Mark Frydenberg: Thank you very much and again, thank you to Silke and Aurelius for the invitation once again this time. I'm talking about the management of hot flushes in advanced prostate cancer. I think we've all sort of seen this man walk into our practices who has been severely bothered by his hot flushes.

As we all know, it's a subjective feeling of warmth in the upper torso in particular followed by excessive perspiration. It occurs in about 80 or 90% of men on androgen deprivation therapy with about a quarter of them actually reporting it is the most troublesome side effect that they're experiencing. They tend to get variable sympathy for this symptom because it's not particularly a life-threatening symptom, and often, unfortunately, their female partners at home are often going through a similar problem. As such, they're either very sympathetic or not particularly sympathetic. It can be associated with quite a significant amount though of patient distress during treatment. A lot of embarrassment because of the perspiration and the feeling of helplessness basically because they realize I have to put up with this as part of their treatment. It can last for the duration of the therapy, affect their quality of life and their sleep quality.

It's important to know that congenital hypogonadism doesn't lead to hot flushes and it's not the absolute plasma sex hormone level that's actually critical here, but it's reduction from a previously normal level that causes a resetting of the thermoregulatory center. It alters the function of brain neurotransmitters, and there's a number of them listed there. Noradrenaline, serotonin, GABA, dopamine and beta-endorphins. These are the mainstay of how we try and manage these medically by manipulating these transmitters.

The reason it occurs is at the thermoregulatory center in the hypothalamus is anatomically close to the LHRH secreting neurons and by the proximity, the thermoregulatory center can be reset. There's a very clear correlation between flushes and attempted LH surges, and it worsens generally with the duration of ADT. It tends to be worse in younger men and also men interestingly with lower BMIs rather than higher BMIs in studies that have been done.

How do we manage the problem? Well, first of all we can try and avoid any stimuli that can actually trigger this. There's some very good diaries. The one that's on the bottom left there is just from Prostate Cancer UK is a very typical example of a free resource that's available. It's a very useful way for people to try and identify triggers that might actually set off the hot flushes. Obviously one wants to try and avoid them like the man on the right who's getting a hot flush as he collects his beer because certainly alcohol, tobacco, caffeine and spicy foods are all known triggers.

It's important to assess the degree of bother and whilst about 40% of men seem to put up with their symptoms quite well to a point where they didn't want to participate in trials, about 60% of them have conversely felt that the symptoms were bothersome enough to actually be involved in studies. We can also have environmental cooling at night. Nighttime tends to be the time that bothers men the most. Obviously one can have fans and one can even have open windows, but that doesn't always make people very popular in the evening. Certainly during the day, one can dress in layers. Obviously it's a lot easier if you can actually quickly take off some clothes when a flush occurs and use open weaved fabric such as cotton and linen. There's some very simple practical things that can be done that can sometimes assist.

Obviously one relatively straightforward thing that we can do is manipulation of the androgen deprivation therapy, in particular using intermittent androgen blockade. Hot flushes tend to peak about four months after initial LHRH agonist administration, but interestingly it takes about twice as long for the testosterone to recover and for the flushes to disappear. But nonetheless, it can be a very useful strategy when it's safe and appropriate to do so. There have been studies looking at LHRH antagonist versus agonist, really finding that the problem is equal really in both groups. Equally, people have looked at the role of monotherapy with really very uncertain data whether that actually changes anything as far as the flushes are concerned.

We then look at specific treatments that we've used, and the first two are really ones that have been tried and to a larger point been discarded. Oestrogens certainly reduced central LH surges and that's mostly been in the form of diethylstilbestrol either given orally or transdermally. It does reduce the intensity of hot flushes by 70%, but it's usually only a modest reduction with only 20% having a greater than 50% improvement. We're all aware of the thromboembolic problems with oestrogen and to a large degree, these have been abandoned for the treatment of hot flushes. Interestingly, recently there was quite a good study looking at an oestrogen receptor alpha agonists with actually quite promising results. But interestingly, there's been really no further research in this area and it is probably an area that should be looked at.

