Alright, next we have Dr. Celestia Higano. She
was formerly a professor in the Departments of Medicine and Urology Division of Medical
Oncology at the University of Washington and the clinical division of the Fred
Hutchinson cancer research center. She is an adjunct professor in the departments of urologic
sciences at the University of British Columbia and she previously was the medical director of
the Prostate Cancer Supportive Care Program at the Vancouver Prostate Cancer Center back in 2013.
Dr.
Higano is an internationally renowned expert and clinical researcher focusing on prostate
cancer and at UW (University of Washington) she led the prostate cancer clinical research groups
that participated in developing agents such as zoledronic acid, Sipuleucel-T, enzalutamide,
apalutamide, abiraterone, and radium-223. Over the years her clinical research
has impacted the standard of care for prostate cancer patients around the world.
So, without further ado here's Dr.
Higano. So I'm going to talk about the side effects
of androgen deprivation therapy today — what are they, and how can they be managed? I'd
like to do this in the context of the program where I'm medical director called the
Prostate Cancer Supportive Care Program so you can see how we use education in the
context of this program to help patients and families manage with these side effects. So,
first of all, the Prostate Cancer Supportive Care Program—and this is the website listed here—is
comprised of seven modules which encompass the whole range of situations for someone with
prostate cancer ranging from early diagnosis towards developing metastatic disease, and
each module is optional for patients to attend. So, it depends on their situation and what
they really want. So module one is actually a module teaching patients about prostate cancer
and the primary treatment options.
Module two has to do with sexual function and intimacy after
treatments. Module three has to do with exercise, nutrition, so-called lifestyle management.
Number four is recognition and management of side effects of androgen deprivation therapy that
I'm going to address today. Five is about pelvic floor physiotherapy for urinary incontinence. Six
is emotional counseling, and seven is an education session about metastatic disease. (And
why am i having trouble with this, okay.) So, androgen deprivation therapy — well what is
it? Well, first of all, we know that testosterone is the main male hormone and we know that prostate
cancer cells are stimulated by testosterone. Way back when, Dr. Huggins discovered that if he
removed the testicles which make the testosterone in men who had pain related to metastatic
prostate cancer, the pain was magically relieved. Removal of the testicles was the
only way to deal with that until the 1980s when we finally
had medical treatments to lower the testosterone the same level as
what we see with removal of the testicles. So, testosterone has a lot of different
functions and this slide is sort of showing all of the places in the body that
testosterone can have an important effect. So, how how can we control testosterone
levels? Well, I already alluded to one of them — one is we can remove the testicles,
and also now, luckily, since the early 1980s we've had more medical approaches to that which include
any of the following injectables and I've put both the generic name and the brand name so you
may recognize one of these if you're on one. There's also another way to lower the
testosterone level.
These drugs are more recent, these antagonist drugs, Degarelix or Firmagon is
an injectable and that's been around for a while, but just a few months ago an oral form of this
antagonist became available called Relugolix. So, there's another option for men who need to
have ADT or androgen deprivation therapy. So again, just to quickly review when we remove
the testicles with a so-called orchiectomy we're actually removing the place where
the majority of testosterone in a man's body is produced. Otherwise, when we give the
injectables, either the agonist or the antagonist, we basically turn the testicles off
through this hormonal mechanism. So, when we have, you know,
a person who's been treated with um either surgery or radiation, you know,
we we have these kinds of side effects which, you know, many of you may know well.
When
we then add androgen deprivation therapy, we're kind of adding insult to injury
because, really, when you put these together there's a lot of overlapping issues
and so, you know, it's really important to address these and know about these beforehand so
you can be prepared um on how to deal with them. So, I like to think of the side effects of
ADT in these categories… First of all, "what the doctor will commonly tell you," and
there are three things and we're going to discuss these. They talk about loss of sex drive or
libido, erectile dysfunction, hot flashes, and that's commonly the only thing you'll hear
from the doctor. Now sex drive, unfortunately, as many of you may have found out, there is no
magic pill to improve your sex drive or libido. We also know that many men as they age—not
all but many—the libido tends to decline anyway.
There are very interesting
strategies to actually enhance your libido and we work on this with our sexual health
nurses in our so-called second module. They look at all these different
strategies for improving libido. So, if your libido is kind of blah or none,
usually you don't like to have good erections and furthermore, if you've had surgery, in particular,
you may not have too good erections to begin with. So, you know, we know that there are various
treatments for so-called ED erectile dysfunction — medications, vacuum pumps, penile injections,
etc. We, with our sexual health nurses, we incorporate couple based coping and education,
some psychological and relationship counseling, but what one of the things that's very important
and many patients nevermind many physicians do not know this fact that just because you
cannot get an erection does not mean you cannot get an orgasm. So, many couples will
experiment with that and how to best allow orgasms to occur if that's
something that you want as a couple.
