Managing the Complications of Androgen Deprivation Therapy - Mark Frydenberg

October 15, 2019

A more common but often less talked about negative side effect of androgen deprivation therapy is the presence of hot flushes in men. In this discussion with Carmel Pezaro, Mark Frydenberg highlights solutions to this issue ranging from simple everyday adaptations to investigating alternative complementary therapies and drugs.


Mark Frydenberg, MD, Vice President, President-elect, Urological Society of Australia and New Zealand Urological Oncology Fellow, Mayo Clinic, 1991-2 Chairman, Department of Urology, Monash Health 1997-present Professor, Department of Surgery, Monash University 1997-present Clinical Chairman, Prostate Cancer Research Group and CAPTIV collaboration, Monash University 1997-present Chairman, Clinical Institute of Speciality Surgery, Epworth Healthcare.

Carmel Pezaro, BHB MBChB, FRACP, DMedSc, MHPE.  Yorkshire Cancer Research (YCR) Senior Clinical Research Fellow.  Dr. Pezaro is a medical oncologist and researcher, with an interest in prostate cancer. Following oncology training and a doctoral degree in urothelial cancer, she spent two years working in the Prostate Cancer Targeted Therapy Group at The Institute of Cancer Research / Royal Marsden.  From 2013 until 2018 I worked as a medical oncologist at Eastern Health and Monash University in Melbourne, where she participated in laboratory and clinical research programs. She was the deputy chair of the Australian and New Zealand Urogenital and Prostate trials group (ANZUP) prostate cancer subcommittee and was actively involved in collaborative and industry trials. Her research output includes 70 publications since 2008 and both chief and co-investigator grant funding. As a complement to her academic research interest, she undertook a Master of Health Professional Education, which I completed in mid-2018.  In October 2018 she moved to Sheffield to commence a 5-year clinical research fellowship with Yorkshire Cancer Research, alongside clinical duties.

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Carmel Pezaro: So I'm delighted to be joined by another Australian colleague. I have Mark Frydenberg with me. He is a Professor of Urology Surgery at Monash University and Cabrini. Mark, thank you so much for making time for me today.

Mark Frydenberg: My pleasure, thanks for inviting me.

Carmel Pezaro: Well, it's my pleasure. Now again, you were in one of my favorite sessions yesterday talking about management of the complications of ADT, and particularly the very fraught subject of hot flashes. So, can you give us a little summary of that talk?

Mark Frydenberg: Sure. So basically, first of all, it is a very significant complication of ADT in men. Most of the studies have shown, and I think it's shown by our own clinical practice, that probably 80% to 90% of men suffer to it to at least some degree. About 27% of the research says that it's the major problem that they experience with ADT. The problem with it is that it causes quite a lot of social embarrassment. They get this horrible feeling of warmth, they're perspiring, and they're often in social situations where it's really embarrassing. They're going red, they're perspiring, and it's in front of other people. So the problem is that it's something which they get distressed about, and it is something that they feel a bit helpless about too because they feel that this is the therapy that's being prescribed and they just have to take it on the chin, so to speak, that they just have to accept this. They feel a degree of helplessness about it, and they found that it really is quite a severe, disabling problem for them.

It's really important to just recognize that it is a significant issue and often very simple things will actually help them in the vast majority of cases. So, you don't always have to rush straight to pharmacological treatments, but there's a lot of very simple, practical things that people can do.

So the first thing was to try and see if there's a trigger. Occasionally, there's a trigger that sets off the hot flash. Now, a lot of the times men don't know what the trigger actually is, so that there are actually quite good hot flash diaries that you can get. The one that I actually think is a really excellent one is from Prostate Cancer UK. It's just based on their website and you can easily download it and access it, but it's really good at trying to actually identify, what have you been doing in the half-hour before a flash? To try and see if there's a pattern, and if there is a pattern, then you avoid it. Now, the typical ones are alcohol, caffeine, sometimes spicy foods, but there are a few triggers like that that if you just avoid them, then that can often mitigate the hot flashes significantly.

The second thing is just to do simple environmental things. I mean, if during the day, what men need to be instructed is first of all try and wear clothes that are fairly light, but also layer them so that if it's a cold day and they're wearing a jumper, just something they can easily take off. So that they can cool themselves down. So, just simple, practical things that they can do and at night time, obviously having a fan or an open window, or something like that, can actually help them mitigate the hot flashes during the night time. So again, very simple, practical things.

Then if that then fails, then it's really a matter of even modifying a hormonal therapy or using drugs that might help. So again, in my practice generally what I'd look at is an intermittent blockade. If they've had a successful biochemical response, their cancer is under very good control and it's safe to use an intermittent blockade, then, in fact, it's reasonable to give them a break off. Now, it will take sometimes six to nine months for the testosterone recovery to occur, but at least during that period of time what'll often end up happening is that their flashes will decrease. Interestingly, I have a lot of patients where we do intermittent blockade and we time it according to the seasons. So for example, if I know that it's coming to wintertime, then we're more likely to use the androgen deprivation therapy during winter because I don't mind the hot flashes so much when it's cold.

Carmel Pezaro: I love that.

Mark Frydenberg: Then I do the exact opposite during summer. If I can time it so that the recovery will occur during the summer months when it's hot outside ambiently. So, we try and do it that way. So if we use the intermittent blockade, we try and time it according to the seasons a little bit.

Carmel Pezaro: Good. You do have flexibility, don't you?

Mark Frydenberg: Yeah.

Carmel Pezaro: You can have a little longer with the PSA fully suppressed before you choose to start the restart.

