Oxygenation and erection are cornerstones of rehabilitation strategies, expert says

Nov 1, 2006 Urology Times

Q. How important are validated questionnaires in evaluating erectile dysfunction?

A. For the average community physician, unless you're particularly interested in looking at your outcomes, I don't think that's essential. If you're performing a lot of open, laparoscopic, or robotic prostatectomies and you plan to present your data, you'll want to provide questionnaire-based data.

Whether you should use the International Index of Erectile Function (IIEF) or the Sexual Health Inventory for Men is debatable, as long as you're using a validated instrument. Their value is in providing a baseline score and a serial score postoperatively at 6, 12, 18, and 24 months, for example, and each one includes a frequency question. The IIEF, for example, asks the question, "Mr. Smith, over the last 4 weeks, how often were you able to penetrate, maintain, etc.?" It really gets to the consistency of the patient's response.

Q. What's your approach to treating ED in these men? When do you start it, and which agents or techniques do you use?

A. Treatment approaches can be classified in two ways, depending on whether a man presents with ED early or in a delayed fashion after surgery. In those who present in a delayed fashion, we are really focused on getting him back to having sexual relations, so the treatment is designed to give them erections for sexual relations. We don't consider somebody who comes in after 18 months a rehabilitation candidate, but someone who comes in after less than 12 months after radical prostatectomy would be a rehab candidate.

We like to see patients before surgery to give them realistic expectations and to outline their "homework" for the first 4 weeks after surgery. We encourage our patients to come in within the first 2 months because the incidence of venous leak in those first few months is practically zero. If a man has good erections, undergoes nerve-sparing surgery, and he comes in within the first few months after surgery, it's unlikely he's going to have permanent structural changes.

We tell our nurses that when the catheter comes out, whether after an open or laparoscopic prostatectomy, the man should be challenged with a PDE-5 inhibitor. We want the patient over the ensuing 4 to 6 weeks to use a PDE-5 inhibitor at maximum dose on at least four occasions. When they come back to see me, they're going to be asked: Did you get an erection with the PDE-5 inhibitor? Did you get a 6/10 on the hardness scale (penetration hardness)? If so, I tell them they are oxygenating their penis well enough and can use pill-based rehab-ilitation.

If the patient comes back to see me and has not responded to medication, we move him directly to penile injection therapy. Like many others, I believe the cornerstone of rehabilitation is erection and oxygenation, and that the regular use of PDE-5 inhibitors is a useful adjunct. A clinical trial by Pfizer, which is not yet published, has shown that a man has an increased chance of preserving his preoperative erectile function by using regular sildenafil. That's bolstered by strong animal data. If you expose animals to nerve injury and you give them PDE-5 inhibitors regularly after surgery, you can actually improve erectile function by reducing apoptosis and improving endothelial factor preservation.

We encourage men to get three erections a week with whatever works (pills or injections) and then on non-erection days, to take a low-dose PDE-5 inhibitor before going to bed at night.

Q. What is your opinion on giving PDE-5 inhibitors before surgery?

A. There's a lot of interest at the moment in endothelial preconditioning: giving patients PDE-5 inhibitors before surgery. Some cardiologists believe that we might even look at administering statins because they are very potent en-dothelial protectants. We anticipate data about this in the next 2 or 3 years.

Q. If a patient doesn't respond to initial therapy with a single PDE-5 inhibitor after 2 or 3 weeks, would you immediately proceed to injection therapy or to a combination of a PDE-5 inhibitor with, perhaps, a vacuum device?

A. Combining PDE-5 inhibitor therapy with a vacuum device is a very interesting concept. I believe that rehab is related to cavernosal oxygenation, and there are no data to show that vacuum devices oxygenate the penis. I hope the vacuum device companies will start some clinical trials to answer the question of whether vacuum devices are useful as an adjunct.

Only two papers have shown a benefit with combination therapy, and they involved the combination of an oral PDE-5 inhibitor and transurethral prostaglandin (MUSE), although these were studies of men in the general ED population—not the post-prostatectomy population—who had failed oral or transurethral therapy (Eur Urol 2000; 38:30-4, Int J Impot Res 2002; 14[suppl 1]:S38-S42).

The problem with prostaglandin E1 suppository (MUSE) use is that the cavernous nerves, when injured, are hypersensitized, and there is a significant incidence of penile pain at high MUSE doses, so we typically move directly to penile injection therapy using Trimix and high-dose prostaglandin E1.

Interestingly, when we talk to patients about it, close to 85% of the patients actually do injection training. One year after they start injections, almost two-thirds of them continue to inject at least once per week.

The way we pitch injection therapy is to tell them, "We're putting you on injections now to minimize the chances of you needing injections for the rest of your life." It's a rehabilitation strategy.

Q. How do you define therapeutic success in these patients?

A. Probably the most functional way to define it is the ability of a man to have sexual intercourse whenever he wants to have it. What level of consistency does that have to be? At least 75%, but for a young man, at least 90% of the time.

