because some tiny cells aren’t measurable?

  4. Jim Waldenfels and I have been traveling a similar journey with our cancer treatment having moved to ADT. I will turn 78 in December, and with 14 years of on/off/on/off and recently back on ADT medicadtions, I have experienced little change in cognitive function. And I have learned to manage and tolerate the side effects that can accompany this treatment that does become necessary and is no longer simply an option to be considered. How we take care of ourselves with appropriate exercise as well as involving ourselves in activities that challenge our minds has much to do with participating in managing our cancer. So many men lay the blame for their perceived reduction in cognitive functioning to the ADT medications, yet this reduction also accompanies the normal aging process. For some, cognitive functioning can become impaired early on, for others not until later in life. I am unable to blame the prescribing of ADT medications that have continued my life with prostate cancer for the past 14 of my 18 years since diagnosis on the physicians who accept the responsibility of trying to preserve our lives when cancer attacks our bodies. It behooves we patients as much as it does the physicians to research our cancer to become sufficiently knowledgeable to be a partner with our physicians in our treatment. It is not cruel to be administered ADT, though I can agree that the prescribing physician should describe the side effects that might occur as well as methods to alleviate those effects. The alternative to ADT just might be aggressive progression and early demise.

  5. Tracy,

    Thank you! You’ve done a wonderful job of summarizing the symptoms and feelings I know I have endured in 5 years of being on and off various ADT medicines. I probably owe them my life … but only via making a Faustian bargain. The person known as John Arnold is still alive, but the John Arnold who is alive today is not the same person that existed 6 years ago. As you noted, how do you take that much of a person’s essence and energy away, and not do immeasurable damage?

    As for cognitive changes, absolutely they can occur, maybe not in all men who use them, but in enough of us that it ought to have shown up in this study. I know absolutely that I am not as mentally sharp or able as I was before I went on ADT. On Lupron, I eventually became extremely depressed and suicidal. Thank goodness I was in a situation where I could switch to another ADT medicine, Trelstar, which for me has proven much more tolerable. But even then, I am retiring 6 years earlier than I had intended to because I simply haven’t the energy, stamina, or mental abilities to continue doing the job I have done for the past 21 years.

    So yes, ADT medicines do have a role to play in slowing the progression of prostate cancer, but no one should ever be in any doubt about the possible side effects. They might be mild, or they might be so bad as to be not worth it.

  6. Both Charles Maack and John Arnold are right.

    Our mental and physical capabilities deteriorate with age in any case. It’s called getting old and it varies from one person to another.

    Yes, it would be great if there was a medication that killed prostate cancer with no side effects. It would also been great if we were all healthy and rich.

    It would also be great if we had a 100% precise test for prostate cancer. But alas, life is not perfect and nobody promised us a rose garden.

  7. FOLLOW-UP STUDIES OF QOL FOR ADT/IADT PATIENTS?

    Hi Reuven. In the second response (November 3, 2010 at 12:44 pm) you wrote, with my responses interspersed:

    “The studies cover a population of men 50 to 87 years old in age. This is quite a large spread. I believe it is necessary to have a follow-up study with a larger population more uniform in age.”

    JIM RESPONDING: Age does seem to make a difference, with younger men more often experiencing more intrusive side effects (if uncountered) than older men. While my experience constitutes a clinical trial of just one, that’s what I have experienced over three cycles of ADT and vacations off therapy. For instance, when I started at age 56, hot flashes and sweats, though tolerable, were more frequent, longer lasting and more intense. I remember noting three flashes during just 1 hour on a number of occasions during that first cycle. During my last 19-month cycle of blockade, at ages 66 and 67, hot flashes were a minor nuisance at most: quite mild, short, and varying in number from zero to the most common upper bound of 7, with some excursions up to 11, and twice hitting 14. (I kept careful track, including night flashes.)

    YOU WROTE: ‘For statistical reasons it is important to analyze the effect of ADT on quality of life — physical and mental — for different age cohorts. The natural decline at an advanced age may be more pronounced than at a younger age.”

    JIM RESPONDING: There is an additional point for follow-up studies, and it is critical: the extent of use of countermeasures for side effects and their impact. To me, as an 11th year veteran of IADT3, the experience on ADT is dramatically different depending on whether countermeasures are used, and many fellow ADT veterans have had similar experiences.

