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Comparative Effectiveness of Intralesional Therapy for Peyronie’s Disease in Controlled Clinical Studies: A Systematic Review and Network Meta-Analysis
PEYRONIE’S DISEASE
REVIEW
Comparative Effectiveness of Intralesional Therapy for Peyronie’s Disease in Controlled Clinical Studies: A Systematic Review and Network Meta-Analysis Giorgio Ivan Russo, MD, PhD,1 Giovanni Cacciamani, MD,2 Andrea Cocci, MD,3 Thomas M. Kessler, MD,4 Giuseppe Morgia, MD,1 Ege Can Serefoglu, MD, FECSM,5 Maarten Albersen, MD, PhD,6 and Paolo Verze, MD, PhD,7 on behalf of EAU-YAU Men’s Health Working Group
ABSTRACT
Introduction: Medical treatment of Peyronie’s disease (PD) in terms of intralesional therapy is still a matter of debate. Aim: To compare the efficacy of different classes of intralesional therapy with a network meta-analysis (NMA) method. Methods: The search was conducted using documents published in PubMed, Scopus, and Web of Science databases until September 30, 2017. We included randomized controlled trials comparing at least 1 intralesional therapy with a placebo therapy or with another drug for the treatment of PD. All intralesional therapies have been considered: collagenase Clostridium histolyticum (CCH), hyaluronic acid, verapamil, and interferon a-2b. Main Outcome Measure: Outcomes of the study are the mean change in penile curvature (PC) and in erectile function (EF) assessed with the International Index of Erectile Function questionnaire. Results: In total, 8 comparisons matched with the inclusion criteria, which includes 1,050 patients. With regard to PC (degree) improvement, hyaluronic acid and verapamil showed worse outcomes when compared with CCH (6.66 and 2.30) and interferon a-2b (6.75 and 2.38). When considering improvement in EF, hyaluronic acid, verapamil and interferon a-2b showed a slight increase in mean change when compared with CCH (þ2.39, þ1.77, and þ0.65). Moreover, verapamil and interferon a-2b showed slightly worse mean change in comparison to hyaluronic acid (þ0.62 and þ1.74), whereas interferon a-2b was worse than verapamil (1.12). Clinical Implications: Based on this NMA, empirical therapy for PD should be avoided to offer the patients the best treatment in terms of level of evidence. Strengths & Limitations: In this NMA, we have provided, for the first time, evidence of the efficacy between different intralesional therapies for the treatment of PD. We were not able to compare all specific outcomes (ie, pain, plaque size, patient satisfaction) of PD, because of the lack of homogeneity across relevant studies. Moreover, because of the few included studies, a meta-regression analysis of predictive factors of treatment response was not calculated. Conclusion: This is the first meta-analysis comparing all available intralesional treatments for PD. CCH and interferon a-2b showed the best outcome in terms of PC, whereas hyaluronic acid was most efficient in relation to EF. Russo GI, Cacciamani G, Cocci A, et al. Comparative Effectiveness of Intralesional Therapy for Peyronie’s Disease in Controlled Clinical Studies: A Systematic Review and Network Meta-Analysis. J Sex Med 2019;16:289e299. Received September 28, 2018. Accepted December 24, 2018.
