Recent advances in managing Peyronie’s disease

Potaba

Two placebo-controlled randomised controlled studies (RCTs) have shown evidence that Potaba may reduce progression and pain^20,21. Weidner et al. demonstrated that penile plaque size was stabilised in the Potaba group compared to placebo. This subsequently reduced the progression of curvature in the treatment group when compared to placebo; however, it did not reduce any established curvature. This group did not demonstrate any evidence of improvement in pain relief. This is in contrast to the earlier RCT by Shah et al., which demonstrated no evidence of improvement in curvature/plaque; however, it did show there was some improvement with regard to pain. Based on these two RCTs, Potaba currently is the only oral medication that has any recommendation for use within the EAU guidelines.

More recently, Potaba monotherapy was compared to combination therapy (tamoxifen, L-carnitine, and tadalafil) by Park et al.²². Perhaps the most striking result was that two-thirds of the patients in the Potaba arm withdrew for various reasons, although treatment side effects were cited as the largest single factor. The study failed to show any statistically significant difference between the two treatment arms owing to the high dropout rate. Overall, the most clinically relevant conclusions from this study showed that the side effect profile of Potaba may lead to very poor compliance and a high discontinuation rate.

The potential adverse effects of treatment alongside the limited evidence of efficacy therefore limit the recommendation of Potaba use, which is why it is not recommended by the AUA or ICSM at the time of writing.

Vitamin E and antioxidant therapy

Vitamin E is a fat-soluble, naturally occurring antioxidant that has previously been shown to improve pain, curvature, and erectile function scores (IIEF) and has been utilised in combination therapy with verapamil injections, non-steroidal anti-inflammatories, and herbal antioxidants, as reported in two recent randomised trials^23,24.

The same authors have performed a further study in combination therapies using vitamin E. This case series was not randomised or controlled. A total of 141 patients were included in the study and assigned to one of five treatment groups that used varying amounts of antioxidant, analgesia, and injectable therapies including vitamin E, silymarin, Gingko biloba, topical diclofenac, and pentoxifylline injections. Throughout all groups, there was prevention in progression of disease. As the number of treatments increased, there was an improved outcome, particularly in IIEF score, reduced curvature, and improved quality of life/bother scores. The curvature improvement was minimal (4–6°) and likely clinically insignificant. In view of the study design not being randomised or controlled, the results must obviously be taken with caution²⁵.

Phosphodiesterase-5 inhibitors and tamoxifen

A recent scientific study has investigated a new model to test potential medical therapies in PD. The team describe an in vitro model that mimics the cellular changes seen in PD. It is well understood that myofibroblasts play a large role in the remodelling of the extracellular matrix and the production of profibrotic mediators and inflammatory cytokines^26,27. These cell lines have also been isolated in PD plaques²⁸. The authors were able to create a screening assay to assess the effectiveness of multiple treatments on the transformation of fibroblasts to myofibroblasts. Using this innovative model, they assessed the efficacy of 21 commonly studied oral therapies. The only compounds that proved to be effective on the fibroblast model included phosphodiesterase (PDE)-5 inhibitors and tamoxifen. These medications were then tested further in separate testing systems. The authors noted that each medication has the potential to prevent progression of disease in the active phase but is unlikely to reduce the plaque or curvature. They also identified that there was a synergistic effect with the two medications combined compared to either medication alone²⁹.

Pentoxifylline

Pentoxifylline is a non-specific PDE inhibitor that also has some effect in reducing TGF-β tissue levels and therefore may have an antifibrotic role and thereby a therapeutic role in PD³⁰. The evidence of its efficacy is limited as a monotherapy; however, there is some evidence to suggest its benefit as a combination treatment.

Smith et al. investigated the effect of pentoxifylline monotherapy on plaque calcification and subjective improvement of the clinical condition. They studied 71 men in a cohort study, of whom 62 were treated with pentoxifylline and nine received no treatment. The study showed that 92% of patients treated with pentoxifylline compared to 44% with no treatment had stable or improved plaque calcification. There were no objective outcomes to suggest improvement in curvature; however, there was subjective patient-reported improvement, which makes it somewhat difficult to make any firm conclusions regarding its true clinical benefit³¹.