Some say we really need to get people back to where they were before surgery. But if we look at our patients critically and the percentage of patients who get back exactly to where they were before surgery without using a medication, it's probably less than 10%.

Q. Following rehab, what percentage of men will eventually have reliable successful intercourse, with or without a PDE-5 inhibitor?

A. According to the paper you and I published from our database, research suggests that with rehabilitation, ie, getting three erections per week, 52% of men at 18 months were functioning on their own, without pills. We tell our patients that if you have good erection function before surgery—an 8/10 on the hardness scale—and if you have bilateral nerve-sparing surgery and you commit to rehab, you have between a 70% and 80% chance of being a full PDE-5 inhibitor responder at 18 to 24 months. The percentage might even be higher in younger patients (J Sex Med 2005; 2:532-40).

Q. Even patients who achieve success don't defy the effects of aging on performance. How durable are the results?

A. If you follow patients over 5 years, you have to factor in aging and vascular risk factors, such as hypertension, hyperlipidemia, and cigarette smoking. In those first 18 to 24 months when men get their erection back, most of them will continue to use a pill because of an erosion of confidence. They need that boost. Many of them will wean themselves off, but many men with really good erectile function use a PDE-5 inhibitor to boost their confidence.

That's a methodologic challenge for us because patients come back to us and say, yes, I'm functioning, and they fill out a questionnaire. Is that questionnaire being filled out for pill use or for natural erection? That's a real problem.

Q. What's on the research horizon in this area?

A. The research is very exciting. I think we'll start seeing animal models of endothelial preconditioning. These studies will examine whether there is a benefit in pre-treating these animals with PDE-5 inhibitors or statins to ramp up endothelial function before they get the nerve injury associated with endothelial change.

Research is also examining the role of neuromodulatory drugs in protecting a man's nerves from injury during surgery or to help those nerves regenerate. One trial of a drug known as GPI 1485 is already completed. A study of FK506 (tacrolimus) is near to closing enrollment, so we'll have data on that in 2 years. These drugs are immunophilin ligands, and they work on immune tissue and nerve tissue. There's some robust animal data showing these drugs do really good things. We presented data this year on FK506, and Dr. Tom Lue presented some interesting data on a new non-immunosuppressant immunophilin ligand, FK1706, that shows significant preservation of erectile function in animals mediated through neural protection.

We're also looking at perineural therapeutics that might be administered to the nerves via a gel or another agent that contains a nerve growth factor. A fellow in our lab is working on that, and he's working with a company to develop a delivery system. Finally, we want to look at a good, robust rehabilitation trial that will answer the question of whether rehab really works.

Q. A lot of patients are concerned about penile length after RP. Is it a real issue?

A. Penile length issues are real. Three current papers suggest that somewhere between 40% and 70% of men have documented penile length change, some up to 4 centimeters (Mol Urol 1999; 3:109-15, Urology 2001; 58:567-9, J Urol 2003; 169:1462-4).

Penile length changes fall into one of two groups. First is the complaint of the penis being withdrawn into the body and difficulty finding it when the patient needs to urinate. In a man with this complaint, his circumcised penis in the flaccid state looks uncircumcised, and this is due to sympathetic hypertonia. In the early stages after autonomic nerve injury, the sympathetic nerve fibers are in the ascendancy, which is called "competitive sprouting." Unfortunately, the sympathetic nerves in the penis are contractile nerves, so there is a contraction of the smooth muscle in the penis. We know that because when you stretch that man's penis, he has perfect stretch, with no structural changes.

However, at 6 months and beyond, cavernosal hypoxia—absence of erections—can lead to permanent, irreversible structural changes, causing venous leak. So rehabilitation strategies may not just prevent venous leak, but they may in the future be shown to preserve penile length.

The other contributor to shortened penile length is Peyronie's disease, which develops in some men in the first 6 to 12 months after surgery. We don't understand why, but Peyronie's disease causes a scar that contracts, and these men develop permanent penile length loss.

There's a common belief that the Peyronie's disease is a result of penile injections. But many patients' plaque is located distally, nowhere near where they've been injected. Some of our patients have failed oral therapy after 8 weeks, and they're going on injection, per our protocol. At the first training visit, 8 to 12 weeks after surgery, they get a curved penis—and it never happened preoperatively. There are some men who are probably genetically susceptible to Peyronie's. If that's the case, perhaps there's something about radical pelvic surgery, and we've seen it post-cystectomy as well, that may be involved in the genesis of Peyronie's.

Q. What is the natural history of Peyronie's disease?

A. I don't know that I can tell you what that is after radical prostatectomy. In general terms, about 50% of men with Peyronie's disease get worse over 12 months, and about 10% of men get better. I don't know if it's different in a radical pelvic surgery patient.

Editor's note: Dr. Mulhall is a research consultant for Pfizer, a consultant for Lilly-ICOS, a consultant for Auxilium, and a consultant for Johnson & Johnson. He has also received a grant from Astellas.