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Urology sectioneUniversity of Catania, Catania, Italy;
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Urologic Clinic, University of Verona, Verona, Italy;
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Department of Urology, University of Florence, Italy;
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Department of Neuro-Urology, Spinal Cord Injury Center & Research, University of Zürich, Balgrist University Hospital, Zürich, Switzerland;
Department of Urology, University Hospitals Leuven, Leuven, Belgium;
Department of Neurosciences, Reproductive Sciences, Odontostomatology, Urology Unit, University of Naples, Naples, Italy
Copyright ª 2018, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jsxm.2018.12.011
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Department of Urology, Bagcilar Training and Research Hospital, Istanbul, Turkey;
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Copyright 2018, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. Keywords: Peyronie’s Disease; Penile Curvature; Intralesional Therapy; Verapamil; Collagenase; Hyaluronic Acid; Medical Therapy
INTRODUCTION Peyronie’s disease (PD) is considered a connective tissue disorder that affects the tunica albuginea of the penis. Until now, the etiology of the disease is still unknown, but repetitive injuries of micro vessels has been considered as a hypothesis.1e3 Understanding the pathogenesis of PD has contributed to different attempted intervention strategies for patients, including oral, transdermal, and intralesional therapies.4e6 Unfortunately, until now, the lack of level 1 evidence of the best intralesional treatment has determined the diffusion of heterogeneity between protocols. Recently, collagenase Clostridium histolyticum (CCH), a purified mixture of 2 microbial collagenase AUX-I and -II, has been introduced in the market, thanks to the ability to degrade the predominant collagen types found in PD plaques.7,8 The clinical benefits of intralesional therapy are secondary to the adequate drug penetration inside the plaque that may significantly slow, prevent, or reverse PD plaque formation.9 Intralesional injection therapy with CCH was approved by the US Food and Drug Administration for the treatment of adult men with PD with a palpable plaque and curvature deformity of at least 30 at the start of therapy. CCH studies, including the Maximal Peyronie’s Reduction Efficacy and Safety Studies I and II randomized clinical trials, showed significant improvement in both penile curvature deformity and PD-specific psychosexual aspects (ie, Peyronie’s Disease Questionnaire PD Symptom Bother domain score), when compared with placebo treatments.3,4 However, very few studies have been conducted with standardized methods in comparison to placebo or other drug regimens. Consequently, there is no meta-analysis in the literature comparing all regimens for PD. In this regard, network meta-analysis (NMA) may be helpful in synthesizing data from a network of trials involving more than 2 competing healthcare interventions. The integration of direct evidence (from studies directly comparing interventions) with indirect evidence (information about 2 treatments derived via a common comparator) increases the precision in the estimates and produces a relative ranking of all treatments for the studied outcome.10
Aim The aim of our NMA was to analyze the clinical efficacy of intralesional therapies for PD in randomized controlled trials in terms of improvement of penile curvature (PC) and erectile function.
METHODS This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses Statement.11 A PICO review protocol has been created by the authors, and the study was registered at PROSPERO (CRD42017077050).
Search Strategy and Selection Criteria The search was conducted using studies in Medline, Scopus, and Web of Science databases published until September 30, 2017, without restriction on year of publication and using the following search terms for each database: "Peyronie’s" OR "Peyronie’s disease" OR "penile curvature" and "medical therapy" OR "treatment" OR "intralesional" OR "intralesional therapy" OR "management." Additional relevant studies were also searched from reference lists of retrieved articles and reviews selected. Randomized controlled trials were also included, comparing at least 1 intralesional therapy with a placebo or with another drug in the treatment of PD. Any crossover trials, case-series studies, single-arm studies, open-label studies, and studies without sufficient data were excluded to construct the NMA. All intralesional therapies were considered: CCH, hyaluronic acid, verapamil, and interferon a-2b. In case of overlapping data on the same study protocol, the most complete report was chosen.
Outcome Measures and Data Extraction Data were extracted in duplicate by 2 researchers (G.C. and G.I.R.), and a third reviewer (E.S.) resolved any disagreements. Continuous data, including summary estimates per group (mean, changes in means) with measures of variability (SD, 95% CI), were extracted as available. The primary efficacy outcome of the study was represented by the change in PC from baseline to final follow-up. The secondary efficacy outcome was represented by the change from baseline to study end in the Erectile Function domain score of the International Index of Erectile Function (IIEF). The geometric plot of the comparison network for the included studies was constructed.
Quality of Evidence The quality of the evidence from direct evidence and NMA was assessed by using risk analysis, which is the recommended approach for assessing risk of bias in studies included in Cochrane reviews. There are 4 levels of quality of evidence: high, moderate, low, and very low.12 The quality of evidence for each outcome was based on 5 domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias.
Statistical Analysis The pooled data were analyzed for all treatments with random effects models, within a Bayesian framework, using Stata J Sex Med 2019;16:289e299
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Figure 1. PRISMA flowchart of included studies. Figure 1 is available in color online at www.jsm.jsexmed.org. software, version 14 (StataCorp LP, College Station, TX, USA). Summary effect sizes were calculated as weighted mean difference for PC (degree) and IIEF with 95% prediction intervals.13 The surface under the cumulative ranking curve (SUCRA) was also calculated for different treatments.10 This tool ranges from 0e100%, where 100% reflects the best treatment with no uncertainty and 0% reflects the worst treatment with no uncertainty.10 Publication bias was examined through visual inspection of the funnel plot.
