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BackTable / Urology / Podcast / Transcript #98
Podcast Transcript: Testosterone Replacement in Prostate Cancer Survivors
with Dr. Rodrigo Valderrabano
On this episode of BackTable Urology, Dr. Jose Silva invites endocrinologist Dr. Rodrigo Valderrabano onto the show to discuss the impact of testosterone replacement therapy on hypogonadic patients and prostate cancer survivors. You can read the full transcript below and listen to this episode here on BackTable.com.
Table of Contents
(1) The Function of Testosterone in the Body
(2) Low Testosterone Treatment Options
(3) Benign Prostatic Hyperplasia & Testosterone Treatment
(4) Testing for Hypogonadal Symptoms: The Workup
(5) Testosterone Treatment in Prostate Cancer: Recent Evidence
(6) The Patient Perspective: Balancing Symptoms, Risk & Reward
(7) Expected Impact of the Clinical Trial
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[Dr. Jose Silva]
Hello, everyone. Welcome back to the BackTable urology podcast, your source for all things urology. You can find all previous episodes for all our podcasts on iTunes, Spotify, and at backtable.com. I am Jose Silva, your host this week. Today we have a special episode. We have Dr. Rodrigo Valderrábano. Dr. Rodrigo is not a urologist. He is actually an endocrinologist that specializes in men's health. Dr. Valderrábano did his fellowship training at Stanford University Medical Center and he's currently at Brigham and Women's Hospital in Boston. Rodrigo and I have been friends for a long time. We went to the same high school. We were in Boston at the same time. I am two years older. He is the cousin of a very good friend of mine. We actually did one year of residency together in Puerto Rico. So, Rodrigo, very excited to have you here on BackTable. Welcome to BackTable.
[Dr. Rodrigo Valderrábano]
Happy to be here and delighted about this invitation.
[Dr. Jose Silva]
We'll be talking about testosterone and cancer, prostate cancer more specifically. I understand that you have a few disclaimers you want to mention.
[Dr. Rodrigo Valderrábano]
Yes, I have to throw them out there. The stuff I'll be discussing today are my personal opinions and my own interpretation of the existing data. I do feel like I need to do this disclaimer because we will be talking about some controversial topics. I am not in any way representing the Brigham and Women's Hospital or Harvard Medical School. I am also not representing the American Society for Bone and Mineral Research or the National Bone Health and Osteoporosis Foundation of which I sit on committees. That's it. Other than that, the only disclaimer is that I really enjoy talking to Jose, so I’m happy to be here.
[Dr. Jose Silva]
Rodrigo, you went to Stanford to do your fellowship in endocrinology. How did this love for men's health develop?
[Dr. Rodrigo Valderrábano]
When I was at Stanford, I started focusing on bone health. I have always had a large interest in exercise and how that can affect health and how we can do exercise interventions as treatment. That's why I got into bone health. I was at the University of Miami for a while and directed their bone clinic. I was starting to see all of these older men, people with prostate cancer, how they weren't doing well. My interest there started through bone health because that's why people were referred to me.
It has really morphed into this interest in how do we promote function, especially in older individuals, by any means, which means andrology and testosterone. It also means exercise. It also means proper nutrition. That's really where my path intersected with men's health. It's an area that still needs a lot of attention. I think there's a lot of hype out there. People bring their own opinions to the fray a lot more than in other conditions I feel like. Some people just are all on board with testosterone and some people are completely against it.
(1) The Function of Testosterone in the Body
[Dr. Jose Silva]
No, exactly. You mentioned bone health. We as urologists, we treat prostate cancer and we start patients on Lupron or other anti-hormonal treatment. We mention the consequences, but not going into details or follow-up in terms of what's going on with the patient's body. Let's talk about what testosterone means in the body and why we need it.
[Dr. Rodrigo Valderrábano]
Sure. Testosterone is the male-type hormone. It is secreted in men mostly from the testicles. It's controlled by the pituitary gland, so we have hormones that go from the brain and tell the testicles what to do and then testosterone and estrogen get sensed in the brain. That's how we maintain our balance. Testosterone has a huge role in development obviously of a male phenotype, so male characteristics, but in adulthood, it is very important to maintain sexual function. It's important to maintain energy and vitality and also proper muscular strength and muscular mass.
[Dr. Jose Silva]
The relationship between bone and testosterone, what is it?