A further cohort study conducted by Alizadeh et al. compared pentoxifylline with intralesional verapamil and a combination of both therapies. A total of 90 patients were enrolled into three treatment arms (n = 30) with no control group. They reported improvement in curvature, plaque size, pain, and erectile dysfunction in all groups. Outcome measures were not quantitative and therefore no conclusions about degree of curvature change can be made³². Recently, an older double blind RCT conducted by Safarinejad in 2010 using pentoxifylline monotherapy has since been redacted because of statistical incongruities³³.

A study exploring pentoxifylline as part of a combination therapy has been recently completed by Ibrahim et al.³⁴; a total of 46 patients were included in this retrospective cohort study, which aimed to assess the effect of colchicine or pentoxifylline with penile traction therapy (PTT) (Andropenis® extender) on plaque size, degree of curvature, and penile Doppler parameters. Patients were assigned to oral pentoxifylline (n = 27) and colchicine (n = 18) with all advised to use PTT for 1 hour daily for a total of 6 months. The study reported an improvement in curvature of 14° (55.8° versus 41.4°) and also reported improvement in peak systolic velocity and reduction in plaque size. They found no statistically significant difference in the colchicine or pentoxifylline arm. The study has significant limitations in that there was no control group; therefore, it is possible that the improvement may have been purely spontaneous. It must also be noted that all patients received PTT, which potentially could explain why these parameters improved rather than as a result of any efficacy from the oral therapies. The efficacy of the Andropenis® extender is discussed further in this paper.

Collagenase

Collagenase clostridium histolyticum (CCH) has been studied for use in PD in the experimental field since 1982³⁵. Since 2013, CCH has been approved by the United States Food and Drug Administration as well as the European Medicines Agency. Treatment comes in the form of an injection of two collagenases, which act synergistically to cleave tropocollagen. Its use is recommended by the AUA for PD curvature between 30° and 90°, and the EAU guidelines currently advise a grade B recommendation; however, these guidelines precede the largest published RCT¹⁷.

IMPRESS I and II were large RCTs comparing CCH and penile modelling against penile modelling and placebo with 417 and 415 patients included in the study, respectively. Exclusion criteria included any patients with an hourglass deformity, significant erectile dysfunction non-responsive to PDE-5 inhibitors, proximal plaques, and curvature outside 30–90°. The treatment protocol involved two injections of CCH (0.58 mg) 24 to 72 hours apart. This cycle regimen was then repeated up to four times, alongside penile modelling by the clinician at the time of injection as well as by the patient three times daily thereafter until review. Curvature improved by 17° and 9° (34% versus 18.2%) in the treatment and placebo arms, respectively. There was also similar improvement in IIEF scores (+1 and +0.4, respectively) as well as penile length (0.4 cm and 0.2 cm, respectively). PD questionnaire (PDQ) bother scores were also improved in the treatment group; however, one-third of the cohort did not complete the questionnaire at one or both measurement points, and the PDQ is still not validated psychometrically^18,36.

Ralph et al. conducted a randomised study comparing CCH, modelling, and vacuum therapy to CCH and vacuum therapy alone. This small pilot study (n = 30) did not show any statistically significant difference between the two groups in terms of curvature improvement or patient-reported outcome measures. There was a clear improvement in curvature of 23.7° in the CCH, modelling, and vacuum therapy group compared to 23.3° in the group without penile modelling. The injection protocol was similar to that in the IMPRESS trial with the addition of vacuum therapy being initiated following the second injection twice daily throughout the remainder of the study. There was only clinician modelling performed, with no patient modelling performed in either arm of the study^36,37.

A further study by this same group explored a modified injection protocol in a single-centre study of 53 patients alongside vacuum therapy during remodelling. The injection protocol consisted of three injections of 0.9 mg of CCH every 4 weeks. This was accompanied by manual modelling as well as vacuum therapy, and results showed equivalent outcomes to the IMPRESS trial with mean reduction in curvature of 17.3° (31.4%). This treatment regime reduced the need for multiple visits for injections and clinician modelling, which has the potential to lower costs and time for treatment³⁸. More recently, Capece and colleagues used the modified injection and remodelling protocol to perform a non-randomised, non-controlled multicentre study of 135 patients. They were able to reproduce the efficacy as described previously, with a mean reduction in curvature of 19° (42%). They did, however, note a slightly higher complication rate in the form of ecchymosis and haematoma when compared to the IMPRESS trial³⁹.