RESULTS Figure 1 shows the flowchart of the search according to the PRISMA statement. In total, 1,721 articles were identified after the electronic search in PubMed (n ¼ 646), Scopus (n ¼ 629), and Web of Science (n ¼ 446). After the global assessment, 8 comparisons matched with the inclusion criteria, including 1,050 patients (Figure 1). Table 1 lists the characteristics of included studies. Figure 2 shows the geometric plot and the contribution plot of the comparison NMA for the included studies.14e20
Data Synthesis and Analysis The mean age range of patients tested with CCH, hyaluronic acid, verapamil, and interferon a -2b ranged from 52.0e58.2 years. The protocol of infiltration for CCH (0.58 mg) was 4 treatment cycles, each separated by 6 weeks, with 2 injections per cycle separated by approximately 24e72 hours, with the second injection of each followed 24e72 hours later by penile plaque modeling.15 The protocol for interferon a-2b was biweekly for 12 weeks17 or weekly for 6 weeks,18 with a dose of 5 106 U; once a week for 6 months,19 twice weekly for 12 weeks,20 or once a week for 12 weeks,14 with 10 mg of verapamil. Hyaluronic acid has 2 methods; for the first 12 weeks, every 5 days, J Sex Med 2019;16:289e299
and from week 13, every 7 days with the molecular weight of hyaluronic acid between 0.5e1.2 million Daltons 16 or weekly for 12 weeks with 0.8% highly purified sodium salt hyaluronic acid at 16 mg/2 mL.14 The mean follow-up ranged from 3e13 months. There was some heterogeneity between studies based on duration of protocol and follow-up. Figures 3 and 4 show the risk of bias according to the included studies. We found consistent heterogeneity between studies. With regard to PC improvement (degree), Figure 5 shows the forest plot for overall efficacy. The black solid lines represent the confidence intervals for summary mean between treatment, and the red dashed lines represent the respective predictive intervals. Table 2 lists the summary of mean changes for penile curvature and erectile function for all treatments. In detail, the mean efficacies vs placebo treatments were as follow: CCH 0.41 (95% CI 19.0 to 18.17), hyaluronic acid 6.25 (95% CI 13.56 to 6.06), verapamil 1.88 (95% CI 14.56 to 18.32), and interferon a-2b 0.50 (95% CI 18.47 to 17.47). For mean changes against CCH, hyaluronic acid and verapamil showed worse outcomes, 6.66 (95% CI 20.50 to 33.83) and 2.30 (95% CI 22.52 to 27.11), whereas interferon a-2b exhibited similar results (mean change: 0.09; [95% CI 25.94 to 25.76]). Compared with the mean changes against hyaluronic acid, verapamil and interferon a-2b showed better penile curvature improvement, 4.37 (95% CI 24.17 to 15.43) and 6.75 (95% CI 33.49 to 20.00), respectively. Finally, interferon a-2b showed better improvement than verapamil (mean change 2.38; [95% CI 26.74 to 21.97]). When considering the improvement of erectile function assessed through the IIEF questionnaire, the mean efficacies
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Table 1. Main characteristics of included comparative studies Study
Year Design
Number of Interventions patients
57.46 ± 10.19 (Ver); 55.14 ± 10.93 (HA) CCH vs 401 (CCH); 57.6 ± 8.5 Placebo 211 (CCH); (Placebo) 57.9 ± 8.3 (Placebo) HA vs 83 (HA); 81 56.59 ± 10.59 Control (Control) (HA); 56.33 ± 8.25 (Control) IFN a-2b 53 (IFN a-2b); Overall: 55.1 vs 50 years Placebo (Placebo) (range 30 to 75) IFN a-2b vs 19 (IFN a-2b); 56.80 ± 2.29 Placebo 20 (IFN a-2b); (Placebo) 54.60 ± 1.95 (Placebo)