[Dr. Rodrigo Valderrábano]
That's an interesting and maybe a more loaded question than you thought. Testosterone interacts with bone in many different ways. Testosterone gets converted into estrogen and estrogen maintains bone. That's why women after menopause will lose bone mass. Actually, many people thought that estrogen was for women and testosterone was for men. Actually, it's also estrogen for men that controls bone density, but all of the majority of estrogen in men is derived from testosterone. Anything that affects testosterone will, in effect, then move on to estrogen and then to bone.
In the setting of prostate cancer, it's incredible to me that we don't pay attention to this as much as we should. When women get treated with anti-hormonal agents for breast cancer, it's a huge deal. It's really come more into the forefront of therapy, especially now that our treatments are getting better and now we worry about long-term effects of our medications. Definitely, testosterone is indirectly the main driver of bone health in men. Obviously, if you have low testosterone and you have low muscle mass and strength, that also will by virtue of decreased loading on bone and decreased torsion and tension on bone, you will also start losing bone over time.
[Dr. Jose Silva]
You mentioned low testosterone. You as an endocrinologist, what are the parameters to say that the patient has low testosterone? Based on symptoms or a combination of both? Because I know it's always changing. Or people have their own information, their own opinion on what exactly is low testosterone.
[Dr. Rodrigo Valderrábano]
Yes, this is exactly why I had to give that disclaimer because you can get into trouble with all these. I think it's important to recognize a couple of things. Number one, the radioactive immunoassays, the regular tests that are used for testosterone are pretty bad in terms of that they're not very precise. That's one thing. If you got a blood test done on separate assays, if you've got five blood tests and got them done at the same time but on different assays, you might get different numbers.
Another thing that's really important, testosterone naturally goes down during the day. We did a study when I was at Stanford in Palo Alto where we looked at people that had gotten their testosterone level at the VA and outside. The take-home message is even just an hour later, testosterone could be lowered by like 100 points, so it could make a real difference. We try to use good tests. We try to standardize it, do it early in the morning, 8:00 to 10:00 in the morning. Then, don't just think about the number. There's a lot of other things that can affect testosterone like sex hormone-binding globulin. Exercise and stress can move it around and then it bounces back naturally. We really want more than one test to determine whether testosterone is really low. Current guidelines agree that around 300 or maybe under 275 total testosterone is considered low. In terms of free testosterone, which we look at as well, if you directly measure free testosterone, you can use those numbers too, but I like to think about the number 75 micrograms. That's because in our group when we looked at young men who didn't have diseases, everyone was 75 or up for free testosterone.
When you see low testosterone, you start thinking about it, and then you have to have symptoms. That's really the thing. You need to have especially sexual symptoms, so you asked about are people having morning or nighttime erections. You ask about libido, sexual desire. The caveat is that there are many things that go into sexual desire: state of mind, whether you've slept or not. All of these things are also important. You really need the low number and you need symptoms to really determine whether someone's hypogonadal.
It gets dicey because people that have obstructive sleep apnea or people that are obese can have lower numbers for their testosterone, but it doesn't mean that they are hypogonadal. It's just that their comorbidities are bringing testosterone down. There ideally, you would have someone lose weight and testosterone would bounce back up, whereas for someone that has an organic disease due to pituitary problems or testicular problems, you really do need to think about giving testosterone.
[Dr. Jose Silva]
Then that patient that you just mentioned, sometimes I see that they have elevated estrogen. Is it something that you should start those patients on aromatase inhibitors to boost their testosterone or it depends just on the symptoms?
[Dr. Rodrigo Valderrábano]
Like I was mentioning before, most of the estrogen in the body comes from testosterone in men. The more fat mass you have, the more aromatase you have, and so you have higher levels of estrogen. There you would want to treat the root cause. You would want to try and get someone to lose weight and that could go away. There are no FDA-approved indications for the use of aromatase inhibitors for men that have high estradiol levels. There are some case reports that it can help, certainly, but you have to be careful about how you do it. You could also affect bone density by giving aromatase inhibitors. That's the big thing in women with breast cancer, that you can lose 10 to 15% of your bone mass in a year. Very, very high levels of bone loss, so because of my focus on bone, I'm less keen on using aromatase inhibitors. We always want to at least try to get the person to lose some weight beforehand. Improving sleep apnea may help with testosterone levels as well. At the very least it's a good idea.
