Dr. Leonard Gomella spoke at the 24th International Prostate Cancer Update on Friday, February 21, 2014 on “Avoiding Toxicity in ADT.” In his presentation, Dr. Gomella discusses toxicity with androgen deprivation therapy and ways to minimize the side effects.
androgen deprivation therapy (ADT), bisphosphonates, osteoporosis, fracture, bone calcium, denosumab
How to cite: Gomella, Leonard G. “Avoiding Toxicity in ADT.” Grand Rounds in Urology. January 14, 2015. Accessed Jun 2020. https://grandroundsinurology.com/prostate-cancer-leonard-gomella-toxicity-in-adt/.
Avoiding Toxicity in ADT
What we’re going to talk about is toxicity with androgen deprivation therapy. It’s a necessary evil to use androgen deprivation therapy but there’s certain things we have in our toolbox that we can use to help minimize the side effects, things we didn’t have 10 or 15 years ago. We’ll try to focus on the ones that we can actually use today that we have concrete evidence-based medicine findings on in doing this.
Androgen deprivation therapy we know should be used immediately on the diagnosis of metastatic prostate cancer with radiation therapy in intermediate and high risk prostate cancer, which is supported by extensive randomized clinical trials. It is used occasionally for volume reduction for brachytherapy and using it after treatment failure of localized disease either after radiation or radical prostatectomy is controversial; however, the fact is it is used very often in that setting.
What is the optimal androgen deprivation therapy? The current bottom line is less than 50 nanograms per deciliter. Tremendous literature and it’s been talked about at this meeting. It will be talked about more tomorrow morning, a tremendous interest in getting the testosterone level as low as possible, but for our purposes optimal androgen deprivation right now in the literature and in NCCN guidelines is less than 50.
The role of combined androgen blockade the benefit is unclear in metastatic disease. At best some investigators have shown a small 3 to 5% improvement; however, many individuals including when you treat people with external beam radiation and androgen deprivation is considered to be the standard of care.
I think it’s less controversial to use anti-androgen deprivation for 7 to 14 days before LHRH analog to theoretically avoid any problems with flare. There has been a strong increase in the use of patients receiving androgen deprivation therapy for all stages of prostate cancer as we talked about from early stage disease in combination with radiation to later stage disease in patients with frank metastatic disease.
We know what our androgen deprivation therapy options are. Clearly the LHRH agonists and the LHRH antagonists are really the backbone of androgen deprivation therapy, and one of the things that we have to remember that’s only come into being in our stream of consciousness is the fact the newer agents for metastatic castration-resistant prostate cancer such as abiraterone that are pushing T levels down that we have never seen before so low that it can’t be measured by our standard assays, is something to keep in mind. We’re going to keep an eye on this as patients live longer and longer on supra-maximal androgen deprivation far below we’ve ever seen before. We’re going to have to keep our eyes and ears open for how this may play out.
Let’s talk a little bit about the prevention and treatment of adverse effects associated with androgen deprivation therapy. This goes by many different names in the literature; androgen deprivation syndrome, androgen withdrawal syndrome, LHRH syndrome, medical andropause, and it’s not one thing but it’s a constellation of symptoms and now what we have shown is medical conditions that are associated with a low testosterone state. Now that we’re using androgen deprivation therapy more and more in non-metastatic prostate cancer I think that that long-term impact on a man’s life who may—he’s not going to be at that last three to five years of living with metastatic disease but living much longer with a longer period of time with androgen deprivation, I think the concern is increasing that the prolonged exposure of men to androgen deprivation may be more of a concern than we ever have had before.
These are the common adverse effects of androgen deprivation therapy that everyone in this audience are very familiar with. The ones that we’re going to spend most of our time on are the ones where we have some of the best literature to support management strategy, we’re going to talk about obesity, diabetes, a little bit about cardiovascular disease, a little more time talking about osteoporosis and fractures because that’s actually something we actually can prescribe medications for and help our patients with. Lastly we’ll talk about hot flash management.