Favilla et al14
2017 Randomized Ver vs HA
Gelbard et al15
2013 Randomized
Gennaro et al16
2015 Prospective Controlled study
Hellstrom 2006 Randomized et al17
Kendirci et al18
2005 Randomized
Mean age (years)
69 (Ver); 63 (HA)
Baseline penile curvature
Baseline erectile function
Post-treatment erectile function
Post-treatment penile curvature
Followup
90.5 30 (Ver); 0.0 ± 0.0 (Ver); 19.22 (IIEF-5) ± 5.25 Changes: 1.16 4.60 ± 5.63 95.7% 30 (HA) (Ver); 19.44 ± 3.95 (IIEF-5) ± 1.94 (HA) (HA) (Ver); 1.78 ± 2.48 (HA) 50.1 ± 14.4 (CCH); 5.6 ± 2.4 (CCH); Changes: 1.0 ± 2.4 33.1 ± 16.8 (CCH); 49.3 ± 14.0 5.6 ± 2.5 (CCH); 0.4 ± 2.4 40.0 ± 16.2 (Placebo) (Placebo) (Placebo) (Placebo)
12 wks
13 wks
21.52 ± 7.27 (HA); 21.88 ± 11.16 (Control)
21.41 ± 3.54 (HA); 21.31 ± 4.02 (Control)
0.0 ± 0.0 Changes: 0 ± 1.24 (HA); 1.77 ± 2.77 (HA); þ15.37 ± 16.00 (Control) (Control)
49.9 ± 2.4 (IFN a-2b); 50.9 ± 2.5 (Placebo) 48.75 ± 4.41 (IFN a-2b); 47.75 ± 2.84 (Placebo)
18.32 ± 1.21 (IFN a-2b); 17.98 ± 1.33 (Placebo) 17.85 ± 1.67 (IFN a-2b); 17.65 ± 1.52 (Placebo)
20.80 ± 1.19 (IFN a-2b); 19.05 ± 1.32 (Placebo) 21.10 ± 1.56 (IFN a-2b); 19.05 ± 1.48 (Placebo)
36.4 ± 2.1 (IFN a-2b); 46.4 ± 2.2 (Placebo) 36.75 ± 4.53 (IFN a-2b); 44.10 ± 3.02 (Placebo)
52 wks
6 wks
6 wks
CCH ¼ collagenase Clostriudium hystoliticum; HA ¼ hyaluronic acid; IFN a-2b ¼ interferon a-2b; Ver ¼ verapamil.
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interferon a-2b (mean change 0.65 [95% CI 0.06e1.25]) showed a slight increase in mean efficacy with respect to CCH. Moreover, verapamil and Interferon a-2b showed slightly worse mean change when compared with hyaluronic acid, 0.62 (95% CI 1.38 to 0.14) and 1.74 (95% CI 2.52, 0.95), and interferon a-2b was worse than verapamil, 1.12 (95% CI 2.21, 0.02) (Figure 6).
Figure 2. Plot of the acute mania network (efficacy outcome) using colored edges according to adequacy of allocation concealment estimated as the level of bias in many of the trials and weighted according to the number of studies in each comparison. Figure 2 is available in color online at www.jsm.jsexmed.org.
compared with placebo treatments were as follow: CCH 0.61 (95% CI 1.01, 0.20), hyaluronic acid 1.78 (95% CI 1.31e2.43), verapamil 1.16 (95% CI 0.16e2.16), and interferon a-2b 0.04 (95% CI 0.39 to 0.48). When considering the comparison among active treatments, hyaluronic acid (mean change: 2.39 [95% CI 1.62-3.15]), verapamil (mean change 1.77 [95% CI 0.69e2.85]), and
Based on the SUCRA rankograms, interferon a-2b and CCH showed the highest scores, 56.9% and 56.3%, respectively, compared with other active treatments, 48.5% for verapamil and 30.7% for hyaluronic acid (Figure 7). The SUCRA is a numeric representation of the overall ranking and presents a single number associated with each treatment. The higher the SUCRA value, and the closer to 100%, the higher the likelihood that a therapy is in the top rank or 1 of the top ranks. The closer to 0 the SUCRA value is, the more likely that a therapy is in the bottom rank, or 1 of the bottom ranks, when using a placebo treatment as comparator. Finally, Figure 8 shows the net-funnel plot for all included studies, demonstrating diffused heterogeneity between comparisons.