[Dr. Jose Silva]
Because those patients, they always say, "Well, I don't have the energy to lose weight. I need something now." Then, they want the testosterone. I say that in my clinic I see both. I have the patient that just continues doing nothing. He says that testosterone doesn't work, but the other one that really motivates himself and starts losing weight and at some point, like you said, maybe they don't need the testosterone anymore. I think the few cases of patients that once I start testosterone they don't need any more are the ones that lose a lot of weight.
[Dr. Rodrigo Valderrábano]
Yes, that definitely does help. Testosterone is an anabolic hormone, if they don't also increase their physical activity, they're going to actually gain weight with the testosterone but you're right, there's a subset of people that have terrible symptoms and you give them testosterone and they do really well. I've had patients like that as well in my clinic. That's why you have to personalize what you do.
For these people that have obesity and sleep apnea, you could also consider using clomiphene. Clomiphene is a serum, a selective estrogen receptor modulator that is used in fertility. Essentially what it does is it helps increase cycling of our pituitary hormones, on our gonadotropins and some people do really, really well on the clomiphene. It's an off-label use, but there are studies that have taken it out to two to three years and it's very safe. Without the risk factors that we deal with when we treat with testosterone. Honestly, there's less bother in the prescription and it's not a controlled substance and some people do excellent on it.
(2) Low Testosterone Treatment Options
[Dr. Jose Silva]
Yes, recently, I think there's a shortage of clomiphene, clomid, and it is been a challenge for patients to continue their treatments, but we're using compounding pharmacies and definitely that has helped but the regular pharmacies, for some reason they don't have it at least in the Orlando area. Rodrigo, in terms of treatment options for testosterone, I find myself always giving injections at the end of the day because that's mostly what the insurance covers. What's your preference?
[Dr. Rodrigo Valderrábano]
Yes actually, the injections are totally reasonable, but my preference is actually the gels.
[Dr. Jose Silva]
They're more natural. They do what the body is supposed to do. They boost in the morning, but they don't at night.
[Dr. Rodrigo Valderrábano]
Yes, that's right. I do it because you get less pituitary suppression. If somebody's on injections for a long time, they can have androgen withdrawal when you try to wean them off. With the gels, you get an even level of testosterone. You don't get these peaks and valleys. Most people do well on it.
The thing to consider with the gels is that if you have small kids or if you have a female spouse, it can get dicey if they get the gel on them. It really dries within 15 minutes but there is some trace gel there for several hours after. If you have small kids and they're jumping on you and they get some of it on them, things can get hairy, literally.
The injections are very good too. Generally, my second go-to are usually the injections, but what I find is sometimes at the tail end, so if you're doing for example, 200 milligrams every two weeks at the tail end, some people are running out and then they feel really fatigued at the tail end, but what you can do then is instead of doing 200 every two weeks, you could do 100 every week and that's good. Some other forms, there's patches as well. I've seen that work for some people, but they do cause a lot of dermatitis and the patch falls off and then that's the problem, but that's available.
[Dr. Jose Silva]
Yes. Especially patients that sweat a lot. It falls. Yes. They're going to the gym, yes.
[Dr. Rodrigo Valderrábano]
Definitely in the Orlando area it's a bigger problem than in the Boston area, but those are good. You have the-- I don't know if you implant the pellets? Some people really like those.
[Dr. Jose Silva]
No, I'm not doing that in the clinic. I started doing it, but it was a mess trying to get the insurance to cover it. It took too many resources from the office so I just stopped doing it.
[Dr. Rodrigo Valderrábano]
People like it while it's on, and then they can get some scar tissue. I've never seen someone that really stays on it for years and years. They'll use it for a while and then they'll stop. Then, there's a pill now that's a testosterone undecanoate pill. That one, it's hard to cover because it's newer and more expensive. That also in the clinical trials, it did increase blood pressure a little bit. I sometimes hesitate to use those in people that have high blood pressure.
[Dr. Jose Silva]
There's also, I think it's new: the intranasal one, have you seen that one? They use it four or five times, I think it's three or four times a day. I usually use the intranasal chart. Supposedly in terms of the axis, it doesn't have any major side effects. That's how they sell it because it is short-acting, but I think I tried twice for patients and the insurance didn't cover it.