This is a big problem with abdominal obesity and the so-called sarcopenia during androgen deprivation therapy and sarcopenia is this abnormal deposition of a mid-abdominal subcutaneous fat and this is from Matt Smith’s article from three or four years ago where he did some serial studies and actually show men after six months to a year on androgen deprivation therapy develop the typical mid-abdominal bulge associated with a lot of subcutaneous and also intra-abdominal fat deposition.
Along with that the GnRH agonists also increase serial lipids in men with prostate cancer. Again, we, as urologists, as a group, tend not to follow these things that closely but tomorrow we’re going to get a little bit into the brave new world of men’s health. Matt Rosenberg is here and going to talk about it. While we may not manage these lipids, and cholesterol, and triglyceride levels it’s important that we know about them and work in partnership with our primary care colleagues to manage them, but there is a very significant increase and in particular triglycerides go up most dramatically in men treated with LHRH agonist. It’s not the drug; it’s just the effect of lowering the serum testosterone. The other thing is that the GnRH agonists have been shown to decrease insulin sensitivity on non-diabetic men.
We already know it can throw men out of whack who have diabetes who go on an LHRH analog or antagonist but even in men who are not diabetic you can see problems with glucose intolerance and with a decrease in insulin sensitivity, so I think we’re becoming much kinder and much more sensitized as urologic surgeons that we really do a lot of metabolic disruption when we use androgen deprivation therapy.
You can see in keeping along the theme that we just spoke about you see an increase in coronary heart disease in men on versus not on ADT, increase in diabetes, and a small increase in men having myocardial infarctions on androgen deprivation.
There’s a lot of conflicting literature out there. You can show this data. The one that’s most controversial is the coronary heart disease and stroke. Diabetes is generally agreed to. The coronary artery disease and MI and things like that is a little bit controversial. Some people say there’s a clear association. We had that discussion yesterday about testosterone replacement therapy and using testosterone replacement. I can show you some articles that the hypogonadal state increases cardiac risk. Other articles show that there’s really no association. Across the board obesity and insulin resistance has been clearly agreed to by everyone that we do induce either a diabetic or a pre-diabetic state.
What are some practical recommendations and this first part of androgen deprivation toxicity for diabetes? You should consider testing in all men who are going to be treated with ADT at baseline and yearly thereafter. This is something that we’re not used to doing but in partnership with the primary care doctors looking at hemoglobin A1C and making some determinations, and if someone is noted to be pre-diabetic before you start them on androgen deprivation therapy you try to correct any correctable factors, and the most important ones here, and these are the most common sense ones that we can intervene with, are basically encouraging lifestyle interventions such as encouraging patients to lose weight. There is data that suggests if a man can lose about 5 to 10% of his bodyweight before starting androgen deprivation therapy that he can minimize his risk of developing diabetes. Lastly, greater than 2? to 3 hours of physical activity. They’re pretty easy recommendations for us.
Cardiovascular disease, I think a lot of this falls into what a normal primary care doctor would be doing anyway looking at target LDL levels and looking at the National Cholesterol Program for adult and adult treatment, looking at their target levels of what lipids and cholesterol levels should be. The emphasis on this should be primary prevention. Tobacco cessation is the mantra today in medicine trying to get everyone to stop smoking although, obviously here on Colorado we’re having a mixed message about that on TV, that it’s okay to smoke marijuana but not okay to smoke tobacco. We’ll see how that plays out.
Treatment of hypertension versus the American Heart Association guidelines and I think some of you know that follow this literature it became very controversial over the last year. There were all these guidelines that came out in the fall from the American Heart Association and they were met with a lot of controversy. It’s not our job to deal with the controversy but again, our primary care colleagues should hopefully be dealing with this and Matt Rosenberg tomorrow may be able to fill us in. All the common sense things; lifestyle intervention, what’s good for the heart as we always say it’s good for the prostate, low fat diet, increased physical activity, aspirin is recommended for men who have greater than a 10% risk of MI over ten years and again, statins first line for hyperlipidemia if lifestyle does not allow you to match your target.