Ziegelmann et al. compared CCH and PTT versus CCH alone using a similar injection protocol to the IMPRESS trial with the addition of PTT for 3 hours per day. They found no significant difference in outcomes for CCH alone versus CCH and concomitant PTT. Overall curvature improvement was similar to that of the IMPRESS study, with a mean of 34% improvement. They reported poor adherence to the traction therapy with reducing compliance throughout the study, therefore likely limiting its effect. Ultimately, the authors felt that further RCT studies will be required to determine the role of traction therapy with CCH⁴⁰.

The latest published study in CCH treatment from an Italian group demonstrates a matched-pair comparison analysis of CCH in combination with sildenafil during the modelling phase. Using the same injection protocol as described in their previous study, they added sildenafil 25 mg BD 30–60 minutes prior to patient modelling. This was a small cohort study of 50 patients comparing the modified CCH protocol against CCH with the addition of sildenafil. They were able to show improved outcomes in curvature, IIEF scores, and PDQ scores, which were deemed to be statistically significant; however, the overall cohort was small. Curvature was improved by 25.6° in the CCH + sildenafil group compared to 17.4° in the group given CCH alone. This is clearly a promising outcome but needs further study in larger RCTs prior to any firm conclusions or recommendations being made⁴¹.

CCH has clear robust RCT data showing definitive benefit in patients with PD and a penile curvature between 30° and 90°. There are numerous single-arm studies assessing variable treatment protocols that suggest that dosing adjustments can be made with associated accelerated treatment times and cost savings without compromising outcomes or safety parameters. It must also be noted that the IMPRESS studies showed a clear curvature improvement in the penile modelling group that is likely greater than placebo alone; this indicates that mechanical/modelling therapies alone may well have some efficacy, as outlined later in this article.

CCH clearly offers a less-invasive approach when compared to surgery; however, it is clear that the degree of curvature improvement is not as significant as is seen with surgery. Nevertheless, it does offer a treatment option for a select group of patients who may not be amenable to surgical intervention and would prefer conservative treatment if possible. The ‘real world’ paper by Anaissie et al. succinctly concluded that ultimately CCH needs further study to understand the optimal patient and which treatment regime produces the most efficacious result in terms of curvature improvement without being prohibitive on cost⁴². We therefore eagerly await the results of larger, multicentre, and randomised studies to further focus on predictive factors for treatment success or failure and provide guidance for implementing CCH treatments in socially funded healthcare systems.

The most recent unexpected update regarding CCH is its untimely removal from the European market by the manufacturers. This is an evolving situation, and the authors hope that an alternative product will be available in the near future⁴³. A summary of the salient studies and most recent clinical evidence in CCH can be found in Table 2.

Verapamil

Intralesional verapamil injections are within the recommendations for treatment in the EUA, AUA, and ICSM guidelines. However, their use is supported by overall poor evidence and hence is given a grade C recommendation by all guidelines^17–19.

Verapamil is a calcium channel blocker that has been shown to interfere with fibroblast proliferation and can decrease collagen deposition by upgrading collagenase activity. There are only two trials comparing verapamil treatment and control subjects.

Rehman et al. produced a small randomised control study comparing intralesional verapamil injections against placebo in a group of 14 patients. They used 10–27 mg injections weekly for 6 months. They were able to show a reduction in plaque length, curvature (7.9° in the treatment group compared to 2.2° in the placebo group), and penile pain⁴⁴. A further RCT by Shirazi et al. compared 10 mg verapamil injections to placebo. A total of 80 patients were enrolled and randomised 1:1 to either the treatment or the placebo arm. In the treatment group, patients were given 10 mg injections twice weekly for a total of 12 weeks. In contradiction to Rehman et al., they were unable to find any significant improvement in curvature, plaque size, or penile pain reduction when compared to placebo⁴⁵.