DISCUSSION In this NMA, we have provided, for the first time, evidence about the efficacy between different intralesional therapies for the treatment of PD. For those patients, prioritizing efficacy of PC,
Figure 3. Contribution plot for the network meta-analysis. The size of each square is proportional to the weight attached to each direct summary effect (horizontal axis) for the estimation of each network summary effects (vertical axis). The numbers re-express the weights as percentages. Hyal ¼ hyaluronic acid; Interf ¼ interferon a-2b; Pla ¼ placebo; Ver ¼ verapamil. Figure 3 is available in color online at www.jsm.jsexmed.org. J Sex Med 2019;16:289e299
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Figure 4. Panel a shows a risk of bias graph. Review authors’ judgments about each risk of bias item presented as percentages across all included studies. Panel b shows a risk of bias summary. Review authors’ judgments about each risk of bias item presented as percentages across all included studies. Figure 4 is available in color online at www.jsm.jsexmed.org. J Sex Med 2019;16:289e299
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Figure 5. Network meta-analysis for penile curvature improvement for different treatment effects. Hyal ¼ hyaluronic acid; Interf ¼ interferon a-2b; Pla ¼ placebo; Ver ¼ verapamil. Figure 5 is available in color online at www.jsm.jsexmed.org. CCH and IFN a-2b seems to be the best treatment of choice. On the other hand, for men wishing to receive benefit in terms of erectile function, hyaluronic acid shows better clinical outcomes. Many conservative treatment options have been tried, including extracorporeal shockwave therapy; iontophoresis; and intralesional, topical, and oral agents.21 However, among all literature data, no meta-analysis has been performed because of the lack of large and well-designed clinical trials. In this context, new drugs have been introduced in the market, but no direct comparisons with previous empirical protocol have been performed. We should also consider that some treatment could be considered historical. In a recent survey by Bole et al,22 53% (86 of 162) of men had tried at least 1 therapy for their PD, whereas 20% (32 of 162) had tried 2 treatments. Surprisingly, nearly half of the men (47%; 76 of
162) elected never to pursue treatment for their PD. Among those who chose to pursue treatment, vacuum erection devices were the most commonly used modality (50%, 43 of 86), followed by oral medications (34.9%, 30 of 86) and surgery (33.7%, 29of 86). However, details on characteristics of drugs were lacking. Recently, CCH (Xiapex, Swedish Orphan Biovitrum AB, Stockholm, Sweden; Xiaflex, Endo Pharmaceuticals, Malvern, PA, USA) is the first treatment approved by the US Food and Drug Administration and the European Medicines Agency for the non-surgical management of PD. CCH is an intralesional drug injected into the Peyronie’s plaque in men with stable disease and a curvature of 30 to 90 .23,24 The only 2 clinical trials included in the present NMA that analyzed CCH are the Maximal Peyronie’s Reduction Efficacy
Table 2. Summary of results for penile curvature and erectile function after the network meta-analysis for all treatments Erectile function†
Penile curvature (degrees)* Drug
CCH
IFN a-2b
HA
Verapamil
CCH
IFN a-2b
HA
Verapamil
CCH IFN a-2b HA Verapamil
— 0.09 þ6.66 þ2.30
þ0.09 — þ6.75 þ2.38
6.66 6.75 — 4.37
2.30 2.38 þ4.37 —
— þ0.65 þ2.39 þ1.77
0.65 — þ1.74 þ1.12
2.39 1.74 — 0.62
1.77 1.12 þ0.62 —
CCH ¼ collagenase Clostriudium hystoliticum; HA ¼ hyaluronic acid; IFN a-2b ¼ interferon a-2b. *Minus sign () means a greater decrease in penile curvature for the drug on the left side; plus sign (þ) means a worse penile curvature for the drug on the left side. † Minus sign () means a worse erectile function for the drug on the left side; plus sign (þ) means a greater increase in erectile function for the drug on the left side. J Sex Med 2019;16:289e299
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Figure 6. Network meta-analysis for IIEF-5 improvement for different treatment effects. Hyal ¼ hyaluronic acid; Interf ¼ interferon a-2b; Pla ¼ placebo; Ver ¼ verapamil. Figure 6 is available in color online at www.jsm.jsexmed.org.
Figure 7. Plots of the surface under the cumulative ranking probability for all treatments in the Peyronie’s disease network. The area under the curve represents the cumulative rank probability of each treatment (the larger the better). Figure 7 is available in color online at www. jsm.jsexmed.org.
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Figure 8. Comparison-adjusted funnel plot for the Peyronie’s disease network.The gray line represents the null hypothesis that the study-specific effect sizes do not differ from the respective comparison-specific pooled effect estimates. Different colors correspond to different comparisons. Figure 8 is available in color online at www.jsm.jsexmed.org.