That pretty much covers some of the things associated with the metabolic syndrome, the diabetes, the increase in the lipids, the sarcopenia. Let’s move now to something that we have a little bit more control of and the reason I say this, this is something that really falls into an ability to prescribe medications that have been shown to not only improve osteoporosis but also decrease skeletal-related events in men who have known metastasis with androgen deprivation. The interest in things such as Zometa and denosumab over the last couple of years has brought this focus back into urology. As men’s health issues evolve these things which appear to be very peripheral to us are going to become more centric to what we do in our practice, again in coordination with our primary care colleagues. We know that the use of GnRH agonists can decrease bone mineral density in men with prostate cancer significantly. This is the data that has been certainly well used in talks on Zometa and denosumab over the years showing the portion of fractures one to five years after prostate cancer diagnosis with and without the use of androgen deprivation therapy, again showing a statistically significant increase in any fracture and about a 3% increase in any fracture requiring hospitalization.
When we look at these things we also have to consider the normal aging of men. A healthy man will lose 0.5% of bone mineral density following them above age 50. If you look at the loss that happens on androgen deprivation therapy it goes from 0.5% up to almost 5%. This is measuring the bone mineral density at the lumbar spine at one year. Probably relating to testosterone decline and decrease in physical activity men will see a normal reduction in bone mineral density but clearly it really, really is accelerated by androgen deprivation therapy as we all know.
The longer you’re on androgen deprivation therapy the increased incidence of osteoporosis up to ten years almost 80% of men will have a documented osteoporosis based on bone mineral density determination.
This is the thing I think to me was actually more startling in that we tend to think of little old ladies with hip fractures and not doing well but actually the mortality and survival of a man who undergoes a hip fracture is far worse than ladies who undergo a hip fracture, so you could see that hip fractures in particular are very, very daunting and have a real impact on survival for men.
I think when we look at this osteoporosis data we have to be a little bit careful. We talk some big numbers sometimes but what happens is in a lot of the studies that are done they look at what’s called morphometric fractures. A fracture that you might not ever clinically notice or pay attention to but they are subtle collapses in the vertebral body that you might not image or pick up but if you do specific imaging of the spine you will find these bone morphometric fractures and these explain why there’s a slow decline in height sometimes, again, more apparent in women than men, but it also occurs in men.
The diagnosis of osteoporosis whether it’s androgen deprivation therapy related or not is bone mineral density, the gold standard. It’s one of the best determinates of bone strength and has the strongest correlation with future fracture risks and it works just as good as blood pressure predicts the ultimate development of a stroke. Those of you that do DEXA scanning looking at bone mineral density you have your standardized reports that come out based on the particular machine that you’re using, but this is all based on the T score and as T score normalizes to that of a young healthy male in the 20 to 25 year age range and any T score of -1 or above is considered to be normal. Decreased bone mass is anything which is a -1 to -2.5 and osteoporosis is greater a number of less than 0.25 so going down to negative 3.0 or negative 3.5. These have been standardized. If you look at the literature eight or ten years ago these numbers were all over the place but the WHO has stepped in and said these are the hardcore criteria that we can look at and low bone mass is also termed osteopenia on some of the papers that you read.
This is the WHO FRAX risk assessment and a lot of us will use this in specific patients. This is one of the most reliable tools out there. It comes out of Sheffield, England and the questionnaire asks all sorts of specific questions; age, the weight, the height, previous fracture, medications, glucocorticoids, and the like, and it gives you a risk assessment of developing a fracture. Basically the National Osteoporosis Foundation in the United States has come up with prevention guidelines for men based on the following; any man who has a vertebral or a hip fracture, any man with a femoral neck or spine T score of less than minus 2.5 or if you go on the FRAX website and you run the probability and its greater than 3% of a hip fracture or any major fracture of greater than 20%, the National Osteoporosis Foundation recommends the guidelines for treating the man for osteoporosis and when you plug in androgen deprivation therapy it really does increase a lot of these probabilities of hip and major fracture.