So, hot flashes. So, this is another thing that
doctors will tell us about when we're gonna go on hormone therapy. A lot of times people think
they get through the first month and they don't have any of these side effects well oftentimes
these side effects don't even really start coming on until the second month because many
of these drugs do not cause the testosterone level to go down to that you know undetectable
level until the end of the first month. So, just because you're in your first month and you
have side effects don't assume that's going to be this the same throughout the course. So, what kind
of things makes hot flashes worse? Various dietary substances like alcohol, spicy food, caffeine,
heat makes hot flashes worse so, you know, try to stay cool and well hydrated, and then stress,
okay, being in the middle of a traffic jam on the freeway; that's a sure thing to bring out hot
flashes.
So, what can help with the hot flashes? You know, various materials — anybody whose wife
has gone through menopause and knows that there's certain kind of materials that are desirable when
you're having hot flashes. Also sleeping with layers of clothing can be helpful so that you can
take them off, and use a fan. I mean my husband not only sleeps with the window open, but he he
sleeps with with the overhead fan and he's not even on ADT. So, anyway massage and acupuncture
has been shown to be helpful but also, and this may be a little bit counterintuitive, exercise
can help hot flashes, and so can something called cognitive behavioral therapy which, you
know, can can really help with that. Now, there's a variety of things that people
try. I would say most of these things don't have, you know, much data behind them to show
that they work with certain frequency but, you know, some people seem to benefit — maybe
it's a placebo effect; I'm not sure, but these things shouldn't be added to your regimen without
really talking your doctor because some of these items can actually interfere with with medications
you're on, but there there are medications that do have some proven benefit for treating hot flashes
— Gabapentin is one, Venlafaxine is another, and the nice thing about Venlafaxine is not only
does it help hot flashes but it also can help with some of the depressive symptoms that some
patients will get which I'll address later on.
Then the next category is "what do you see
on yourself when you're treated with ADT?" So, let's talk about that.
We're going to go into these things in detail. So weight gain
can be a real problem. First of all, more than 40 percent of men are already overweight
at the time they're diagnosed with prostate cancer so if you're going to start ADT this is likely
going to get worse unless you do something about it.
It's very common to see people gain 10
kilos—so that's 20 pounds—over six to nine months related to increased appetite and probably other
metabolic changes that are shifting calories to fat instead of more productive places. T his fat
comes on as you can see in this patient right here around the waist, hips, and thighs — sort of more
like, you know, feminine types of body fat tend to be and even in the breast tissue, and this is
associated with loss of muscle mass and strength, and this even if you are going to be on androgen
deprivation therapy for a limited amount of time it's often very difficult to lose the weight
even if you stopped the ADT. So, that is very important so we counsel people to be physically
active with both aerobic and resistance exercises and engaging in healthy lifestyle habits.
So, that gets us to our module three education sessions where we talk about
both exercise and and good nutrition.
Shrinkage of the penis and testicles — This
is kind of… This can be very disturbing if your doctor didn't warn you about it, and
I certainly had patients come to me early in my career wondering if everything was going
to disappear into their body and so we have to — this has to be discussed — that this could
happen. Again, sometimes penis length is already less because of surgical retraction and
then when you add weight gain and all that, that just can make it even worse. So,
this kind of change usually stops after a year to a year and a half of starting
ADT, but there are some strategies that might be helpful in in minimizing this effect
when you work with a sexual health clinician. What about — hair changes is
another thing that you can see. Commonly there's thinning or loss
of body hair on the trunk, arms, and legs, beard gets softer, and sometimes
some men say they don't need to shave. Some men think it's great, and other
men are really bothered especially by the loss of that nice chest hair that
they used to have.
Clearly this is not a health issue but it can be distressing if the
person is not informed that this could happen and this is one of one of the more easily
reversible side effects when ADT is stopped. And what about what you don't see? So, there's
a whole list of things that you don't see. So one of them is bone density. We can't feel or see
our bone density, but we know that hormone therapy lowers your bone mineral density and causes an
increased risk for fractures and many men already have low bone mineral density before starting
ADT, but we don't usually think about it. We think about low bone mineral density associated
with women who've gone through menopause. And then when you add loss of muscle mass and
strength and even balance (with risk for falls) patients under these conditions can be at much
higher risk for fractures. So loss of bone mineral density does not just stop magically either; it
just continues while patients are on ADT.