    The analogy I like is body armor for a soldier: those going into battle without body armor are going to have a much less favorable experience than those going into battle with body armor. Those going into ADT without employing countermeasures are going to have a much poorer experience than those using countermeasures.

    Studies need to make this a key point. Frankly, countermeasures are so important that I don’t see a great deal of value in just documenting the ADT experiences of those who do not employ countermeasures. Further, in view of what has already been proven about the effectiveness of countermeasures, allowing some men to go into a study without information about countermeasures, or to randomly assign men to a non-countermeasures arm of an ADT QOL trial, raises serious ethical questions.

  8. VITAL IMPORTANCE OF COUNTERMEASURES FOR PSYCHOSOCIAL, EMOTIONAL AND SEXUAL QOL WHILE ON ADT (plus one non-issue)

    Hi Tracy. I’m responding to your post on November 3, 2010 at 3:21 pm, and I’ll intersperse comments. You raise some very important concerns, but you are suffering from misconceptions about ADT. The situation is far more favorable than what you presently think it is.

    YOU WROTE: “These studies don’t address psychosocial, emotional, sexual, or gender identity issues.”

    JIM RESPONDING: True, but other studies do. Try a search on http://www.pubmed.gov.

    YOU WROTE: “They don’t address cognitive functioning in any meaningful, day-in-day-out, how-to-make-life-really-work way. If you’re 87, perhaps it’s not such a problem. If you’re 50 and trying to try court cases, help your kids with their homework, do engineering, drive a combine, preach a sermon, or, perhaps, … do surgery on some other guy’s prostate — you pretty need and deserve your fully cognitive capacity.”

    JIM RESPONDING: You are raising very practical, real-world issues, but fortunately the reality is typically far better than the one you fear. Any study is limited in how it can mirror the real world. Personally, I think these studies took a pretty good stab at it, giving what researchers call “operational definitions” of the physical and cognitive capabilities that matter in the real world.

    My own experience, and that of men on ADT with whom I have communicated, is encouraging regarding the psychosocial and emotional issues. From late 1999 until January 2004 when I retired (4 full years), I continued to hold a mentally demanding job involving traits like in-depth quantitative and qualitative analysis, negotiation and other personal interaction frequently, persuasion, active listening and perception, writing, creativity and problem solving, high financial stakes, occasional assertive confrontation, diligence, perseverance, and energy. I was aware of and used countermeasures for ADT side effects during these years (on ADT for an initial period of 31 months). I was able to perform my work well, earning bonuses and initiating/managing acceptance of a suggestion with potential savings of hundreds of thousands of dollars, against opposition. Aside from coping with disturbed sleep during the early months of ADT, I did very well.

    Dr. Charles “Snuffy” Myers, one of our experts in treating prostate cancer, is another ADT veteran. During the 18 months he was on blockade, he continued to treat patients for much of the period (until radiation side effects required a leave period), and he also continued to speak and publish his newsletter.

    Chuck, who replied above, is another example. If you look at what Chuck has done recently, and if you are aware of what I am doing, I think you will see that we are keeping up our effectiveness despite being older and having been on ADT.

    I am absolutely convinced that, while ADT does not make our cognitive work easier, many of us can do quite well in performing our usual work, PROVIDED WE USE COUNTERMEASURES to those of the typical side effects that affect us! It is of key importance that men not be discouraged by an unrealistic portrait of their likely experience on ADT!

    YOU WROTE: “These studies have been done to rationalize an existing treatment of arguable ethics and efficacy, rather than as speculative studies done to see if a treatment meets the standard of “do no harm.”

    JIM RESPONDING: Your statement is unsupported and ventures far beyond what research has established. What “arguable ethics and efficacy”? That’s pure baloney. As for do no harm, almost all medical interventions do some harm, even if its just the temporary discomfort from a shot or mild risks for most of us from taking aspirin. The key is the concept of “therapeutic index,” basically getting at whether the benefit outweighs the cost in side effects, complications, etc. Research supports that ADT, especially intermittent ADT, has a positive balance of benefits versus cost.

    YOU WROTE: “There probably is a place in prostate cancer treatment for the use of ADT, but physicians who choose to ignore (and fail to frankly and explicitly inform their patients about) the extraordinary risk to their patients of a treatment that has the capacity to meaningfully change their personalities, body type, body image, to measurably reduce cognitive function, and to eradicate all vestiges of human sexuality are cruel.”