[Dr. Rodrigo Valderrábano]
Yes, I haven't been able to access that myself either. I'm not as familiar with the data on those, so I can't comment on the effectiveness of it, but I know it is out there.
(3) Benign Prostatic Hyperplasia & Testosterone Treatment
[Dr. Jose Silva]
Rodrigo, let's talk about testosterone and the prostate. Prior to going to prostate cancer, let's talk about just BPH (benign prostatic hyperplasia) because we always tell the patient, “hey, you might start having more symptoms when you start testosterone.” In terms of the patient, he's fine. Then, he might see some URI symptoms because of growth. What does the literature show in terms of the effect of the prostate?
[Dr. Rodrigo Valderrábano]
Yes, that's a great question. The thought process there is changing some. A lot of these retrospective studies: these studies looking at existing data as opposed to a planned clinical trial. A lot of these retrospective studies of people with benign prostatic hyperplasia found associations with people that were taking testosterone. The thought process there was, oh, that testosterone's making your prostate bigger but actually, now we have some pretty good data looking at people that have benign or hypogonadal, have low testosterone between essentially some criteria and then doing biopsies before and after testosterone treatment.
Actually, what people have found is that inflammation in the prostate through biopsies can actually improve what you treat with testosterone. This is not set, there's a lot of debate around this, but actually, there have been some studies looking at lower urinary tract symptoms: LUTS. LUTS gets better in a lot of people after testosterone treatment. Then these biopsy studies actually saw reductions in inflammation in hypogonadal men treated with testosterone. I think that's the key. If you have somebody that has benign prostatic hyperplasia, has low testosterone and is hypogonadal, then this is somebody that actually may benefit from testosterone therapy.
I've seen it in my clinic. People with significantly lower urinary tract symptoms, it gets better when you treat them if they're clearly hypogonadal. We need more randomized clinical trials in this space, but I think that people are coming around to thinking maybe there's nuance to it. It isn't a blanket statement you can just say for everyone.
(4) Testing for Hypogonadal Symptoms: The Workup
[Dr. Jose Silva]
Awesome. No, that's great information. Rodrigo, when a patient goes to your clinic, they have hypogonadal symptoms, what test do you order?
[Dr. Rodrigo Valderrábano]
Again, very important. Generally, I'm the testosterone guy, I'll do a little bit more extensive workup. Generally, when they come to me, they've already had some testosterone level. I generally will look at what they've had done. A lot of the time the testosterone levels get drawn in the afternoon, especially in younger men when they go to clinics after work. I will order a total testosterone and free testosterone measured by mass spectrometry liquid chromatography. That's still not perfect, but it's better than radioactive immunoassay. You can order sex hormone-binding globulin. A lot of older men have lower levels of sex hormone-binding globulin and that will bring your total testosterone down and make it look like you have low total testosterone, but then you get the free testosterone and that's normal. Sex hormone-binding globulin carries testosterone and the total testosterone level is an additive of testosterone that's bound to sex hormone-binding globulin and free testosterone. If you find a low total testosterone, but a low sex hormone-binding globulin and a normal free testosterone, this is a person that may not have hypogonadism. Then to confirm, what you want to do is look at the LH and FSH, the luteinizing hormone and follicular stimulating hormone. People that have secondary hypogonadism that might be normal or it might be slightly low. In people that have testicular problems, that should be high.
One thing that never fails to surprise me are people that have had mumps in childhood. If you go out long enough, there's almost 50% of people that eventually get low testosterone levels after having mumps, mumps orchitis. They don't always remember having testicular swelling in childhood but I think it's- you get a hit and then when you're young and healthy, your testicles are able to overcome the hit and make up for it, then as you get older and you get less vascular supply, things start changing and then eventually, the testicles can't keep up and you make low testosterone. There you would see high LH and FSH and for me, that's a slam dunk because if the end organ isn't working, those are the easiest cases, then you definitely will treat with testosterone.
Sometimes people get hit by trauma to the testicles, which could do it, and then you have high LH and FSH. I had a guy who practiced Krav Maga and I guess he had an overzealous instructor that kicked him in the testicles a couple of times then he actually had hypogonadism.
[Dr. Jose Silva]
Wow. FSH and LH, you would order all the time? It just depends on the patient if they're younger?
