Episode 2 – Prof Francesco Montorsi

I’m Joseph Ischia

I’m Nathan Lawrentschuk.

Joseph: And we’re Talking Urology where we discuss landmark urological papers and chat to the authors to get some insights into these practice changing studies. This podcast is made possible by an educational grant from Ipsen and we really appreciate their ongoing support. Today we are talking penile rehabilitation and if you’re right now thinking of a cartoon penis doing push-ups in a gym, then we’re on the same page.

Nathan: No Joseph, I think it’s just you.

Joseph: How about checking in to a rehab centre with Charlie Sheen?

Nathan: No. Still just you. The paper we are discussing today is called “Effects of Tadalafil Treatment on Erectile Function Recovery Following Bilateral Nerve-sparing Radical Prostatectomy: A Randomised Placebo-controlled Study (REACTT)” with first author and the Italian Stallion himself, Francesco Montorsi. This study was published in European Urology in 2014. Francesco is a Urologist from Milan and well known for his interest in post-prostatectomy sexual dysfunction, adjunct secretary general of the EAU, and former editor in chief of European Urology,

Joseph: Where I we should note he was responsible for pumping up its impact factor.

Nathan: Seriously, you going to keep this up?

Joseph: Now you’re getting in the spirit, Nathan.

Nathan: I think this is a really interesting paper because we can all truthfully say that erectile dysfunction post radical prostatectomy is an issue which we see almost every single day in clinical practice. Of equal importance, a lot of men, particularly younger ones, may put off having surgery for their prostate cancer in the first place because of their desire to remain potent. So papers like this which illustrate the likely fate of men’s potency after surgery and more significantly, their likely recovery and treatment options, are crucial for us to be able to counsel men appropriately. I think there are a lot of men’s partners who will be equally intrigued by this paper too!

Joseph: To set a bit of background, all men, whether they realise it or not, have been getting regular nocturnal erections ever since they were a baby. No doubt the majority of men are aware of this fact and are very proud of it! Why this happens is not clearly known but one good theory is that the penis needs to get regular erections to keep the penile tissues healthy.  Regular erections bring in fresh, oxygenated blood and maintain stretch on the penis, and stop the permanent closure and fibrosis of the fine capillary networks of the corpora tissue.

Nathan: Using an analogy of an injured arm can help explain the subject of penile rehabilitation a bit further. If you fracture your arm and it is placed in a plaster cast for a few weeks, you will notice that after the cast is discarded, your arm muscles have shrunk significantly or “atrophied” and become weak.  You then need to do “rehabilitation”, such as physiotherapy and exercises, to get your muscles back to peak strength and function.  Similarly, when the penis is unable to get regular erections, its musculature and vessels can also shrink and become atrophied, although no man will ever like to hear that! However, unlike the muscle in your arm, which is skeletal muscle, the muscle in the penis is made of smooth muscle.  While skeletal muscle has a great capacity to rehabilitate even after prolonged periods of inactivity, smooth muscle in the penis can develop irreversible scar tissue as a result of prolonged periods of little or no erectile function.

Joseph: With the knowledge that regular erections are important for maintenance of penile health, the concept of penile rehabilitation was born. It sounds pretty painful and like some form of corporal punishment for misbehavior but it’s actually a very big area in Urology now.

Nathan: (sigh)

Joseph: The goal of penile rehabilitation is to maximise erectile function recovery by using strategies that help the penis restore the regular erections it needs to prevent scar tissue from forming.  Furthermore, when you get an erection, it helps to maintain stretch on the penis which may help prevent penile shortening in the long run.

Nathan: It’s postulated that a key facet of penile rehabilitation is taking regular erectogenic medications such as Sildenafil, Tadalafil or Vardenafil, collectively known as phosphodiesterase inhibitors or PDE5-Inhibitors. PDE5 inhibitors encourage blood flow to the penis and hopefully prevent a lot of those terrible side effects from taking place. It has been found that these drugs are endothelial protectants.  Endothelial cells line all blood vessels in the body.  In your penis they are abundant and many of the substances required to get an erection are made inside these cells such as cyclic GMP which causes the release of nitrous oxide with subsequent decreased tone of vessels and increased blood flow in to the penis, and voila, an erection. By taking these tablets regularly, you are helping to protect these cells that are vital for getting erections and further help to prevent scar tissue from being laid down. Or so the theory goes. And what better way to test a theory than with a well conducted randomized double blind trial.