So, to mitigate that we commonly recommend a combination
of calcium and vitamin D at these doses. You know, going up to high dose vitamin D is not a
good thing to do unless your doctor is monitoring your vitamin D levels, so it is the same thing
with calcium — more is not better. So, I know Dr. Moyad commonly talks about some of these things in
his talks, so I'm not going to belabor that, but the message is "more is not better," but is it's
when on ADT it's good to take a combination. We know from testing that some men are at
increased risk for fracture and so those patients could be treated with bone building drugs
either once or twice a year depending on what drug your doctor picks, but again, resistance
exercises meaning weights, bands, whatever and high impact exercises also help
preserve bone mineral density.
The way we measure bone mineral density is
with a DEXA scan which is a very easy scan. There's no IVs, you don't have to fast
for it, you just lie underneath the DEXA scanner and it will give out a reading that your doctor
can determine whether you have normal bone mineral density or whether you have low bone mineral
density to start with, so-called osteopenia ,or actually if you happen to have osteoporosis
and men do have osteoporosis just like women — it's just usually its onset is about a
decade later than when we usually see it in women.
What about diabetes and cardiovascular
disease? Well, this is a this is a nice large study that showed men of equal
ages in groups that were treated or not treated with androgen deprivation therapy
and you can see that in red those treated with androgen deprivation therapy have more diabetes,
cardiovascular disease, heart attack, and sudden death than the men of same age who are not on
ADT. So it's very important to know what your cardiovascular risk is, in other words, have you
already had some of these even before starting ADT that may impact what drug
your doctor chooses for you? Okay, and (oops sorry) — So,
metabolic syndrome is when you have three out of these five things going on.
Low HDL cholesterol, high triglycerides, visceral obesity (meaning in the the abdomen), insulin
resistance or hypertension high blood pressure. So three of any of those things is metabolic
syndrome. We know that when we treat men with ADT, fat masses increase, lean body mass or muscle
mass decreases, insulin levels go up, lipids can go up and down—it's not always predictable
but oftentimes it's not in good direction—high blood pressure or hypertension tends to get
worse, blood sugar levels tend to get worse, and patients commonly have some level of
low blood…
And this says the mechanism is not clearly understood. Actually that's
not true, the mechanism is understood, it has to do with lack of testosterone which is
well known to stimulate the red blood cell line. So as as doctors we like to encourage our
colleagues who are prescribing ADT to think of the ABCDE's that we should be preemptively thinking
about. So, "A" stands for awareness and aspirin. So, and as a patient you can be proactive about
this talk to your doctor about metabolic syndrome. Some patients may benefit from the addition of
low dose aspirin to their regimen. Blood pressure should be taken; your doctor should know where you
start and whether or not ADT impacts your blood pressure and if it does you should be treated
with it — not just wait until you go off ADT. Cholesterol and cigarette smoking, though again,
those cholesterol levels or so-called lipid panels should be tested prior to starting ADT so they
can be followed and treated with medication if needed or diet depending on what the situation
is, and certainly if you are a cigarette smoker, it would really benefit you to
try a smoking cessation program. Again, diet and diabetes — follow a healthy
diet.
We frequently are sending patients to a registered dietitian. Monitor your
weight and have your blood sugar levels followed. And then exercise — there's various
recommendations. Currently in the United States, the recommendation by the American Society of
Sports Medicine I believe recommends 150 minutes per week of moderate to vigorous exercise and two
to three resistance training sessions per week. So that just gives you a guideline but, you know, you may you may need further
input on how you could accomplish that. And then, finally, the last category of side
effects of ADT has to do with what you actually feel, okay, so we've gone through "what the doctor
tells you," "what you see," "what you don't see," and now "what you feel." So, let's go on to talk
about that. So it is not uncommon that patients will complain of ADT associated muscle aches and
pains. The exact mechanism of that certainly is not clear to me, but it might have something to do
with muscle wasting and changes in the tendons and ligaments.
There are some non-drug related ways of
dealing with this like, again, exercise (I mean, you see the theme). Sometimes acupuncture helps
with these aches and pains and then the other thing that I think we don't emphasize enough is
really getting some stretching in. I mean, I don't care what you call it, yoga, tai chi, there's any
number of ways you can do stretching, and probably even if you weren't on ADT as we age it's probably
a good thing to be doing stretching anyway. So what about pharmacological? You know, you can use
non-steroidals and other drugs such as Cymbalta. I won't belabel — belabor that (sorry) because you
can walk into a pharmacy and find that out. Now, depression you know again is something that you
feel and it's really important to understand that it's not uncommon for men to have what we call
emotional lability after starting ADT.
