Penile Fibrosis (Non-randomized studies: observational studies and clinical trials)
In total, 20 non-randomized studies (retrospective observational cohort, and clinical trials) reporting the absence or presence of penile fibrosis in long-term followup (at least 6 months) met the eligibility criteria for inclusion in the review (in 20 publications).364–383 Of these, 13 were clinical trials of prospective design364–366, 368–371, 376–378, 380, 381, 383 and seven were retrospective cohort studies.367, 372–375, 379, 382
The number of subjects included in the 20 studies ranged from 10370 to 1089.374 The majority of the study subjects were middle aged (mean age range: 50–62 years). Four trials included special population subgroups such as patients diagnosed with diabetes,366, 369 multiple sclerosis,381 and prostate cancer followed by prostatectomy.367 One study evaluated ICI therapy in geriatric men (age >65 years).382
Prostaglandin (PGE1) alone or in combination with other vasoactive agents (papaverine and/or phentolamine) was evaluated in 15 studies.364–378 Papaverine alone or in combination with phentolamine (or verapamil) was evaluated in 13 studies.366, 367, 369, 371,373, 374, 376, 377, 379–383 The duration of treatment ranged from 3 months368 to 10 years.366 In the majority of studies, the approximate frequency of PGE1 injections was up to twice per week with a mean dose of 20 μg or lower.365, 370, 372, 375, 378
Of the 20 studies, five explicitly reported the absence of new cases of fibrosis.367, 368, 370, 371, 378 and six studies reported the incidence of fibrosis to be under 5 percent.373, 376, 377, 379–382
The proportion of patients with fibrosis in studies that used PGE1 alone after at least one year of followup ranged from 4.4 percent365 to 23.3 percent.372 In two of these studies no cases of fibrosis were observed.370, 378 For example, one retrospective cohort study in Australian men372 reported an incidence of fibrosis in 57 of the 245 patients (23.3 percent) who had been treated with PGE1 2–60μg (mean 13μg) for 2 years on average. The total amount of PGE1 (p = 0.0062) and the total number of injections (p = 0.0032) over the whole treatment period were statistically significantly greater in the men with fibrosis. However, there were no significant differences between the men who developed fibrosis and men who did not with regard to duration of followup, injection frequency, or dose per injection.372 In contrast, in another prospective trial,365 only three (4.4 percent) of the 68 PGE1-treated patients (the mean PGE1 dose: 11.6μg) developed fibrosis after at least one year of followup. Of these three patients, only one patient injected PGE1 more frequently and at a higher dose (20–60μg every 2–3 days) than it was prescribed (one injection 10–20μg per 5–7 days).
The largest study that evaluated and compared adverse events in patients receiving ICI injections with different medications was a retrospective U.S. study of 1089 patients who had received either 5–10μg PGE1, trimix (1.47μg PGE1 plus 4.41 mg papaverine plus 0.5 mg phentolamine), papaverine plus phentolamine, or 10μg PGE1 plus 30 mg papaverine for up to 80 months. This study investigated reasons for attrition in each treatment group. Of the subjects discontinuing the treatment, penile scarring/nodules was the reason for study withdrawal in 23 percent (6/26), 11 percent (4/36), and 10 percent (8/75) of the subjects receiving triple therapy (PGE1/papaverine/ phentolamine), combination papaverine and phentolamine therapy, and PGE1 monotherapy, respectively. None of the patients receiving the combination of PGE1 with papaverine developed penile scarring/nodules.374 In a controlled trial conducted in Taiwan,377 51 patients with ED (mean age: 58 years) received self-injections either with 20μg PGE1 or 30 mg papaverine for about 12 months (range: 1.5–30.5 months). Two patients (3.9 percent) developed fibrosis after 60 mg papaverine injections. No cases of fibrosis were observed in patients after PGE1 injections.377 Similarly, in a trial conducted in Turkey,376 69 patients with ED (mean age: 52.6 years) were divided to receive injections either with 10μg PGE1 (n = 13 patients) or 15–30 mg papaverine (n = 56 patients) for approximately 12 months. Two patients (3.6 percent) in the papaverine group developed fibrosis versus none in the PGE1 group. In a retrospective North American cohort study,373 108 ED patients received self-injections with either 30 mg papaverine (n = 21 patients), the combination of 25 mg papaverine with 0.83 mg phentolamine (n = 77), or PGE1 (n = 2 patients) were followed-up for 5 years. Only one of the 108 subjects developed fibrosis (the assigned intervention not reported). (Table 29)