and Safety Studies I and II, which are 2 large, randomized, controlled, phase III clinical trials investigating intralesional CCH injection in men with PD. The treatment protocol consisted of 4 cycles, 6 weeks apart, of intralesional CCH (0.58 mg), followed by investigator modeling of the penis. Interestingly, the authors demonstrated a mean 34% improvement in PC, compared with a mean 18.2% improvement in placebo-treated men (P < .0001), whereas the change of erectile function was not superior compared with placebo treatment when both trials were considered separately. The benefits of CCH are mainly due to the disruption of the collagen Peyronie’s plaque.25 Taking into consideration hyaluronic acid, preliminary results for improvement of plaque size, PC, and overall sexual satisfaction have been previously reported.26 Only 1 study by Gennaro et al16 showed a benefit of HA over placebo drugs, whereas 1 other study by Favilla et al,14 comparing HA vs verapamil, found advantages of HA only in terms of PC and patient satisfaction. In this context, the benefits of HA are hypothesized to be secondary to the decrease of oxygen-free radicals and inhibition of apoptosis, promoting cell survival and decreased concentrations of inflammatory proteins.27 Among the other compared drugs, interferon a-2b is thought to improve PC and reduce plaque size in PD,28 whereas verapamil is thought to modify the inflammatory response in the early phase of the disorder and the inhibition of fibroblast proliferation in the plaques.29 Although differences among all intralesional drugs should be taken into account when considering the clinical outcomes, no J Sex Med 2019;16:289e299
meta-analysis has been conducted up to now. Therefore, herein we provide direct and indirect comparisons between these drugs, offering both physicians and patients a tool for choosing the best relevant treatment for PD. Despite the lack of comparative clinical trials between CCH and hyaluronic acid, we postulate that the differences among clinical efficacies could be attributable to the different mechanism of action. However, we would also point out some limitations. Unfortunately, we were not able to compare all specific outcomes (ie, pain, plaque size, patients’ satisfaction) of PD, because of the lack of homogeneity across relevant studies. Moreover, because of the few included studies, a meta-regression analysis of predictive factors of treatment response was not calculated. For the efficacy analysis, we pooled 4 outcomes, because efficacy endpoints varied between studies, but all are clinically relevant. Finally, we did not analyze adverse effects of drugs because of the low number of reported events in the studies.
Implications for the Future On the basis of this NMA, empirical therapy for PD should be avoided to offer the patients the best treatment in terms of level of evidence. We agree that the low number of included studies may represent a limitation to draw definitive conclusions about intralesional therapies for PD. However, CCH and interferon a-2b proved to offer the best benefit for PC, whereas hyaluronic acid is best for erectile function, respectively. We recommend further placebo-controlled prospective clinical trials to confirm
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our findings and draw definite conclusions. Future research should develop new drugs acting against specific targets of the disease.
CONCLUSIONS Our data suggest that, among all treatments for PD, CCH and interferon a-2b offer the best benefit for PC, whereas hyaluronic acid is best for erectile function. Urologists should discuss medical therapy with patients before surgical correction, as well as the target of improvement that they expect to obtain. Corresponding Author: Giorgio Ivan Russo, MD, PhD, Urology Section—University of Catania, Via Santa Sofia 78, 95125 Catania, Italy. Tel: 39 0953782710; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Funding: None.
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Giorgio Ivan Russo (b) Acquisition of Data Giorgio Ivan Russo; Giovanni Cacciamani; Andrea Cocci (c) Analysis and Interpretation of Data Giorgio Ivan Russo Category 2 (a) Drafting the Article Giorgio Ivan Russo; Paolo Verze (b) Revising the Article for Intellectual Content Thomas M. Kessler; Giuseppe Morgia; Ege Can Serefoglu; Maarten Albersen; Paolo Verze Category 3 (a) Final Approval of the Completed Article Giorgio Ivan Russo; Giovanni Cacciamani; Andrea Cocci; Thomas M. Kessler; Giuseppe Morgia; Ege Can Serefoglu; Maarten Albersen; Paolo Verze