How do we manage this in men on androgen deprivation therapy either with or without bone metastasis? There was a little bit of discussion about this concerning Vitamin D supplementation but clearly not only from a cancer prevention standpoint but obviously from an osteoporosis standpoint if you have a very low Vitamin D level—again we tend not to measure Vitamin D levels but its commonly done in some men’s health practices and certainly in endocrinologists but you can reduce your risk of fracture by about a third if you get your Vitamin D level up to greater than 480. Maximum bone density is achieved with Vitamin D levels greater than 480. Interestingly the spine mineral density is not as affected by Vitamin D as the bone mineral density is in the wrist and in the hip and that’s just a very curious observation. Calcium absorption in the gut, the reason we need Vitamin D is one of them is to allow for adequate calcium absorption and if you’re Vitamin D deficient you need more calcium intake to actually get your calcium levels and your fracture risk reduced.
Here is Vitamin D supplementation which is recommended, a thousand to 1,200 international units a day. If you are into measuring Vitamin D levels what you do is you measure a 25-hydroxy D you don’t measure 125-hydroxy D which is normal or actually even elevated in Vitamin D deficiency, and if you’re going to put someone on supplementation you recheck them in three months or yearly. Vitamin D supplementation should be a standard for any man that is on androgen deprivation therapy for prostate cancer regardless of whether or not they have metastasis or not. I couldn’t find any literature that said you needed more Vitamin D or more calcium in the presence of boney metastasis so it looks like whether you have male osteoporosis based on androgen deprivation or in the presence of metastasis these recommendations are about the same.
The calcium supplementation of greater than a thousand milligrams has some concern about increased cardiovascular mortality by about 20%, so the latest recommendations from the Endocrine Society are men should get most of their calcium supplementation through the diet and that the days of giving very high doses of oral calcium probably should not be recommended. This is fairly new data that shows that men who have extraordinarily high calcium intake may be at increased risk of dying from a cardiovascular event. Encourage calcium through dietary sources, the obvious things such as cheese and fish, and the like.
One of the most powerful things we can do with our patients with toxicity-related to androgen deprivation therapy is using bisphosphonates whether they’re oral bisphosphonates or parentarel bisphosphonates. Bisphosphonates work by inhibiting osteoclast activity and therefore reduce bone resorption and turnover. They can increase the bone mineral density by 5 to 8% and in the hip by 3 to 6%. While these percentages don’t sound like big differences when you run a FRAX score on people these small percent increases make a big difference in reducing the fracture risk.
One thing we have to remember with bisphosphonates and this is whether you put somebody on an oral bisphosphonate or a parentarel bisphosphonate the issue about ONJ osteonecrosis of the jaw and in fact, this is something we’ll talk about with denosumab as well. We used to think that we were safe with denosumab with ONJ, in fact that’s not true; there’s the same risks of having osteonecrosis of the jaw with denosumab. The important thing is you should strongly consider having patients go for a dental exam and monitor them periodically while they’re on the bisphosphonates.
These are the common side effects of bisphosphonates. The class warning of all the bisphosphonates whether they’re oral or parenteral is that there may be increased joint and muscle pain, osteonecrosis of the jaw, and what they terming more in women than men are atypical fracture of the femoral shaft, the fracture occurs in a different location than it would otherwise be seen in a typical osteoporotic fracture. Some of these are more common. Obviously renal impairment is more of a hit with something like Zometa as opposed to doing something such as Fosamax. We have to realize when we use these bisphosphonates there can be toxicity and we just do have to be aware of it.
