­­­­­­Recent advances in managing Peyronie’s disease

Collagenase

Despite the existence of early studies dating back to 1982⁴, collagenase clostridium histolyticum was approved by the US Food and Drug Administration in only 2013 as Xiaflex™ (Xiapex™ in the European market) for patients with a deformity of at least 30 degrees and palpable disease. Treatment comes in the form of an injection of two collagenases which act synergistically to cleave tropocollagen. The regimen involves up to four cycles of treatment 6 weeks apart, each cycle requiring two injections of 0.58 mg separated by 24 to 72 hours. Patients are also educated in penile modelling to occur three times daily. Approval was gained following the published data from IMPRESS (Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies) I and II trials, identical phase III placebo controlled studies⁵. These studies of 551 men evaluated reduction in curvature and Peyronie’s Disease Questionnaire (PDQ) score as their main outcome measures, and 401 patients made up the final modified intention-to-treat analysis. Curvature was reduced by 17 and 9 degrees (34% versus 18%) in the treatment and placebo arms, respectively. PDQ bother and symptom scores were reduced by -2.8 versus -1.8 and -2.9 versus -1.3, respectively, favouring the treatment group. Serious adverse events were noted in six patients, of whom four (three corporeal rupture and one haematoma) required surgery. All corporeal ruptures were related to intercourse. Overall, there does appear to be at least a modest benefit and it remains the most promising non-surgical therapy. The cost per cycle is £1300; hence, the treatment is currently not available routinely within the National Health Service but is being evaluated by the National Institute for Health and Clinical Excellence. Modification of the trial protocol to reduce the total number of injections and cycles alongside the use of a traction device appears to represent improved health economics and we await availability of published data to that effect.

Verapamil

The role of calcium channel blocker verapamil in PD is thought to be due to an upgrade of collagenase activity and inhibition of extracellular collagen transport⁶. Whilst both intra-lesional and electromotive drug administration (EMDA) verapamil have been shown to provide some benefit in historic studies, direct comparison has not been previously reported. A randomised trial by Mehrsai et al. compared route of treatment in 60 patients undergoing an injection once per week for 6 weeks⁷. The authors found no significant difference in reduction of plaque size alongside a noted improvement in erectile function (albeit not significant). Penile pain assessed by visual analogue scale was significantly reduced in the EMDA group compared with the injection group (-4.1 versus -1.8) at 3 months. Penile curvature was improved in both groups, and increased shift towards a less-than-30-degree group was noted especially in the EMDA category. This improvement, however, was not quantified in more detail or statistically significant. Adverse events were not reported. They concluded that EMDA was at least a comparable and less invasive treatment modality. Notably, the study excluded patients with curvature of greater than 45 degrees and those unable to achieve penetrative intercourse. Recent guidelines from Europe and the US do not recommend routine use of EMDA verapamil^8,9.

Intra-lesional verapamil has also been assessed alongside tadalafil by Dell’Atti et al. in a randomised trial¹⁰. The study compared verapamil (12-weekly) and tadalafil daily alone and in combination. No significant improvement in curvature was noted in any group over the course of a 3-month study period. There was improvement in pain for all groups, most notably in the combination arm; however, statistical significance was not achieved. Only improvement in International Index of Erectile Function (IIEF) score showed significance in the combination group (14.4 versus 18.2 versus 23.1). The authors acknowledge that small numbers limit their study; however, the role of daily tadalafil may augment more traditional strategies¹⁰.

Interferon α-2B

First reported by Duncan et al. in 1991, interferon therapy was shown to affect collagen in PD by inhibiting fibroblast proliferation and promoting collagenase activity in vitro¹¹. There is a paucity of randomised trial data during this period of review, and the last significant trials were conducted in 2006.

These data concluded that interferon provided only modest benefit in conjunction with significant side effects^12,13. A retrospective review by Trost et al.¹⁴ indicated a 54% response rate in 127 patients but a mean improvement in curvature of only 9 degrees. A further review in 2015 from Stewart et al. reported a 91% response rate but with similar modest improvement in curvature¹⁵. The treatment is currently included in both the American Urological Association and European Association of Urology guidance.

Vitamin E and antioxidants

Vitamin E has been the subject of numerous historical trials and the general consensus is that its antioxidant properties improve pain during the acute phase, but not curvature. The most recent controlled trial, by Paulis et al., studied the role of vitamin E 600 mg daily in augmenting a standard treatment protocol of combined intra-lesional/transdermal verapamil, non-steroidal anti-inflammatory drugs, and herbal antioxidants¹⁶. The group receiving vitamin E demonstrated global reduction in curvature in 97% versus 48% of patients in the control group. The noted reduction was modest but statistically significant: mean of 12.2 degrees versus 6.7 degrees. Significant improvements were noted in the treatment group in terms of plaque size as well as subgroup analysis of IIEF scores. Medium-term follow-up of these patients demonstrated durability of these findings and further supported combination therapy¹⁷.

A further randomised trial, by Favilla et al., showed significant improvement in IIEF scores for patients given antioxidants alongside intra-lesional verapamil, compared with verapamil alone¹⁸. No improvement in curvature was noted.

Overall, there is limited evidence to support the use of vitamin E and antioxidants other than as an adjunct to more recognised therapies.

Tamoxifen and Potaba

There are multiple oral agents promoted for use in the early phase of PD development. Typically, tamoxifen and Potaba fall victim to problems similar to those of alternatives such as colchicine and acetyl-l-carnitine because of a lack of recent randomised data to support their routine use. Both treatments are endorsed by international guidelines for improvement in penile pain but not specifically for reduction in curvature. Park et al. report on Potaba versus combination therapy of tamoxifen, l-carnitine, and tadalafil¹⁹. Perhaps the most striking result was that two-thirds of the patients in the Potaba arm withdrew for varying reasons, although treatment side effects were cited as the largest single factor. Resolution of pain was once again significant, and more so in the combination group. Sixty-six percent of patients overall noted an improvement in curvature of 30% or more; however, this does include the large number of dropouts.

Extracorporeal shockwave therapy

Extracorporeal shockwave therapy (ESWT) remains second- or third-line treatment in PD, and decreased efficacy has been highlighted in a single-blinded randomised trial by Hatzichristodoulou et al.²⁰ Similarly, a significant reduction in pain was reported (85% versus 48% in the placebo group). However, no improvement was witnessed in plaque size and curvatures worsened by up to 40% of patients in the treatment group. The authors conclude that the role of ESWT can no longer be justified in the treatment of PD.

Vacuum tumescence and traction devices

No randomised data exist for these treatment modalities. Objective improvement has been seen in a recent controlled study of traction devices, as have significant improvements in curvature, erectile function, and pain. Importantly, 40% of patients avoided surgical intervention²¹. These may be a useful adjunct to treatment, although larger studies are needed and the daily traction time required (up to 8 hours) may prove to be a limiting factor. However, as highlighted in the first section, these devices may have a renewed role in penile modelling techniques with plaque dissolution seen in collagenase-style therapies.