Favilla et al. recently compared intralesional injections of verapamil against hyaluronic acid (HA) in a double blinded randomised study. A total of 132 patients were included and given either weekly 10 mg intralesional verapamil or 16 mg/2 ml injections of HA. Outcomes showed a statistically significant improvement in plaque size (–1.36 mm and –1.8 mm) and IIEF score (1.46 and 1.78) in the verapamil and HA group, respectively. There was no improvement in curvature in the verapamil group in comparison to the HA group, which improved by 4.6°⁴⁷.

There have been a number of further comparative randomised studies of verapamil over the past 10 years that have significant heterogeneity in their treatment regimens and also their comparative treatments. Greenfield et al. compared verapamil with saline in electromotive drug administration (EMDA) for PD. This study failed to show any statistically significant improvement in curvature⁴⁸. A randomised trial by Mehrsai et al. compared treatment in 60 patients treated with verapamil either via injection or EMDA. The authors found no significant difference in reduction of plaque size; however, they did note an 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°’ group was noted especially in the EMDA category. This improvement, however, was not quantified in more detail or statistically significant⁴⁹. Abern et al. compared verapamil, oral pentoxifylline, and L-arginine (group 1) against the same medical therapy and additional PTT (group 2). Both groups had improved penile curvature, and interestingly the PTT group (group 2) had less curvature improvement (11°) when compared to medical therapy and injections alone (15.1°). The authors did not complete any statistical comparison between the two groups⁵⁰.

Interferon α-2B

There have been no recent randomised placebo-controlled studies using interferon (IFN) α-2B. Kendirci et al. and Hellstrom et al. produced two placebo-controlled studies in 2005 and 2006, respectively. Kendirci et al. randomised 5 × 10⁶ IU of IFN against placebo with a total of six injections given once weekly. They showed a statistically significant improvement in penile curvature with IFN of 12° compared to 3.6° in the placebo group. Hellstrom et al. produced similar results to Kendirci with a similar improvement in curvature^51,52.

More recently, Yafi et al. compared IFN with PTT versus IFN alone. This retrospective study had no placebo arm but did show a marginal improvement in curvature of 8.1° in the IFN and traction group compared to 9.9° in the IFN group, respectively. This difference in outcomes between groups was not statistically significant⁵³.

The most recent publication regarding IFN injection therapy was a single-arm prospective non-randomised study performed by Sokhal et al. including 86 patients receiving 3 × 10⁶ IU of IFN once weekly for a 12-week period. Follow-up was limited to only 3 months; however, there was a statistically significant improvement in plaque size, curvature, and IIEF-5 and pain scores. Plaque length reduced from 12.9 mm to 4.3 mm, and curvature improved by 16.2° (34.8° reduced to 18.6°) over the 3-month treatment period⁵⁴.

Hyaluronic acid

Gennaro and colleagues conducted a prospective RCT comparing intralesional HA compared with placebo in 2012. This study comprised 86 patients, with the treatment arm undergoing a total of 30 HA (20 mg) injections over 6 months every 5–7 days. There was a statistically significant improvement in curvature, plaque size, and IIEF when compared to placebo. At 24 months, the curvature was improved by 47% in the treatment arm, which equated to 9°. In the placebo arm, there was a deterioration in curvature of 19° over the same follow-up period⁵⁵.

A single-arm, multicentre, pilot study was published by Zucchi et al. in 2016 and reported on outcomes from a 10-week cycle of HA (16 mg) intralesional injections in a total of 65 patients. They were able to demonstrate a statistically significant improvement in penile plaque length, curvature, IIEF, pain scores, and subjective outcome scores 2 months following the treatment regimen. Curvature was improved by 10° (from 30° to 20°) with no significant adverse events noted throughout the study⁵⁶.

The comparative study by Favilla et al. described previously in this paper also showed advantageous outcomes of HA when compared to verapamil therapy⁴⁷.