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Russo et al 5. Cocci A, Cito G, Urzi D, et al. Sildenafil 25 mg ODT þ collagenase Clostridium hystoliticum vs collagenase Clostridium hystoliticum alone for the management of Peyronie’s disease: A matched-pair comparison analysis. J Sex Med 2018; 15:1472-1477. 6. Russo GI, Milenkovic U, Hellstrom W, et al. Clinical efficacy of injection and mechanical therapy for Peyronie’s disease: A systematic review of the literature. Eur Urol 2018; 74:767-781. 7. Desai SS, Hentz VR. Collagenase Clostridium histolyticum for Dupuytren’s contracture. Expert Opin Biol Ther 2010; 10:1395-1404. 8. Carson CC 3rd, Sadeghi-Nejad H, Tursi JP, et al. Analysis of the clinical safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for adults with Peyronie’s disease (PD). BJU Int 2015;116:815-822. 9. Talib RA, Ibrahim MA, Canguven O. Nonsurgical treatment options in Peyronie’s Disease: 2016 update. Turk J Urol 2016; 42:217-223. 10. Chaimani A, Higgins JP, Mavridis D, et al. Graphical tools for network meta-analysis in STATA. PLoS One 2013; 8:e76654. 11. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535. 12. Puhan MA, Schunemann HJ, Murad MH, et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ 2014; 349:g5630. 13. Salanti G, Dias S, Welton NJ, et al. Evaluating novel agent effects in multiple-treatments meta-regression. Stat Med 2010;29:2369-2383. 14. Favilla V, Russo GI, Zucchi A, et al. Evaluation of intralesional injection of hyaluronic acid compared with verapamil in Peyronie’s disease: Preliminary results from a prospective, double-blinded, randomized study. Andrology 2017; 5:771-775. 15. Gelbard M, Goldstein I, Hellstrom WJ, et al. Clinical efficacy, safety and tolerability of collagenase clostridium histolyticum for the treatment of peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3 studies. J Urol 2013;190:199-207. 16. Gennaro R, Barletta D, Paulis G. Intralesional hyaluronic acid: an innovative treatment for Peyronie’s disease. Int Urol Nephrol 2015;47:1595-1602. 17. Hellstrom WJ, Kendirci M, Matern R, et al. Single-blind, multicenter, placebo controlled, parallel study to assess the safety and efficacy of intralesional interferon alpha-2B for minimally invasive treatment for Peyronie’s disease. J Urol 2006;176:394-398. 18. Kendirci M, Usta MF, Matern RV, et al. The impact of intralesional interferon alpha-2b injection therapy on penile hemodynamics in men with Peyronie’s disease. J Sex Med 2005;2:709-715.
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Intralesional Therapy for Peyronie’s Disease 19. Rehman J, Benet A, Melman A. Use of intralesional verapamil to dissolve Peyronie’s disease plaque: A long-term single-blind study. Urology 1998;51:620-626. 20. Shirazi M, Haghpanah AR, Badiee M, et al. Effect of intralesional verapamil for treatment of Peyronie’s disease: a randomized single-blind, placebo-controlled study. Int Urol Nephrol 2009;41:467-471. 21. Abdel Raheem A, Johnson M, Abdel-Raheem T, et al. Collagenase Clostridium histolyticum in the treatment of Peyronie’s disease—A review of the literature and a new modified protocol. Sex Med Rev 2017;5:529-535. 22. Bole R, Ziegelmann M, Avant R, Montgomery B, Kohler T, Trost L. Int J Impot Res 2018;30:243-248. 23. Abdel Raheem A, Capece M, Kalejaiye O, et al. Safety and effectiveness of collagenase clostridium histolyticum in the treatment of Peyronie’s disease using a new modified shortened protocol. BJU Int 2017;120:717-723. 24. Cocci A, Russo GI, Briganti A, et al. Predictors of treatment success after collagenase Clostridium histolyticum injection for Peyronie’s disease: Development of a nomogram from a
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299 multicentre single-arm, non-placebo controlled clinical study. BJU Int 2018;122:680-687. 25. Herati AS, Pastuszak AW. The genetic basis of Peyronie disease: A review. Sex Med Rev 2016;4:85-94. 26. Zucchi A, Costantini E, Cai T, et al. Intralesional injection of hyaluronic acid in patients affected with Peyronie’s Disease: Preliminary Results From a Prospective, Multicenter, Pilot Study. Sex Med 2016;4:e83-e88. 27. Yu CJ, Ko CJ, Hsieh CH, et al. Proteomic analysis of osteoarthritic chondrocyte reveals the hyaluronic acid-regulated proteins involved in chondroprotective effect under oxidative stress. J Proteomics 2014;99:40-53. 28. Joice GA, Burnett AL. Nonsurgical Interventions for Peyronie’s disease: Update as of 2016. World J Mens Health 2016; 34:65-72. 29. Favilla V, Russo GI, Privitera S, et al. Combination of intralesional verapamil and oral antioxidants for Peyronie’s disease: A prospective, randomised controlled study. Andrologia 2014; 46:936-942.