[Dr. Rodrigo Valderrábano]
No, I would order it in the full workup. Before deciding on treatment, I would do it for sure. It also gives you a baseline, and then if you end up suppressing FSH and LH later-so if it's normal, and then let's say after a year of testosterone, the person wants to stop or wean off, you can get LH and FSH again. If they're very suppressed, they're zero or they're almost undetectable or very low, then you know that they're very suppressed, you have to take it easy and you may want to consider doing something like weaning off the testosterone, but also giving clomid at the same time to boost that axis back up.
[Dr. Jose Silva]
For follow-up, do you always do FSH, or just if you want to wean them off?
[Dr. Rodrigo Valderrábano]
It's case by case. I wouldn't just do FSH, LH all the time in terms of monitoring, but if I want to know whether I have suppressed them or sometimes when people come and they've been on testosterone for years and I want to see where they're at, then I would definitely get that.
[Dr. Jose Silva]
Patients that want to keep fertility, are you doing growth hormone in those patients or?
[Dr. Rodrigo Valderrábano]
Do you mean HCG?
[Dr. Jose Silva]
HCG, yes.
[Dr. Rodrigo Valderrábano]
Essentially, human chorionic gonadotropin, HCG, is essentially a mimic of LH. You would do that when the pituitary-it's a way to bypass the pituitary gland. Typically, people that have received testosterone, you can get away with using clomiphene and restarting the axis, and then if that doesn't work, you could try LH, HCG, and then if that doesn't work, then it's up to you guys in the urology world to do the testicular biopsies and see if they can retrieve some sperm directly, but those are rough, they're associated with very, very high rates of hypogonadism if they aren't hypogonadal.
(5) Testosterone Treatment in Prostate Cancer: Recent Evidence
[Dr. Jose Silva]
Rodrigo, let's go to the more controversial part of our podcast and it's the work that you have done in testosterone and prostate cancer. You were part of a group then you published the paper on patients that are prostate cancer survivors, low testosterone, very symptomatic, and you started treatment.
[Dr. Rodrigo Valderrábano]
That's right.
[Dr. Jose Silva]
Talk to us about the inclusion criteria, how did it come up?
[Dr. Rodrigo Valderrábano]
Sure. This is work that started before, so I've only been at the Brigham now for about a year and a half, almost two years, and this work was started by my principal investigator and the head of our men's health division, Dr. Bhasin, who's a guru in this space and his papers in the 1990s were the ones that showed us that testosterone was actually anabolic to muscle. Before that everybody was sure that it wasn't, so really transformative work.
Really what we're hitting at here Jose is that there's a lot of data out there that retrospective and/or case reports and case studies showing that people that have had prostate cancer do well with testosterone therapy after complete removal and treatment of the prostate cancer. It's a really important area. About 50% of men that have radical prostatectomy will end up having hypogonadism, even with nerve-sparing surgery. It's not completely clear why this happens, but it must have something to do with the affected vasculature or fibrosis or other things that happen after surgery that affect the testicles.
Essentially, we have to differentiate what you might want to do person by person with somebody in a clinic versus what we're trying to do, which is let's create a trial that we can use to give wide-ranging advice. This is the first trial, a randomized double-blind placebo-controlled trial to give testosterone back to prostate cancer survivors. We're being very careful to pick people that had low-grade and very low disease recurrence, so we're being very careful there. Essentially, we're doing a Gleason score of 3 + 4, no extracapsular invasion or any kind of positive lymph nodes or anything like that. These people could not have had a PSA greater than 20 before surgery. We changed that, initially, we had it in PSA no greater than 10.
[Dr. Jose Silva]
10, okay.
[Dr. Rodrigo Valderrábano]
But actually, everything's been so good that we actually changed it to under 20 and people have still done well. Then, we are treating people that are at least two years out and have had a completely negative PSA for the past two years. These are really the people that had a low grade of recurrence. We've treated with radical prostatectomy and then there's no sign that anything's come back and these were people that were not on Lupron or any other kind of hormonal therapies. Really low risk of recurrence. We've now done close to 70 or 80 people and we haven't seen any kind of safety signal whatsoever in the entire trial.
[Dr. Jose Silva]
What's the regimen? Are you using gel, injections?
[Dr. Rodrigo Valderrábano]
No, we're using injections. It's a really difficult study to recruit for and retain people because they have to drive into Boston every week, but then we're doing it here and we're doing it at Johns Hopkins as well. The PI there is Arthur Burnett, who's a guru in the space as well. The regimen is 100 milligrams of testosterone every week and they come and get their injections and that's for 16 weeks, I believe.