    JIM RESPONDING: Many of us who are enthusiastic about ADT (hard not to like something that is likely extending your life) would fully agree with you that physicians need to give their patients contemplating this therapy an objective account of possible side effects, their likely period of onset, the odds of having the effect, and the odds of having it at different degrees of severity, AS WELL AS COUNTERMEASURES that can eliminate or minimize each effect, and their likelihood of effectiveness. It is tragic that so many physicians prescribing ADT are ignorant about the side effect profile and how to minimize side effects. However, you blame that on the therapy, not on the prescribing physicians. Do you consider that fair and objective?

    This idea that you can destroy everything that makes a person who they are and call it a “cure” is heartbreakingly misguided. If you’ve taken someone’s strength, personality, intelligence, and ability to feel and experience normal adult physical love, how can you possibly construe that as a “cure,” just because some tiny cells aren’t measurable?

    Let’s look at each of the areas you put under the phrase “extraordinary risk to their patients of a treatment that has the capacity to meaningfully change:”

    — their personalities: JIM REPLYING: This just does not happen for most of us, except that we often become less testy. Many wives have commented that they actually prefer our less aggressive personalities during this period. However, I can personally assure you that we can still be aggressive, assertive and confrontational when called for by the circumstances. Page 153 of “A Primer on Prostate Cancer” (original 2002 edition) pegs the percentage of patients experiencing “mental/emotional changes as 17%, with 3% in the mild category, 14% in the moderate to needing medical intervention categories. This is based on just one practice, and the extent of countermeasure use is not stated. It’s likely that countermeasures, particularly aerobic and strength exercise, would help.

    — body type and body image: JIM REPLYING: I haven’t seen any of us turn into a Vulcan yet! Seriously, there are some body changes that many of us experience, but many of us take them in stride. We lose some body hair, though, as with other side effects that reverse when the drugs are stopped, it grows back if we are able to take a vacation from the heavier duty drugs as part of an intermittent ADT program. (On the other hand, those of us taking finasteride or Avodart have a good shot at growing substantially more hair in the male pattern baldness areas! Yes!) Testicles commonly shrink (again, reversible during the vacation). Our skin can become somewhat drier (especially during the cold months) — can be countered with moisturizing lotion — and stickier — can be countered with Vaseline. Perhaps most prominent, some of us experience breast enlargement, especially if on antiandrogen monotherapy (can be countered in advance and during therapy). There is often weight gain around the abdomen, and loss of upper body muscle mass, though both can be countered with diet and exercise, especially strength exercise.

    — to measurably reduce cognitive function: JIM REPLYING: As one of the studies demonstrates, consistent with other studies, there can be some effect, but it is often not a major impact. I find it interesting and consistent with my own experience that experts feel that exercise helps us maintain good cognitive function.

    — and to eradicate all vestiges of human sexuality are cruel. JIM REPLYING: This is not some primitive castration sacrifice, but rather use of a proven therapeutic approach to control prostate cancer. Therefore, let’s be straightforward about this: it is the cancer that is cruel, not ADT therapy! What you fear is the extreme and unrealistic prospect of what most of us actually experience regarding sexuality. As I’ll explain below, some of us on ADT actually have a far superior experience than that of veterans of surgery or radiation.

    First, many of us are able to employ intermittent ADT, and on the vacation periods we usually get back to whatever normal was before we started therapy, less some allowance for being a little older, as Chuck mentioned. Due to my challenging case, I never had surgery, radiation, cryotherapy or any other major therapy except ADT. That means my system was not compromised by those therapies. My experience is that I FULLY recover during the vacation periods. For me, I am substantially recovered by the 3-month point and virtually fully recovered by the 6-month point after the Lupron runs out and I stop taking the Casodex (while maintaining with 10 mg daily of finasteride). In other words, I have the same quality of life as before I was diagnosed, with an allowance for being 11 years older and in my latter 60s.

    Men who choose one course of about a year of ADT3 with finasteride or Avodart maintenance as primary treatment for low-risk cases report great recovery of sexual function after they have stopped the major drugs. Unfortunately, well-documented research is scant. Based on my own experience and contacts with ADT veterans, I believe the reports as published informally by several doctors.