Denosumab is something that has really been put front and center with urologists the last few years with the two formulations for both the Prolia for osteoporosis and the Xgeva for frank metastatic disease and denosumab is a monoclonal antibody that binds to RANK ligand and what is does is inhibits the formation and the survival of osteoclasts therefore it reduces bone resorption. It does, depending on the study you look at, maybe a hair better job in increasing bone mineral density by around 7% at 2 years and it does significantly reduce vertebral fractures in men with osteoporosis by about 68% and again, 40% reduction in hip fractures.
When you look at denosumab you can, when you line it up with zoledronic acid you can see that both of them have a risk of hypocalcemia, you’ve got to make sure the patients have adequate calcium supplementation as we’ve spoken about. A little bit of concern about the development of new primary malignancies in patients treated with denosumab but this is something that has to be monitored over the long term.
Medications for osteoporosis, what’s available; bisphosphonates and again you guys got this pretty much right. Boniva and Evista are not FDA-approved in men. They are only approved in women. Bisphosphonates approved in men and women include pamidronate, Fosamax, and Fosamax plus D, Actonel, and of course Zometa in men with metastasis, but not osteoporosis and zoledronic acid is for men with Zometa, the formulation for men with osteoporosis, for mets, and then the Reclast is the IV form which is a much higher dose given annually for men with only osteoporosis. Again, it’s like we have two types of denosumab, we’ve got the Prolia and the Xgeva. One is for osteoporosis, one is for bony metastasis. Same thing with the zoledronic acid; one is for men with metastasis and one is for men with just osteoporosis.
Other drugs are out there but really what happens is that one of these which is an injectable Forteo in men with osteoporosis, the problem is its not recommended for men who’ve had radiation. I think it’s not commonly used by most urologists. Estrogen and testosterone they do very good, they do very nicely when it comes to osteoporosis but obvious reasons they’re not FDA approved. Toremifene is used in women with breast cancer but has not been approved by the FDA for men with osteoporosis.
These are two big denosumab dogs, Prolia for men with osteoporosis or Xgeva. One is given every six months and a different dose is given monthly for men with known metastatic disease from prostate cancer.
What are the practical recommendations for osteoporosis? Consider bone mineral density for all men on androgen deprivation. The majority of the audience here 75% of you do that. I can tell you locally we have a little bit of a challenge with getting that approved by our carriers which is somewhat frustrating. In fact if you move from Philadelphia to the middle part of the state we have different Medicare carriers and our good friend Paul Seibert from Lancaster is a real guru in this area, he has no problem getting bone mineral densities and our local Medicare carrier in Philadelphia constantly denies them for us, so it’s a little bit of a frustration for us. If you’re going to be optimum about it doing bone mineral density testing is best and then do it after one year and then the recommendation is from the endocrine society is to do it every other year. Common sense things; exercise, weight-bearing exercise, quitting smoking, decreasing alcohol intake, very common sense things for men with osteoporosis. Calcium, about a thousand milligrams a day but the latest recommendation is try to get more of your calcium from calcium-rich foods and a Vitamin D about a thousand units a day. If you have men over the age of 50 and have a personal history of a hip or vertebral fracture, a low T score, or the WHO algorithm that we talked about with a ten-year probability of a hip fracture of 3% or a major osteoporosis-related fracture of greater than 20% should be considered for oral or systemic therapy.
Lastly just talk a little bit about hot flashes. I think hot flashes are something that we have a wide spectrum of. We have hot flashes that bother some patients and hot flashes that are really not creating problems but officially they’re found in 50 to 80% of men and the triggers are usually spontaneous but are often related to hot liquid or temperature changes going from a hot environment to a cold environment, although nobody clearly knows what causes vasomotor instability it is generally considered to be something to do with the hypothalamic thermoregulation.
Many different therapies are out there. I think everyone has their own favorite that they like to use. Everything’s been tried. There is no standard of care out there for this. A lot of interest in alternative therapies, lifestyles, soy, flax seed, interesting data that acupuncture can help both men and women with hot flashes. If you look at the data out there, this is one study that was done a few years ago by Jay Smith [phonetic] where they compared DES, Megace, Phenobarbital, clonidine, and there was 70% with DES and Megace a 70% complete response rate and a lower response rate but again the concern about using DES you’ve got a fairly high response rate with it but obviously some concerns with potential thromboembolic or cardiovascular complications.