What is emotional lability? It means your emotions can
fluctuate up and down and even have kind of a short, or I should say shorter fuse then maybe you
had beforehand. We know that major depression has been described in up to 13 percent of men who are
on ADT and we also know that this is about eight times higher than in the general male population
in that age range. If you have a prior history of depression—maybe you had to take medication,
therapy, maybe you were even in the hospital, you know—we need to pay attention to
that at the beginning of starting ADT because we might want to actually work with
the therapist to follow that very closely. So again, sometimes medication, exercise
again is always a good thing to do, and—I'm just advertising—in our module
six we have counseling services needed.
Now, what about cognitive function? You know, this
impacts probably a smaller number of patients. It typically has to do with spatial memory like
where did I park my car, what did I do with the keys, or you know, so those kinds of things. Again
exercise is a really good at helping maintain a cognitive function, and then there's other
sort of you know things that you can do to help sort of clear out your mind but also clear out
your environment by decluttering living spaces, reducing alcohol, and possibly other depressants. Now, fatigue — fatigue is actually, you know, it's
not really exactly a very good description for what men describe I would say.
I mean there seems
to be somewhat of a lack of initiative, weariness, tiredness that that doesn't always improve
with rest, so it's not like the kind of fatigue you get from like a long bike ride, let's say.
Sometimes it can affect people's ability to do the regular things they're used to doing each
day and contrary to popular belief there's really no good medication that's known to
effectively reduce fatigue, but we do know again that exercising really does improve
fatigue, social functioning, mental health, and this is what I mentioned earlier about the
kind of exercise that's recommended, but you know, I think we really really underestimate the effects
of exercise on the brain and so I just want to, you know, show this list on the right to show all
of all the things that have been actually shownin studies that have been published where we see
the benefits of exercise on brain functioning, and then on the left is sort of all of
the other things that exercise can help improve, you know, all all around, so you
know, exercise is is an important thing.
Now, I've been talking about this
regular forms of hormonal therapy and we have a lot of new agents now. These,
drugs enxalutamide, apalutamide, darolutmaide, and abiraterone are the newer second generation
anti-androgens that have all been shown to improve overall survival in men with metastatic
castration-resistant prostate cancer and even in some other settings as well, so it won't be
uncommon that these drugs may be added on to the ADT that we've been talking about and certainly we
know from the clinical trials that there are some issues — I mean these drugs also have side effects
including fatigue (more prominently in the top three) but also issues with high blood pressure,
enzalutamide for example has a small increased risk for seizures, but also patients seem to have
falls more and whether this is related to just more weakness in their muscles or some central
nervous system issues, we don't really have a handle on that right now.
Apalutamide, the
most common thing is a rash and it sort of separates it from the other drugs listed here, but
it's usually a pretty controllable rash. It's not really a game stopper for most patients, and low
thyroid function, and again high blood pressure. Darolutamide of the three
second generation anti-androgens is probably the one with the least side effects,
but having said that none of these have been compared head-to-head or at least published data
yet to actually show that. So, I mean I say that with a grain of salt. And then abiraterone, which
is not a second generation anti-androgen, also has some issues with high blood pressure and more
cardiovascular disease, liver problems, etc.
So, you know it's a lot more complicated story than it
used to be when we just were dealing with regular old ADT. So, the take-home message is really
that ADT can have many side effects although most men don't have all of them and even up to 20%
of men don't have any of these side effects. So, I think it's really important to try to deal with
these side effects proactively and try to avoid the long-term or minimize at least the long-term
side effects of of ADT, and you know, if you do if you didn't get the drift, I mean probably exercise
and physical activity are the most effective treatments that could cover most of the sins,
if you will, of androgen deprivation therapy. It's important for patients to be active
participants in these prevention strategies and, you know, to that end I would suggest reading
a book I recently finished called "Keep Sharp" by Sanjay Gupta.
It really is very inspiring and
might help you get off the couch if you're on ADT. You know, in Vancouver we have our Prostate
Cancer Supportive Care Program to support patients through these changes anywhere in the
sort of prostate cancer journey and the website is accessible. Our talks and
many of our education sessions are online. This is the team that makes
it possible in Vancouver and, yeah, I really enjoy working in this area.
Although I don't see patients there, but it's a really nice program that patients appreciate.
So
thank you very much for your attention on that. Hey everyone, it's Alex and Hunter from
the PCRI. He has his own instagram now: Sirhunterthedal, so go ahead and check him out
for prostate cancer information and men's health. Do you like it? Yes, say "come follow
me," and don't forget to subscribe to our YouTube channel we come out with
new prostate cancer videos every week..
