Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so thrilled to have here with me today a friend and colleague, Dr. Charles Ryan, who is the Director of Hematology, Oncology, and Transplantation at the University of Minnesota in the Masonic Cancer Center, where he is also a GU medical oncologist and Professor of Medicine. Dr. Ryan will be talking with us today about the complications associated with treatment with ADT in men with prostate cancer.

Thank you so much for your presentation, Dr. Ryan.

Charles Ryan: Dr. Morgans, thank you. It's always a pleasure to talk about what we do, which is manage patients on ADT and trying to make their life better while we're controlling the cancer. And so I chose to title my talk, "ADT: The Tumor is Treated - What About the Rest of Him?". And I'm going to take that sort of perspective on things. And life on androgen deprivation therapy for some patients is much, much harder than it is for others. My experience is that there's quite a wide variety of the range of toxicities and changes in life that people will go through.

But as we know, and as we're hearing in these talks, treating prostate cancer with ADT may increase the risk of several metabolic, cardiac, and even cognitive complications. And this is a problem that's going to get worse over time because it's a problem that is in part the by-product of our success. Better survival for men with prostate cancer is coming because we are improving the use of ADT, we're approving the use of secondary treatments, etc. So we have more patients coming into the system, if you want to say it that way, people who are living after a cancer diagnosis and while receiving treatment for their cancer. And there are fewer patients who are frankly going out of the system because they're living longer.

And so it's a much more prevalent phenomenon, and I've decided to break this down and to think about it as sort of from the kind of the tenants of internal medicine. And then those of us who practice medical oncology do have backgrounds in internal medicine, where we spent a lot of time, years, in fact, studying many of these facets that are highlighted here. And I think for the clinicians out there, it's good to think about this in sort of three aspects.

First is you have to know what the risks are, and I'm going to talk largely about that today. Second is you should have a couple of things in your back pocket that you can use as first-level interventions, recommendations to patients, first-line therapies you can use for patients. And then finally, third, you need to integrate your specialist colleagues on various diagnostic tests and therapeutic modalities, etc., as appropriate. And I think the other thing is that it's really important to know that many of our primary care colleagues, cardiologists, endocrinologists may not have any idea that the ADT that their patients are receiving for prostate cancer are associated with these metabolic and cardiovascular risks.

And this is an opportunity for us as treating oncologists and urologists to educate these colleagues about these problems. There is, as Dr. Smith just alluded to, a vast literature on so many of these complications. And if that literature is not being read or disseminated, it's not going to be much good. And so that's part of our mission, I think. I think it's safe to consider that ADT in large part contributes to something we might want to call a metabolic syndrome. That terminology has been controversial in the world of internal medicine, but I think it's safe to use it with regards to androgen deprivation therapy because as this figure highlights, so many factors contribute to adverse cardiovascular outcomes that we should be thinking about as we confront our patients and treat them.

And so with regard to these changes over time, we can expect that many of our patients will gain weight. In fact, some studies demonstrate that total body fat goes up to nine, around 10%, and that comes with a concomitant decrease in lean body mass of several percentage points and a change in body morphology, which is sometimes called sarcopenic obesity which is associated with an increase in mortality. Lipids can also change triglycerides, total cholesterol, LDL. All of the lipids can go in the wrong direction in many cases with the exception of HDL, which actually may go up a little bit with androgen deprivation therapy.

But the net effect of androgen deprivation therapy is one that appears to be pro-atherogenic and contributing to some of the cardiovascular outcomes that have been discussed previously. Again, hypertension, insulin resistance, and many of those other effects do come into play. So these are things we have to know as we begin to confront patients, and we think about their premorbid condition and the risks of our therapy. So not the least of which is the loss of bone integrity that can come with androgen deprivation therapy. And this is something that should be emphasized even in patients who do not have bone metastases.

So we're not necessarily going to talk about skeletal events, but what we're going to talk about is the body mass changes and the bone turnover that come with androgen deprivation therapy that can lead to decreases in quality of life, decreases in mobility, fractures, pain, and many other facets. ADT-associated bone loss is a well-characterized phenomenon, and it ranks right up there with many other medical causes of bone loss that we frequently think of with regards to post-menopausal women, aromatase inhibitor therapies for breast cancer, ovarian failure related to chemotherapy, and even bone marrow transplantation.