Joseph: Nathan, there is no one I would rather be sitting in a cramped sound booth talking erections with than you and this man.

Francesco: My name is Francesco Montorsi, I am a urologist in Milan Italy. I have always had a specific interest in the field of post prostatectomy impotence. We started in 1996 with the idea of proposing the use of intracavernosal injections following the procedure and we were the first to show that by doing this they recovered spontaneous erections without being improved. And from there, all the rest.

Nathan: It was a pleasure to have Francesco join us for his expert insights. No doubt he was a hero to many men with that finding! I must say, Joseph, I’m surprised that penile rehabilitation in some quarters is still a poorly practiced and poorly understood area. We asked Francesco is this is an area we should be paying a lot more attention to?

Francesco: It depends on the perspective you are using. It is very controversial if you look evidence behind that. It is not controversial because everybody is using that. What I mean is that, I don’t know a surgeon who is doing radical prostatectomy himself who is not telling his patients take Cialis, take Viagra, take Levitra. I can’t recall one single colleague who would tell their patient – take nothing. And I’m sure that this is the case in Australia, the UK and wherever. Also for those who are very medicolegally strict, who could say there is no evidence, so what are you going to do? You tell your patient to do nothing? The patient is asking you “ should I take a pill”? And so I take the responsibility as a physician to tell them no, why you want the throw away your money. No-one is doing that.

Joseph: So this study aimed to evaluate the effect of the early use of the long-acting PDE5-I Tadalafil (once daily or on demand) on both assisted and unassisted erectile function in men who developed erectile dysfunction after nerve-sparing radical prostatectomy. The key point there is early which implies rehab rather than just seeing if the tablets work. We know the tablets work and hence this is a phase 4 trial and the multi-institutional, phase 4, double-blind, randomized, placebo-controlled study was born.

Nathan: Key entry criteria are Men<68 years of age at the time of nerve-sparing radical prostatectomy for organ-confined, prostate cancer were eligible to participate if they had no history of erectile dysfunction. An International Index of Erectile Function-Erectile Function domain (IIEF-EF) score ≥22 was required at screening- meaning they had to have quite good erections to start. Men also had to satisfy all of the following eligibility criteria: historical PSA levels <10 ng/ml; a Gleason score≤ 7 (on biopsy); no other significant comorbidities; confirmed bilateral nerve sparing prostatectomy; no need for adjuvant prostate cancer therapy; and importantly they had to have proven erectile dysfunction after surgery, defined by a patient-reported Residual Erection Function (REF) score≤3 – which allowed men up to erections that were hard enough for penetration but not completely hard – I don’t know if the men or their partners had the final say on this one!

Joseph: I think that is a really important point, Nathan. These are confident guys with very good erections coming in, and some had reasonable erections post-op already looking for better, and we must be careful extrapolating any benefits of penile rehabilitation that might have come out of this study to those men with very poor erections pre-op or post-op, or who did not have a great nerve sparing operation. In total 423 men were randomized with about 140 in each arm. As Nathan mentioned, the study excluded men with significant comorbidities such as cardiovascular disease, hypertension or diabetes. Given that nowadays, most of us are overweight, eat ourselves silly and don’t exercise enough, I’m intrigued to know why they were excluded and if the findings of the study might also be applicable to those with the aforementioned comorbidities.

Francesco: The reason why we did not want patients with significant vascular risk factors was because those would be at risk not to recover erectile function. Even more at risk than the normal population. We really wanted to have those who could really have the potential to recover. This is why we tried our best to identify the most healthy patients and the best surgeons. Considering your question, I think that the finding can be extrapolated. Also to those patients ?, but clearly one should expect results which are not so good.