[Dr. Jose Silva]
How often do you do the labs?
[Dr. Rodrigo Valderrábano]
We have PSAs at regular time points, essentially every two to four weeks and it's looking great so far. That's our regimen, how we're doing it. Whether that's really necessary in clinical practice later on, I don't know, but we're just making sure that if we do get a hit and we see biochemical recurrence of prostate cancer, we want to really catch it very early so that's why we're doing it so fast.
(6) The Patient Perspective: Balancing Symptoms, Risk & Reward
[Dr. Jose Silva]
Yes, I have a few patients in my practice, in my clinic. I usually follow these patients every six months, just general hypogonadism, but if these patients, the first ones that I started, I was doing every three months, they're all doing good. I haven't had a patient with recurrence. I have a few that are after radiation because definitely-I had a patient that felt that it wasn't worth living, he felt that bad. I felt obligated to do something. I think his testosterone was in the hundreds or low hundreds and he's feeling great.
[Dr. Rodrigo Valderrábano]
Excellent. That's so great to hear.
[Dr. Jose Silva]
Yes, we discussed the outcome. He knew what to expect, we knew that there's no data out there or not that much data and we're doing it because the patients need it.
[Dr. Rodrigo Valderrábano]
I think at the end of this trial, if everything goes as we hypothesized, I think we will be able to say, and for anyone who wants to see it the protocol and of the trial was published in andrology in January, but I think what we will be able to say at the end of this trial if everything goes like it's looking, is that for people with a low risk of recurrence who have undetectable PSA or very low PSA for many years after surgery, we'll be able to offer it. If you're hypogonadal and you're feeling terrible, which about half of people are, then it's safe and effective to give it.
Our outcomes are sexual health and also physical health, so we're looking at VO₂ max, other strength measures, and aerobic capacity measures. Testosterone has worked in every other trial. I don't see why it wouldn't work here or at most, I shouldn't say every other trial, but most other trials looking at people that we now consider hypogonadal, people have had improvements with testosterone replacement therapy. Then someone like your patient, if they're at higher risk, you have to weigh the pros and cons like everything in medicine and if they totally are just feeling terrible and life isn't worth living and you can make them feel better, then that's a great outcome, as long as they're aware of the risks.
[Dr. Jose Silva]
Exactly. The fear will be that that patient has a full-blow recurrence.
[Dr. Rodrigo Valderrábano]
That's right.
[Dr. Jose Silva]
I guess, if it's going to recur, it's going to recur no matter what, it's just depending on when it's going to, and definitely testosterone will push you sooner than later.
[Dr. Rodrigo Valderrábano]
Oh, sure. Let's not beat around the bush. With this low recurrence rate on the low PSA, we're just trying to make sure that the person is "cured." If you're cured, testosterone isn't going to do anything bad. If you know that there are some prosthetic cancer cells hanging around, if a person really hasn't suppressed PSA or if there was extracapsular invasion and there were lymph nodes positive, you know their cells around there, testosterone will promote prostate cancer growth absolutely.
The question is, depending on the person's expected quality of life, the person's expected lifespan, depending on the degree of disease, is it worth it to them to take that risk? That's why when we do this kind of thing, we have to be really careful to monitor people closely to make sure that is someone that's going to recur quickly, we need to catch them quickly, and that's you put the safety net there and you try to help people as much as you can. At the end of the day, that's what we're all trying to do in healthcare.
[Dr. Jose Silva]
For other symptoms like urine incontinence, erectile dysfunction, more people are treating those patients sooner. Before, just like with testosterone, we waited just to make sure that the patient didn't have any recurrence and then we will talk about the inflatable penile implant or a sling or artificial urinary sphincter to correct the incontinence. I think the trend now is doing it sooner. Definitely not three months after, but before the year, six months if that patient has just like you said, low-risk cancer, very low-risk of metastatic disease, then just treat him.
[Dr. Rodrigo Valderrábano]
Again, it's the difference between giving wide-ranging advice from the results of a clinical trial and personalizing medicine to your patient, and their desires and their tolerance for risk. Somebody that you don't wait at least a year to see the PSA suppressed, it would certainly be somebody who is potentially at higher risk, and we just don't know about it, but I could see someone with a recent surgery that has a totally undetectable or extremely low PSA, and they had a very low-risk cancer to begin with. That's somebody, you could be a little bit braver, follow them up closely, and if they're doing fantastic then, and they're aware of the risks, I don't see--We do this stuff all the time in other aspects of health.