Another one is the alpha 2 adrenergic blockers because again, this is one of the neurotransmitters that are associated with hot flushes. Clonidine, both orally and transdermally, has been used. It's really not particularly helpful with only one study showing 30 to 40% partial responses and several other studies really showing no difference to placebo. In addition to this, it can cause some significant side effects, in particular dizziness from hypotension from the adrenergic effect.

The mainstays of therapy now from a medical point of view with the progesterone related medications, which work centrally to reduce the LH surges and reduce the likelihood of hot flushes. Cyproterone acetate is certainly available in most countries around the world. I understand it's still not available in the United States, but I think certainly in Europe, Australia, Canada and the UK it is. It's certainly the drug of choice in our country for this setting. Typically it can be used at very low doses and titrated upwards, but in the countries that don't have access to Androcur®, one can use medroxyprogesterone acetate or Provera® or megestrol acetate, Megace®, with similar results. This reduces the hot flushes by 70 to 80%, but there is again, potential toxicities there with hepatotoxicities, fatigue and gynecomastia. It's important to try and keep the doses down as much as possible.

The other large group of drugs are the selective serotonin reuptake inhibitors or the selective noradrenaline reuptake inhibitors, and they're all clinically antidepressant drugs. Venlafaxine, which is Efexor®, and Paroxetine or Aropax® were ones that had been mostly studied, although there have been other drugs that have been used as well. They also improved symptoms by about 60%. Of those 60%, most of them had a greater than 50% improvement in the hot flush score. Again, morbidity associated with these medications, and there has been a randomized controlled trial comparing them to the progesterones with the progesterones being very significantly superior to these antidepressant drugs for the controlling of hot flushes.

The next lot of drugs are the gabapentinoids. GABA is one of the neurotransmitters. These drugs are generally drugs that had been used for both seizures and also for pain. Gabapentin is typically used for epilepsy. Lyrica® is used for severe pain. Again, much less effective in the reduction in hot flushes, very significant side effects, especially with lightheadedness and drowsiness, especially with Lyrica®. Then there's a few other drugs that have been tested in women, but really there's no data in men. Oxybutynin and for reasons the mechanism's not particularly clear, but it's been very effective in post-menopausal hot flushes in women. There's really no data on this in men, but certainly, it would be an interesting area to look at given the very high response rate in the refractory group of patients.

Lastly, there's complimentary therapies that people have been looked at. Exercise, again in females but not in males, has been shown that high intensity aerobic and resistance training can reduce our hot flushes by about 40 or 50%. Given the fact that there's a lot of other benefits of the use of exercise in androgen deprivation therapy, it would seem to be a very sensible thing to be looking at.

People have looked at cognitive behavioral therapy. Diet, in particular using phytoestrogens in soy proteins, this has really not been shown to be helpful at all in randomized controlled trials. But the one thing that's consistently actually been very good with hot flushes is actually been the use of acupuncture with a 70 to 80% reduction in flushes with either dry needling or electro stimulated needling. What's been very impressive is even after the cessation of the acupuncture, the reduction in hot flashes appears to be maintained for up to eight to 12 months.

In conclusion, it's certainly a very common and troublesome side effect of androgen deprivation therapy. One needs to avoid the triggers, promote conservative therapies like wearing fans and light clothes. Intermittent androgen blockade when it's appropriate and safe to do so. Primary medical therapy probably should be the progesterone and possibly the SSRI antidepressants, and certainly the use of complementary therapies such as acupuncture and exercise. It is a significantly under-researched area given the severity of this side effect for most men. Certainly whilst it's not a very severe side effect from a life-threatening point of view, certainly for this guy that's busy there at work, if you could figure out a way to get rid of these hot flushes, that'd be great. Thank you very much for your attention.