Penile traction devices

Mechanical therapy for PD as a treatment modality generally suffers from a lack of robust, randomised controlled studies⁵⁷. The purported mechanism of action of traction devices is likely to be secondary to cellular mechanotransduction. The mechanical strain on the cell body leads to multiple signal transduction pathways being activated, which is likely to lead to collagen degradation^58,59. They currently have a grade C recommendation by the EAU and ICSM and are not recommended by the AUA owing to a lack of supportive evidence^17–19.

Gontero et al. described a regime of increasing mechanical traction (Andropenis® extender device) for a median of 5.5 hours a day over a 6-month period. They were able to produce a marginal non-statistically significant improvement of 4° from 31° to 27° following treatment. There was no improvement in IIEF or penile plaque length; however, there was a statistically significant improvement in stretched penile length of 0.8 cm⁶⁰.

Using the same device (Andropenis® extender), Martínez-Salamanca and colleagues studied its use in the acute phase of PD over a 6-month period. This prospective non-randomised study compared traction to a non-intervention arm involving patients also considered to be in the acute phase over a 9-month period. In the treatment arm, the prescribed therapy was use of the device for 9 hours per day; however, because of poor adherence, average compliance was 4.6 hours. In the treatment arm, there was a reduction from 33° to 13°, resulting in a 20° curvature improvement. In contrast, the non-intervention arm had worsening curvature over the follow-up period, increasing by 23°. Outcomes were also improved in stretched penile length and IIEF scores in the treatment arm. There was, however, no statistical analysis comparing the two arms of the study, and potentially it is likely that the non-intervention group may have been on several oral therapies for PD⁶¹.

The first RCT of mechanical therapy has been published recently by Moncada et al. They conducted a study using the PeniMaster® PRO device compared to a control (non-intervention) group with promising results. A total of 93 patients were recruited and assigned to either arm of the study (47 in the treatment group and 43 controls). Follow-up was limited to 3 months, and treatment required use of the device for 3–8 hours daily. There was a clear reduction in penile curvature in the treatment group, which was directly correlated with adherence to device use. Overall reduction was significant at 31.2° (41.1%) compared to baseline, and there was no change in curvature in the control group. This reduction in curvature was enhanced when increasing the usage time. Greater than 6 hours’ use daily resulted in a 36.2° reduction compared to baseline (51.4%), whilst less than 4 hours produced a 19.7° improvement (28.8%). All of these results showed statistical significance. Furthermore, there was also increased stretched penile length and IIEF score. Outcomes overall are promising; however, 43% of patients noted adverse events, which were mainly glans numbness/oedema and local irritation. A total of 6.5% of patients (n = 3) in the treatment arm abandoned the study owing to these adverse events⁶².

More recently, Ziegelmann et al. published a further RCT using a novel mechanical device, RestoreX®. The newer device challenges some of the limitations seen with older, alternative traction devices, namely reduced usage times, increased comfort, and ability to bend the device to exert a focal, non-linear effect. The published trial studied 110 men using the device for only 30–90 minutes a day over a 3-month period. The study group was randomised 3:1 in favour of traction therapy. The results in this trial showed significant promise considering the observed shorter treatment times. A reduction in curvature of 11.7°, improvement in penile length of 1.5 cm, and improvement in IIEF score by 4.3 points were demonstrated⁶³. The control group showed no change in penile length, worsening IIEF, and an increase in curvature by 1.3°. Although this represents a relatively small study with short follow-up time, the results highlight potential positive efficacy and safety outcomes.

Alom et al. continued to study the benefits of the RestoreX® device alongside CCH injections⁶⁴. They performed a comparative cohort study assessing three groups of therapy: CCH alone (group 1, n = 52), CCH plus other mechanical traction devices (group 2, n = 45), and CCH with RestoreX® device (group 3, n = 16). CCH protocol was the same across all patients and used the time schedule described in the IMPRESS trial. However, instead of two injections 24–72 hours per treatment, a single injection of 0.9 mg was used. Various mechanical devices were used in group 2, including the Andropenis® extender as well as the PeniMaster® PRO, which are described earlier in this review. All of these alternative devices required treatment for over 3 hours per day; however, compliance was very poor, with only 16% of this group reaching the required treatment time (median 1.5 hours). In comparison, the RestoreX® group saw a treatment compliance of 97% (median 0.9 hours). The study highlighted an improvement in curvature, which was statistically significant in all groups. Group 1 were able to achieve a 16.5° improvement, group 2 a 20° improvement, and group 3 a 30° improvement. The RestoreX® group also showed a greater improvement in length and various subjective assessments (improved penetration, feeling of meaningful improvement, and estimated percentage improvement) when compared to the other two groups. Overall, the study was able to show the largest degree of curvature change in the literature when compared to any other adjunctive treatment with CCH. It must be noted that these outcomes need to be reproduced in a RCT and in a larger cohort using the RestoreX® treatment group.