When I was at the University of Miami, I really learned a lot from the oncologists. The oncologists when they treat, especially people that are involved in renal cell carcinoma, just really aggressive types of cancer, they are really open to doing other things to help patients. I remember treating somebody for thyroid illness and I told the oncologist, "We're going to give him thyroid medication and then we're going to titrate it every three months, and in about six months to a year, he'll be fine." The oncologist called me back up and said, "Hey man. This guy has a life expectancy of six months. You're telling me you're going to treat him in a year? It's going to be a year 'til he feels good." That opens your eyes, right? Sometimes you have to be a little bit more aggressive and be out of your comfort zone for people that are just feeling terrible, their quality of life is just terrible.
(7) Expected Impact of the Clinical Trial
[Dr. Jose Silva]
Exactly. In terms of the research that you're doing right now, or your protocol, at some point, you will start doing it, move it every year. Instead of waiting two years after the PSA, you think it is going to move to a year?
[Dr. Rodrigo Valderrábano]
Yes. Certainly, this is not a large trial with thousands of people. I think we're shooting for about 120 people, so it'll be solid, and we'll have power to detect a difference in our outcomes. I think that once this trial comes out, this will be the first randomized clinical trial to show that it's safe and effective, and so, if everything goes to plan, of course, and I think that will spark a conversation where then the conversation will be, "Should we be thinking of doing this even sooner? Should we be doing this in everybody?"
I think it'll be some time before we start changing-- This is the initial step or the next logical step, and then once that conversation is then underway, I think we'll have other studies coming out, people that will be brave and will be trying to do this as well.
[Dr. Jose Silva]
What's the timeline for your research, five years? When will you say it is safe?
[Dr. Rodrigo Valderrábano]
Yes. Like I said, I have to say the endpoint of our trial isn't safety, its effectiveness in sexual function and physical function, but when you treat over 100 people and if nothing happens, then that's more reassuring than not having any data for sure. COVID really threw a wrench into our recruitment. Boston was completely shut down for almost six months to almost a year, and then people were very reluctant to come in. I think the trial will be open for about another year. Johns Hopkins has recently gone underway and they're recruiting people as well at a nice pace. Hopefully, in about a year's time, we'll finish recruitment, which will mean, maybe another six months for the trial results, at least the main results to come out, so give it like two years maybe until we actually publish the data.
[Dr. Jose Silva]
Cool.
[Dr. Rodrigo Valderrábano]
Then after that, I'll be back, and we can talk about how to be even more aggressive.
[Dr. Jose Silva]
Yes, because patients want it. Patients want it, but it gets trickier because right now there's a movement within the urology part of this low-risk cancer doing more active surveillance. What happens in those patients that still have active cancer, but they have symptoms of low testosterone, what are you going to do with it?
[Dr. Rodrigo Valderrábano]
Yes. That's really tough.
[Dr. Jose Silva]
It becomes more tricky, yes.
[Dr. Rodrigo Valderrábano]
The other thing about this, the other part of this is that our thinking has changed. Originally, the idea behind, don't treat anyone with prostate cancer with testosterone, that concept came from data that shows that prostate cancer is very obviously stimulated by testosterone, so that's one piece of data, and then people that are frankly hypogonadal or people that are treated with Lupron and other antiandrogen agents do better after surgery, especially metastatic disease.
Those are the two extremes, and so people thought, "Oh, obviously testosterone is bad." Now, the reality is the level that you need to turn on the androgen receptor, the level of testosterone that you need is very low, so, if you have a testosterone of 200 versus a testosterone of 400 total testosterone, you're not really changing the landscape in terms of whether the testosterone, any androgen will be stimulating prostate cancer cells. If you have 0 versus 400, that's a big difference. Even people that are under active surveillance, if they have a lowish testosterone of let's say 200, 250, and you boosted them up gently, you wouldn't necessarily be compromising them. You wouldn't necessarily be overstimulating it. Hey, listen, if you go up to 1000, and you're not being careful, then obviously that's not the best idea. If you already have testosterone on board, going up a little bit doesn't necessarily mean that you're going to stimulate any kind of dormant cells more.