    Here’s a little secret about sexuality and ADT, at least intermittent ADT: if we use countermeasures, including visualization, contact and “appropriate exercise” by whatever means, some of us will maintain some interest and capability even through long courses of blockade! Here’s another secret: about 10% of us will get all the benefits of ADT without suffering significant side effects in the sexual area.

    JIM CONTINUING: GENDER IDENTITY A NON-ISSUE
    I have never heard or read that this is in any way an issue for men on ADT. ADT is not a method of changing your sex. While it can modify some of the physical manifestations of masculinity, I am unaware of any reported experience or research that it promotes a homosexual in men who were not already homosexual, or a female orientation. While we are typically not as romantically capable while on blockade, I’ve noticed personally and have heard and read that we can remain affectionate and focused on our spouses.

    I hope this helps relieve your concerns.

  9. JOHN’S ROUGH EXPERIENCE WITH ADT

    Hi John. I’m replying to your report of a rough experience with ADT, and I’ll insert responses. I’m sorry you drew one of the short straws. You wrote on November 3, 2010 at 9:20 pm:

    “Tracy,

    “Thank you! You’ve done a wonderful job of summarizing the symptoms and feelings I know I have endured in 5 years of being on and off various ADT medicines. I probably owe them my life … but only via making a Faustian bargain. The person known as John Arnold is still alive, but the John Arnold who is alive today is not the same person that existed 6 years ago. As you noted, how do you take that much of a person’s essence and energy away, and not do immeasurable damage?”

    JIM REPLYING: John, Would you mind telling us what kind of blockade you have been on (just Lupron or Trelstar) and the duration of the on- and off-therapy cycles?
    I’m especially interested in whether you are aware of the countermeasures available and whether you have implemented them, especially aerobic and strength exercise, but also nutrition.

    YOU WROTE: “As for cognitive changes, absolutely they can occur, maybe not in all men who use them, but in enough of us that it ought to have shown up in this study.”

    JIM RESPONDING: Medical institutions in Toronto that are highly respected in prostate cancer circles are involved in these two studies, and I would like to know whether the men on ADT in the studies were using some or many of the recommended countermeasures for side effects. That might account for decreased incidence of cognitive issues. It might also be that the incidence of such side effects, at least as operational defined in this study, is truly low.

    YOU WROTE: “I know absolutely that I am not as mentally sharp or able as I was before I went on ADT. On Lupron, I eventually became extremely depressed and suicidal. Thank goodness I was in a situation where I could switch to another ADT medicine, Trelstar, which for me has proven much more tolerable.”

    JIM RESPONDING: What an awful time that must have been! Thanks for that information about the difference switching made for you. I had not heard about switching making such a difference before, though not many of us suffer depression on Lupron, especially extreme depression. Did you ever try any of the recommended antidepressant drugs before switching to Trelstar?

    YOU WROTE: “But even then, I am retiring 6 years earlier than I had intended to because I simply haven’t the energy, stamina, or mental abilities to continue doing the job I have done for the past 21 years.”

    JIM RESPONDING: Your comment suggests you may not have known about the benefits of aerobic and strength exercise for ADT patients. Proper exercise has been reported to benefit energy, stamina and mental abilities in such patients, and my own experience is consistent with that. Diet and proper nutrition also play important roles in all three of these areas.

    I retired at age 60 but was capable of still working in a mentally demanding job that i still enjoyed. Prostate cancer was a factor in the timing, but indirectly. I wanted to do more physical activity as a countermeasure, including gym work, than my work schedule allowed, and I also wanted to increase my involvement in prostate cancer education, research, and advocacy. I am accomplishing those goals.

    YOU WROTE: “So yes, ADT medicines do have a role to play in slowing the progression of prostate cancer, but no one should ever be in any doubt about the possible side effects. They might be mild, or they might be so bad as to be not worth it.”

    JIM RESPONDING: That’s the way I see it too, though I believe the vast majority of us find the side effect burden quite tolerable or even mild. Again, I’m sorry that you have been one of those who have suffered a really burdensome impact from ADT. I’ve encountered a number of patients over the years who have had a course like yours, and such accounts help me appreciate my own good fortune. I’m glad you have found a more tolerable regimen.

    The new book Invasion of the Prostate Snatchers has good information on ADT side effects and countermeasures.

    Take care, and keep your spirits up!

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