Probably one of the strongest papers out there is using injectable Megace or megestrol progesterone acetate looking at 400 milligrams versus 150 milligrams IM and basically what happened was even 25% of the patients who received one or two monthly injections of the Megace ended up having never to come back again, so I think if you look in the literature for those patients that are having the most troublesome hot flashes that the megestrol progesterone acetate is probably the best approach. The downside of it is that it can cause some men to have increased appetite and have weight gain.
Lastly, intermittent androgen deprivation gets a lot of attention when it comes to relieving some of the side effects of androgen deprivation therapy. It’s not for every patient. All patients are not good candidates for androgen deprivation therapy but androgen deprivation therapy does get a lot of attention because it can give over the short term reduction in hot flashes and help with some of the metabolic syndrome. Everyone knows what intermittent androgen therapy it’s a cyclic approach and right now in the literature it is very controversial exactly who, how, what, when, and where you should use intermittent androgen therapy in cases of advanced and metastatic prostate cancer, but the concept is just a variable period of time on and off androgen deprivation therapy and exactly how you do this is really unclear.
An article will be coming out in the Canadian Journal of Urology shortly that lets you pick which study you like because there were studies done by Schwab, international PR7 and SEUG studies where at different starting and stopping points of intermittent androgen deprivation therapy were used. There’s some controversy that patients who had very widespread disease benefitted in the Schwab trial from intermittent androgen therapy and those with less bulky disease did not enjoy the same benefit. I think continuous androgen deprivation remains the standard of care but I think you can go into the studies and dissect out certain patients who may have an optimum benefit from intermittent androgen deprivation therapy and although it’s never been shown to worsen the survival the reason I mention this in this context is that virtually every study has shown an improvement in the quality of life in metabolic parameters of patients on intermittent androgen deprivation therapy.
In conclusion what are some things we can say? This was from a consensus statement about three years ago from the American Heart Association, the AUA, the American Cancer Society, and ASTRO that there’s an association between ADT and cardiovascular disease and its controversial as we mentioned, but it may exist. Clearly the androgen deprivation therapy does impact lipids and insulin sensitivity. Men started on ADT should follow up with their primary care physician. I think most of us as urologists should be partnering and make that clear to our patients the importance of having a primary care doctor to monitor all of these things that we are not used to normally keeping track of. There’s no data that indicates any specific intervention with decreased cardiovascular risk in this setting. Men on ADT with cardiac disease should receive all of the American Heart Association recommended preventions for statin, lipid control, triglyceride, blood pressure, and again as we mentioned with an increased cardiac risk for an event consider low dose aspirin.
At a baseline for the metabolic and cardiovascular complications, and this was a universal consensus from both European urology and United States, at the baseline BMI, circumference, blood pressure, fasting blood glucose, and fasting lipid profile and all the things we talked about, blood pressure control, lifestyle intervention, and again identifying those patients who might be pre-diabetic because of the change in the insulin sensitivity really need to get a good going over by their primary care doctor.
For the osteoporosis you’ve got to really look at the baseline studies. If you can get the DEXA scan and look at them they’re great. With osteopenia you may want to go ahead and start patients on some type of bisphosphonate or denosumab if you think it’s appropriate. At a baseline everybody should do these things. Stop smoking, limit alcohol, weight bearing exercise, calcium with diet or supplement to Vitamin D target level we had talked about. Most of us don’t measure Vitamin D but consider looking at the FRAX score as well if you’re uncertain if somebody should really go on some type of osteoporosis management.
Androgen deprivation therapy can do a lot of things and as urologists we do have a few things that we can do for our patients particularly when it comes to directing them towards the primary care doctor but also some things we have available too such as bisphosphonates and the denosumab to deal with osteoporosis.
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