[Dr. Jose Silva]
Yes, because also those patients that are hypogonadal. You start them on testosterone, PSA starts increasing, then you do the work for elevated PSA, you find cancer and then you have to tell them, "Hey, we need to stop testosterone." Those patients don't like it. They don't like to hear that they have cancer, and they don't like to hear that you're going to stop giving them testosterone, so it becomes trickier.
I always tell them, "Hey, continue the treatment. Let's wait for the biopsy and go from there," because you don't want to stop then just because of the elevated PSA, at least in my opinion. Because if they're feeling good, I don't want them to go back, and that's what the patient doesn't want. They don't want to feel terrible like before.
[Dr. Rodrigo Valderrábano]
It all depends. If it ends up being something very low-grade and obviously if it's something that has where you're seeing lymph nodes and you're seeing metastasis, you could really accelerate it, a critical period where they need to be treated. I don't know, that's where you have to individualize it. We also have to look at why people are on testosterone and if there all are alternative therapies that could help. Testosterone's not necessarily the only answer, and if people aren't feeling well and they have low testosterone because they're obese and they have sleep apnea, then let's treat those and see if they get better.
I don't like to negotiate. You are either deserving of treatment or you're not or you have the criteria, or you don't for testosterone treatment. Sometimes when people are in the gray zone and you're not sure, I say, "Listen, work with me and I'll work with you." At least get on some programs, start losing weight, and start being active and then let's try a low dose and see how it goes, so it really has to be individualized.
[Dr. Jose Silva]
When you say low dose, what do you mean? If it's, let's say with the gel, so are we one pump, for example?
[Dr. Rodrigo Valderrábano]
Yes. You could do like a 1.6% gel, you could do one pump. The important thing is in the initial gel trials, about 10% of people had a terrible response, 10% of people had a ridiculously high response, and then everybody else was in the middle. Just with one pump, you may be getting a pretty good dose effect, and the thing is, somebody that's hypogonadal in the studies that looked at especially sexual function, those studies haven't all been positive. People that have slightly higher levels of total testosterone don't improve symptoms when you give them testosterone, so you may just need to go up the threshold. What the threshold is isn't clear, and it's probably because it's different for everyone, but somewhere around 300 right, just going from 300 to 400 people may feel much, much better, as opposed to going from 300 or 200 to 1000. You don't have to go up that high to see improvement. You use gels or patches that don't have the spikes, certainly. Remember when we do testosterone injections, you're going to have 1000. If you get it two days after, you're going to get 1000, 1,200 of total testosterone. That would not be a great idea when you're treating somebody that's under active surveillance for prostate cancer.
So, when I say low dose, you may want to do something like a gel or a patch, starting at a lower dose. See how it goes. Look at the PSA. If the PSA jumps up, then obviously that person isn't a good candidate for it.
[Dr. Jose Silva]
Great. Rodrigo, you want to add something else? I think it was great.
[Dr. Rodrigo Valderrábano]
Yes. No, I think like everything, medicine, I think everybody should just keep an open mind. We're not saying that testosterone is the cure-all. Certainly, anyone that gets a lot of testosterone is going to feel energized and hyped up, but that doesn't mean it's good for them. I don't want it to come across like we're just trying to sell testosterone no matter what, or give testosterone no matter what. Certainly, there's enough data out there that it's potentially safe.
We're doing this trial, which will come out soon, and that'll be some good baseline data for everybody to base on. We got to give these guys a chance. A lot of these older men after prostate cancer, they feel absolutely terrible. I'm not saying we give testosterone to everybody. I'm actually quite conservative in my own clinic, but we have got to have an open mind and give everybody a chance.
[Dr. Jose Silva]
Exactly. Rodrigo, thanks for being here in BackTable with us and we'll talk again.
[Dr. Rodrigo Valderrábano]
Yes, man. No, thanks for having me. It's been a lot of fun.
Podcast Contributors
Dr. Rodrigo Valderrabano
Dr. Rodrigo Valderrabano is an endocrinologist with Brigham and Women's Hospital in Boston, Massachussetts.
Dr. Jose Silva
Dr. Jose Silva is a board certified urologist practicing in Central Florida.
Cite This Podcast
BackTable, LLC (Producer). (2023, May 17). Ep. 98 – Testosterone Replacement in Prostate Cancer Survivors [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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