Nathan: The study design is very important to understand when interpreting the final result. After the screening period, patients were randomised to one of three groups:

1. Tadalafil 5 mg once daily plus placebo on demand,
2. Daily placebo with Tadalafil 20 mg on demand, or
3. Placebo once daily and on demand.

The intervention was a 9-month double-blind treatment period in one of these three groups; then a 6-week drug-free washout period to get rid of any lingering effects of the active drugs for those who received them; and finally a 3-month, open-label treatment period where all groups got the drug. For on demand dosing, patients were permitted to take up to three tablets per week (and no more than one per day). During drug-free washout, patients received no study drug. During the open-label period, all patients received Tadalafil 5 mg once daily.

Joseph: The primary objective was to evaluate the efficacy of Tadalafil 5 mg once daily and Tadalafil 20 mg on demand compared with placebo when taken over 9 months in improving unassisted erectile function.

Nathan: Secondary outcomes include the actual values and changes from baseline in International Index of Erectile Function score, positive responses to Sexual Encounter Profile (SEP) questions, and changes in stretched penile length in the flaccid state. And I am confident that all men would have been totally honest if it had been self-reporting their penile length.

Joseph:  And now for the results. Drum roll please. The primary objective of the study was not met. There was no statistical difference in the ability of Tadalafil daily or on demand compared to placebo given during the initial rehab phase to give men an unassisted erection during the open label phase. i.e. in this study, penile rehab did not improve men’s ability to get erections down the track. Make no mistake, tadalafil clearly works as evidenced during the initial 9 month phase, where men in tadalafil daily group (but not the on demand group) were statistically significantly more likely than placebo to get a good erection. However, the treatment effect for Tadalafil once daily was not sustained after drug-free washout period. But in the open label phase when all men were on daily tadalafil, men in all three treatment groups experienced improved erections with about 30% of men achieving an International Index of Erectile Function score of 22 or better. It just didn’t matter if they had got the tadalafil early.

 Nathan: Similar findings were evident in the Sexual Encounter Profile (SEP) questions and with only the Tadalafil once daily group showing a significant improvement during the double blind treatment period. Again, no significant Sexual Encounter Profile differences were observed after drug-free washout.

Joseph: Nathan, let’s cut to the chase, the only reason people are still listening is to hear what happened to penile length. You will be ecstatic to discover that there was significantly less shrinkage observed in the once daily group compared with placebo at the end of the double blind treatment period. In fact, the Tadalafil on demand group had more shrinkage and must have felt like they’d been left out in the cold.

Nathan: On that note, let’s ask Francesco to summarise the findings in his own words.

Francesco: The study did not show any difference between the drug and placebo when patients were left alone to see the real recovery without drugs. So the patients were treated, either with Cialis or placebo, then they were left alone for a while and we could not see any difference. We were expecting and hoping that those who were on treatment with Cialis would have shown a continuous improvement of their function which did not happen. This being said, when they were challenged again with Cialis, we found a difference between the response of those who had been receiving Cialis from the very beginning compared to those who had received placebo initially and Cialis later on.  As an additional finding, we measured the length of flaccid penis before and after, and we did find a significant difference in the length. This suggested that probably the use of Cialis is able in some way to protect the integrity of the muscle.

Joseph: I can see tadalafil sales soaring after Francesco’s last comment! Seriously though, do these results not effectively signal the death of penile rehabilitation as we have know it? Is this study just telling us that if men want to have erections, we give them PDE5-Is?

Francesco: I think that the concept of rehab is today mostly the concept of trying to have sex as much as or as frequently as possible. I tell my patients (and you can quote me) is “it is time to go back to high school and to practice masturbation as much as possible”. One could say for e.g.. the vacuum device could also be used for the same reason without using the band at the root of the penis. I have nothing against that. So, rehabilitation would be like… you break your leg and after the operation or whatever, you need to start walking and if you stay on the coach or lay on your bed and do nothing all day then it will be difficult to get your muscle back. It is exactly the same concept. So people should try as much as they can, typically if they try by themselves they don’t have performance anxiety and so it is easier to get better erections. So, if you use them, that would be already the rehabilitation I am talking about. But, if you add drugs things are indeed much better as we have seen over the last 15 years, always. When anyone is using a pill, it is always much better.

