BOSTON—Sildenafil citrate may help to prevent the erectile dysfunction that affects up to 60 percent of men who undergo radiation therapy for prostate cancer, according to findings of a prospective, randomized, double-blind, placebo-controlled trial presented during the plenary session at the ASTRO Annual Meeting here.
“This is the first randomized controlled trial to demonstrate a benefit for a pharmacological intervention for erectile dysfunction in a preventative mode,” the study's lead author, Michael J. Zelefsky, MD, Co-Leader of the Genitourinary Disease Management Team at Memorial Sloan-Kettering Cancer Center, said at a news conference.
Several studies have demonstrated that the phosphodiesterase type-5 (PDE-5) inhibitor sildenafil and other drugs in its class help to restore potency in some 60 to 70 percent of men with erectile dysfunction caused by radiation therapy. And more recently, he said, research has suggested that these drugs may have a role in “penile rehabilitation, preventing the induction of impotence and actually protecting the vasculature, which is the causative factor of erectile loss.”
And in one study early postoperative on-demand treatment with the PDE-5 inhibitor vardenafil increased spontaneous erections among men undergoing radical prostatectomy, which cause erectile dysfunction in up to 70 percent of patients.
“Our goal was to give sildenafil in advance of radiation therapy to reduce the risk that men will ever develop erectile dysfunction,” Zelefsky said.
In the study (Abstract 3), funded in part by Pfizer, the drug's manufacturer, 255 prostate cancer patients treated with external-beam radiation therapy and/or permanent interstitial implantation were randomly assigned in a 2:1 ratio to sildenafil at 50 mg/day or placebo. Sildenafil or placebo was initiated three days before treatment and continued for six months. After treatment ended, men could ask for the drug if they wanted it.
The current analysis focused on 144 men who completed sexual function questionnaires both before treatment and at least once after treatment and who did not undergo androgen-deprivation therapy (ADT).
Patients completed the International Index of Erectile Function (IIEF) questionnaire before treatment and at six, 12, and 24 months post-treatment. All the domains in the index were scored—i.e., erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction—and patient characteristics including age, use of brachytherapy, and baseline IIEF scores were balanced between the treatment groups.
The self-reported overall scores were significantly higher in the sildenafil group than in the placebo group at six months (58.6 vs. 49.4 points), 12 months (56.3 vs. 48.2 points), and 24 months (54.9 vs. 47.6 points) after treatment—“Differences of three to five points are considered clinically significant,” he said.
“Since the most significant improvements were seen at six and 12 months following treatment, with a slight dip at the 24-month mark, future trials need to be conducted to demonstrate if longer treatment duration can further improve patient outcomes.”
The moderator of the news conference, Benjamin Movsas, MD, Chair of Radiation Oncology at Henry Ford Hospital, said, “Erectile function is such an important quality-of-life issue for patients. If we can give a safe medication upfront and prevent erectile dysfunction, that's important. If we wait until sexual problems develop, rather than trying to prevent them, it may be too late.”
Still, it's too soon to recommend sildenafil to patients until the data are peer-reviewed and published, he cautioned. “Then, if all is well, I would encourage conversations with patients.”
In contrast, though, the study's Discussant, Thomas M. Pisansky, MD, Professor of Radiation Oncology at the Mayo Clinic, said he believes it is time to act.
He praised the research for being the first study to try sildenafil in a preventive manner in patients who get radiation treatment, and said that given the success of PDE-5 inhibitors in inducing spontaneous erections when given early after radical prostatectomy and the fact that sildenafil appeared to work as a preventative in the current study, “I would start the discussion now with patients. There is a window of opportunity after which the ability to prevent erectile dysfunction is lost.”
There are a number of limitations to the research, however, he said. For starters, it might be better to test the drug in patients treated in a uniform manner, rather than having a heterogeneous group in which some men were treated with implants and others with external radiation.
Also sildenafil has a relatively short half-life, with its concentration halved in just four hours. That brings up the issue of whether once-daily dosing is optimal: “If it is protecting blood vessel structures, there needs be enough in the system,” he pointed out.
A better choice might be sildenafil's cousin, tadalafil, which has a half-life of about 17 hours, Pisansky said. Also, patients who received ADT should have been excluded from the outset, rather than after they were enrolled, since diluting the pool after the fact weakens the power of the study, he said.
Fortunately, all those issues are being addressed by a new study—the Radiation Therapy Oncology Group 083 trial. Also known as PEDS, the Prevention of Erectile Dysfunction Study, the randomized, double-blind, placebo-controlled Phase III trial will evaluate the effectiveness of tadalafil in preventing erectile dysfunction in men with prostate cancer treated with radiotherapy. Patients who had ADT will be excluded, and the type of radiation the men receive will be more uniform.
All the patients have completed treatment and are now being followed. “If the study shows tadalafil works, it will confirm the principle,” Pisansky said. “If it is negative, it probably will bring Dr. Zelensky's study down with it. But I don't expect that to happen.”