Mark Frydenberg: To take it off, exactly. So just using that would be fine. We've looked at research with regards to sort of an LHRH agonist versus antagonist, it doesn't seem to make a difference. Monotherapy, there's really no data on. So really, I think the best ADT manipulation you can do is an intermittent blockade, which can sometimes mitigate the symptoms at least for a while for patients as well.

Carmel Pezaro: Of course, it's not medically suitable for all patients.

Mark Frydenberg: Absolutely.

Carmel Pezaro: It's a really good reminder, yeah.

Mark Frydenberg: For those that can. Then obviously, then it's a question of looking at complementary therapies and drugs. So the complementary therapies, interestingly there's quite a bit of data there in exercise in women with hot flashes. There's very little, in fact almost no data, in men but in fact it seemed almost counterintuitive that actually making people exercise would reduce hot flashes rather than increase hot flashes. In fact, it's been very well shown in postmenopausal women that it's actually very helpful. I think it'd be a very good area of research in men as well, but seeing there's so many other advantages of exercise in people on ADT, it seems logical that this would be a reasonable thing to be doing anyway.

The other complementary thing, which I know is always very, very difficult to prove the efficacy of, but there's a large number of trials now looking at acupuncture for hot flashes, which actually seem to show very good results. Now, I know it's often very hard to try to separate it from a placebo effect, but the reality is, is that there seems to be at least enough in there that it should be at least in the mix of things that we think about for patients.

Then the last thing is drugs and medications. The three main groups, we also talked about it yesterday. I won't go over it now, but estrogens and clonidine to a large degree really have been and gone. They're certainly not as effective as the other drugs. They've got some significant morbidities associated with them, and really in 2019, there's probably no role for either of them at the moment.

The three main classes of drugs, well the main classes of drugs, would be using the progesterones. It's caused a bit of controversy yesterday in the discussion, but exact drugs, the selective serotonin reuptake inhibitors or the SNRIs, if it's reuptaking the noradrenaline, and also the gabapentinoids. So, things like Lyrica®. They're the three probably common drugs that are being used. Certainly, my experience in Australia using the progestins, there was certainly a lot of concern yesterday that maybe there's some anecdotal evidence that it might actually cause harm as far as the actual biology of the prostate cancer.

Personally, I've not seen that in the patients because the dosages that we're talking about are not the typical dosages that we had been using for prostate cancer management in the past. I mean typically, cyproterone acetate, which is available in most parts of the world other than the USA, cyproterone acetate, normally we're using in the dose of 300 milligrams a day. You're using it at probably 50 to 100 a day for hot flashes. It's often the temporary thing anyway, just for a period of time. So, I personally haven't seen it but obviously there were some cautionary tales from some of the colleagues in the audience, which we should take note of.

Carmel Pezaro: I guess it's a nice reminder. I love that you've put drug therapy last, but it's a nice reminder that there is more than one.

Mark Frydenberg: Yeah.

Carmel Pezaro: So that if the first doesn't work, perhaps to try another. If you do find something to work that works in terms of a drug therapy, you said it tends to be a temporary thing. So, how long do you recommend men are on treatment?

Mark Frydenberg: Stay on it? Listen, I think if you are using those drugs it would probably just be worthwhile to get the flashes under control. So what I usually just try and do is to give it over a two or three month period, and then actually wean off again and see how they go. A lot of men actually have durable responses and they don't seem as bothered by the hot flashes as they were previously. So, I tend not to try and use a lot of these drugs as a long term thing. Obviously, if you're using the antidepressant drugs, that has its own challenges with medical management because you can't immediately just withdraw those ones. You've probably going to taper them off over a period of time. I must admit they're some of my less favorites. I don't like using those, the antidepressants or the gabapentinoids very much due to their overall effect on the person. I think it has very significant effects on, I guess not only their mood but also sometimes a bit of fatigue and tiredness and just the way that they function.

Then there were a few other interesting new things, again, coming I guess from the female hot flash literature that I think they're worth exploring. Probably the most interesting of which was oxybutynin, which is a drug that we use for bladder overactivity very recently. For reasons from a physiological point of view can't quite work out really the physiology why it works because the cholinergic pathway isn't really associated with that thermogenic center in the hypothalamus. Having said that in, again, 70% to 80% of women with postmenopausal flashing it seems to help. So, it might be a really interesting area of research and again, there were some anecdotes from some of the people that it actually worked very well. So, certainly worth some research.

Carmel Pezaro: Well, it's a lovely thought that there's perhaps hope that things will continue to evolve in this space because I think in many ways, this has been a somewhat neglected space. It really feeds into that wider issue of survivorship that I know that you have a strong interest in. So in terms of giving a message for men with prostate cancer, what would your message be in terms of survivorship and where things are going?

Mark Frydenberg: I think it's critical because as clinicians, we do an enormous amount of research to try and work out, what's the best therapy or combination of therapies that will improve long term survival? Obviously, that's a critically important endpoint for the vast majority of people but at the same time though, I think that it's often very under-researched, the effects that those treatments or combinations of treatments have actually on the person.

We've also got to get a really good balance between quantity and quality as life as well and if we're making people live longer, we want to make sure they're living longer with good quality. Not living longer with poor quality and with a lot of very poor side effects of the treatments. It's not just in androgen deprivation therapy but I think it's surgical management, it's radiation management on top of the surgery in many cases, and it's also the toxicities that come with chemotherapy as well. So, I think we've got to realize that there are toxicities to all the treatments that we do, and sometimes when we're doing multimodality therapy, we're in fact adding all those toxicities in together on the patients. I think survivorship issues have got to really be front and center because at the end of the day, we're treating a person and that person wants to live as long as they can for their family. At the end of the day, they want to live well, and as well as we can make them.

Carmel Pezaro: That's a fantastic place to stop. Thank you so much for your time.

Mark Frydenberg: You are very welcome, and thanks for having me.