Nathan: Hilarious Francesco, I love it, “it is time to go back to high school and to practice masturbation as much as possible”! I never thought I’d hear those words uttered on one of our podcasts.  Men are going to love you now that you’re recommending as much sex as possible. The next obvious question for me concerns the choice of drug in the study. I wonder if all PDE5-Is might show the same response or is it that Tadalafil’s longer half like might be contributing to a better response? Let’s get Francesco’s thoughts.

Francesco: This is a good question. From a pharmacological perspective Tadalafil should be considered the best possible drug but if you use on the contrary also a short acting drug which is used frequently though, every day, every other day combined with sexual stimulation. We just don’t know what is the difference. And perhaps it is absolutely the same so today in my country the decision from the patient is mostly a decision based on cost. The cheapest thing is what they will do. At this moment, Sildenafil generic which cost 1/5 of Cialis in my country, is the no. 1 drug.

Today I would tell my patients to take Sildenafil 100mg and to practice sex including masturbation, sex with a partner and to do that as much as possible.

Joseph: Best advice I have ever heard! Sounds like an excellent recommendation! I am a bit curious as to why the rate of return of good erections was lower in Francesco’s paper than compared to other studies during the open label phase.

Francesco: The major problem there is always that you cannot compare apples and oranges. Because, patients are different and unless one is really looking at the same patient population there will always be differences.

Nathan: Just another thought, Joseph, some of our listeners will already be using injectables for their ED. Where does all this leave injectables in the treatment algorithm? We asked Francesco his thoughts.

Francesco: First of all, if the patient received a bad operation which means a very significant operation, the disease was bad to start with, I am indeed telling him…. listen, we did all we could to save something but as for sure we did not save it all, so we use the injections. For those who are in the elderly range of the population we would tell them use injections.

With those who tell me, I had sex before but I had to take Viagra and sometimes it was so, so; I would tell him you should have injections. All the others they will start with the pills.

Joseph: I really like this paper and I love Francesco’s refreshing approach to it all. So Francesco, what is your take home message after all of that, apart from encouraging men to have sex as frequently as they possibly can?!

Francesco: That unfortunately although we do not have a robust scientific evidence about the value of this treatment we all know that there is some effectiveness and that patients are happy to use the pills and that I foresee that more and more patients will be using these.

Nathan: I didn’t think we needed any other take home message Joseph. The only message I’m taking home, and presumably most of our men out there, is that lots of sex is good for maintaining erections. Seems like a win-win situation!

Seriously though, Francesco, what’s the next study you’d like to do, in an ideal world, to advance our knowledge and understanding of penile rehabilitation?

Francesco: The clear study that would need to be done would be one where the drug has to be joined with a good frequency of sex – that has never been studied. So leave the patient alone and he does whatever he wants to do compared to the patient is instructed to try to practice masturbation or whatever 3 times per week for e.g.. after the operation. That has never been done. But his should continue for at least 2 years. And then you could expose the patient to nothing, what I mean is; practice by yourself without the pill or combined with the pill. Because this is at the end of the day what the patients are doing. If everybody has been seeing an improvement in the recovery of erections after a robotic prostatectomy going ahead for at least 21/2 years or so, not only the first year.

Joseph: A really interesting paper. Like we said at the outset, it’s a topic which we encounter nearly everyday in clinical practice. Thanks so much for joining us Francesco – you were very entertaining! We’ve been Talking Urology today with Francesco Montorsi. We still have some great podcasts coming up including Neil Fleshner discussing his REDEEM study on Dutasteride in men on AS for prostate cancer

Nathan: Thanks for listening. We hope you enjoyed the show. You can contact us with questions, corrections, or updates at talkingurology@gmail.com.

You’ve been listening to a Talking Urology Podcast with Joseph Ischia and Nathan Lawrentschuk. Written by Mark Quinlan and Joseph Ischia. Produced by Joseph Ischia and Cara Webb. And proudly supported by Ipsen who put the A in to ADT.