So what we see here is the lumbar spine bone mineral density loss after one year of therapy in an androgen deprive patients is about 5%, which is a little bit more than a patient who undergoes a bone marrow transplant, but less than some of those other conditions that I mentioned previously. A very nice editorial on this topic addresses some practical factors that one can undertake to address bone health in men with prostate cancer and really divides the question up into those who have bone metastases, which is shown on the right, versus those who do not have bone metastases.

And this table is wanting to maybe take a screenshot of and think about because it really gives a nice series of recommendations for what to do in terms of a baseline workup for bone health, what to prescribe for patients in terms of exercise, etc., etc. Whenever I start a patient on androgen deprivation therapy, by the way, I talked to them about exercise and I specifically focus on resistance exercise and factors that can mitigate the loss of bone.

There is a scoring system called the FRAX scoring system that one can use. It's available online where you enter in certain factors of the patient's condition. And it can give you an estimate over 10 years of the probability of them developing either a hip fracture or some other major osteoporotic fracture. Other factors to consider include calcium and vitamin D, which is shown here that for men under the age of 70, a general recommendation of a thousand milligrams per day. I tell patients that that's two Tums tablets if they want to put some context in that. Over the age of 70, the recommendation actually goes up to 1,200 milligrams. Vitamin D similarly is recommended for younger men, 400 to 800 IUs, and for older men about 50, 800 to a thousand international units.

This does not take into account the fact that many men, especially in North America, are vitamin D deficient, and that consideration should be given to testing vitamin D well before starting androgen deprivation therapy as it may allow you to provide greater benefits to your patients and better recommendations. The upper limit of normal for vitamin D is about 4,000 international units per day. Above that, if you're correcting a deficiency, there can be problems that can arise from excess calcium in the blood.

Diabetes, as Dr. Smith just talked about is something that is felt to be very related to androgen deprivation therapy. If not a direct result of it, it's an indirect result of the changes in body mass, the loss of lean body mass, and the increase in adipose tissue. And a very simple way to think about this is to before starting a patient on ADT to perform a fasting serum glucose or hemoglobin A1C and to decide if they are somebody you need to, again, monitor, to test further, or to refer on to a specialist for diabetic therapy, diabetic management. In all cases, diet and exercise are prudent things to recommend for our patients. And I think it's pretty well known now what a good diabetic preventative diet would be.

Dr. Smith in his talk talked about cardiovascular disease. And it's important to point out that while we discuss the relationship of androgen deprivation therapy to cardiovascular disease, it's simply important to note that cardiovascular disease is the number one killer of men and women in the United States. And for prostate cancer patients, cardiovascular disease is the second leading cause of death. And so this is something that we should think about as we begin our approach to prolonging the life and improving and sustaining the quality of life in our men with prostate cancer. I won't go into these data in great detail, but it has been known for a few decades now. And this is Dr. Keating's work demonstrating the increased relative risks of increased cardiac disease, myocardial infarction, and even sudden cardiac death in patients receiving LHRH agonist therapies.

One piece of data that is somewhat surprising, worth pointing out, is that in studies looking at the prevalence of cardiovascular events in patients receiving ADT, there is a hint that perhaps patients with the greatest risks of cardiovascular disease are those who have had recent cardiovascular events. And as this data shows, the red line is somebody who has had two or greater previous cardiovascular events in the previous year is at a fairly significant risk for having an early cardiac event once starting ADT. And this is something that we might need to think about with regards to LHRH agonist drugs versus LHRH antagonist drugs. And there's a lot of literature emerging on that and a lot of conversation in the field about whether or not LHRH antagonists may be superior with regards to cardiovascular outcomes.

So coming back to this idea is that as clinicians, we need to know the risk of our patients, we need to have in our back pockets a few first-level interventions that we can do. Online sources for managing blood pressure are very simple to read and many first-line blood pressure types of control medications are quite easy to give and don't interfere with anti-cancer therapy. Calcium, vitamin D, exercise, etc., all very easy to consider, even starting Metformin as an oral hypoglycemic in an early stage diabetic is reasonable and not inconsistent with good care for men with prostate cancer.

So finally, as I think about this, I try to think about the four FLAB components for how we want to move forward in terms of what I need to think of as I work up a patient pre-ADT and that's FRAX, lipids, A1C, and blood pressure. And I think if you're paying good attention to those four factors at the beginning of their therapy, then you'll do a lot to help address their underlying health at baseline and over time as you treat them with androgen deprivation therapy. Thanks for your time.