The above trials on mechanical therapies have been tabularised in Table 3 with a brief outline of the clinical outcomes.

Surgical techniques and outcomes

There have been no significant advances in PD surgical management in terms of randomised controlled data. In keeping with historical trends, there have been numerous retrospective reviews of modifications to traditional plication and grafting techniques. Nevertheless, plication remains the standard of care for patients without erectile dysfunction and a curvature of less than 60° provided that the associated loss of length is not problematic. Incision and grafting are indicated in patients falling outside these criteria, although plaque excision without grafting has been reported previously as a simplified technique⁶⁶.

Inflatable penile prosthesis (IPP) and manual remodelling have been re-assessed in a retrospective review by Chung et al. comparing choice of device manufacturer⁶⁷. They found high satisfaction (79%) and 5-year mechanical survival (87% or greater) in both AMS CX® and Coloplast Titan® devices as well as comparable revision and complication rates of below 10%. Further results regarding implant insertion and simultaneous plication demonstrated similar levels of satisfaction. Implant surgery remains the mainstay of treatment for patients with significant curvature and erectile dysfunction. Caution remains regarding a distinct lack of evidence to support universal surgical reconstruction in most men in order to provide safe and significant penile lengthening, as advocated by some surgeons globally.

Graft materials

Graft materials in those undergoing excision of the tunica albuginea in severe PD have been much debated and researched over recent years. The perfect graft material should be traction resistant, be easy to manipulate, and adhere to surrounding tissues with low risk of rejection. It should also be resistant to tension to prevent any aneurysmal dilation during normal erectile function. In addition, it should be economically viable and easily available. There has therefore been a large number of different grafting materials proposed and used in recent research for PD surgery including autografts, allografts, xenografts, and synthetics. Garcia-Gomez et al. recently reviewed the current evidence for all graft materials in tunica albuginea excision and grafting procedures. They concluded that the published series has significant heterogeneity in terms of patient selection, outcomes, and follow-up periods, therefore making definitive conclusions difficult. The authors did note that buccal mucosa, pericardium, porcine small intestinal submucosa (SIS), and TachoSil® are being used more extensively than most other materials, but unfortunately there is limited evidence to suggest one material over the other⁶⁸.

Of note, TachoSil®, which is a fibrin-coated collagen fleece, is becoming an increasingly studied graft material because of its surgical advantages (no requirement to suture graft material). Two comparative studies have reviewed TachoSil® and SIS in penile grafting procedures. Falcone et al. compared the graft materials after plaque incision during penile prosthesis implantation in 60 patients. They noted a reduced operative time in the TachoSil® group of 120 minutes compared to 145 minutes in the SIS cohort. There was no difference in functional outcomes or complication rate at 35 months between the two groups⁶⁹. Rosenhammer et al. produced a similar study with a matched-pair analysis to aid in comparative outcome measure. They retrospectively matched 43 patients who underwent penile plaque excision/incision and grafting using SIS with a prospectively collected cohort who had similar demographics and preoperative penile curvature undergoing the same procedure using TachoSil® as the graft material. Once again, operative times were significantly reduced in the TachoSil® group compared to SIS: 80 minutes and 104 minutes, respectively. The TachoSil® group also showed no evidence of recurrence compared to SIS (9%). Shortening was 28% in the SIS group compared to only 5% in the TachoSil® group, which was statistically significant. Complication rates were similar in both groups at under 10%⁷⁰.