REVIEW
Comparative Effectiveness of Intralesional Therapy for Peyronie’s Disease in Controlled Clinical Studies: A Systematic Review and Network Meta-Analysis Giorgio Ivan Russo, MD, PhD,1 Giovanni Cacciamani, MD,2 Andrea Cocci, MD,3 Thomas M. Kessler, MD,4 Giuseppe Morgia, MD,1 Ege Can Serefoglu, MD, FECSM,5 Maarten Albersen, MD, PhD,6 and Paolo Verze, MD, PhD,7 on behalf of EAU-YAU Men’s Health Working Group
ABSTRACT
Introduction: Medical treatment of Peyronie’s disease (PD) in terms of intralesional therapy is still a matter of debate. Aim: To compare the efficacy of different classes of intralesional therapy with a network meta-analysis (NMA) method. Methods: The search was conducted using documents published in PubMed, Scopus, and Web of Science databases until September 30, 2017. We included randomized controlled trials comparing at least 1 intralesional therapy with a placebo therapy or with another drug for the treatment of PD. All intralesional therapies have been considered: collagenase Clostridium histolyticum (CCH), hyaluronic acid, verapamil, and interferon a-2b. Main Outcome Measure: Outcomes of the study are the mean change in penile curvature (PC) and in erectile function (EF) assessed with the International Index of Erectile Function questionnaire. Results: In total, 8 comparisons matched with the inclusion criteria, which includes 1,050 patients. With regard to PC (degree) improvement, hyaluronic acid and verapamil showed worse outcomes when compared with CCH (6.66 and 2.30) and interferon a-2b (6.75 and 2.38). When considering improvement in EF, hyaluronic acid, verapamil and interferon a-2b showed a slight increase in mean change when compared with CCH (þ2.39, þ1.77, and þ0.65). Moreover, verapamil and interferon a-2b showed slightly worse mean change in comparison to hyaluronic acid (þ0.62 and þ1.74), whereas interferon a-2b was worse than verapamil (1.12). Clinical Implications: Based on this NMA, empirical therapy for PD should be avoided to offer the patients the best treatment in terms of level of evidence. Strengths & Limitations: In this NMA, we have provided, for the first time, evidence of the efficacy between different intralesional therapies for the treatment of PD. We were not able to compare all specific outcomes (ie, pain, plaque size, patient satisfaction) of PD, because of the lack of homogeneity across relevant studies. Moreover, because of the few included studies, a meta-regression analysis of predictive factors of treatment response was not calculated. Conclusion: This is the first meta-analysis comparing all available intralesional treatments for PD. CCH and interferon a-2b showed the best outcome in terms of PC, whereas hyaluronic acid was most efficient in relation to EF. Russo GI, Cacciamani G, Cocci A, et al. Comparative Effectiveness of Intralesional Therapy for Peyronie’s Disease in Controlled Clinical Studies: A Systematic Review and Network Meta-Analysis. J Sex Med 2019;16:289e299. Received September 28, 2018. Accepted December 24, 2018.
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1
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Urology sectioneUniversity of Catania, Catania, Italy;
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Urologic Clinic, University of Verona, Verona, Italy;
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Department of Urology, University of Florence, Italy;
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Department of Neuro-Urology, Spinal Cord Injury Center & Research, University of Zürich, Balgrist University Hospital, Zürich, Switzerland;
Department of Urology, University Hospitals Leuven, Leuven, Belgium;
Department of Neurosciences, Reproductive Sciences, Odontostomatology, Urology Unit, University of Naples, Naples, Italy
Copyright ª 2018, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jsxm.2018.12.011
5
Department of Urology, Bagcilar Training and Research Hospital, Istanbul, Turkey;
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Copyright 2018, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. Keywords: Peyronie’s Disease; Penile Curvature; Intralesional Therapy; Verapamil; Collagenase; Hyaluronic Acid; Medical Therapy
INTRODUCTION Peyronie’s disease (PD) is considered a connective tissue disorder that affects the tunica albuginea of the penis. Until now, the etiology of the disease is still unknown, but repetitive injuries of micro vessels has been considered as a hypothesis.1e3 Understanding the pathogenesis of PD has contributed to different attempted intervention strategies for patients, including oral, transdermal, and intralesional therapies.4e6 Unfortunately, until now, the lack of level 1 evidence of the best intralesional treatment has determined the diffusion of heterogeneity between protocols. Recently, collagenase Clostridium histolyticum (CCH), a purified mixture of 2 microbial collagenase AUX-I and -II, has been introduced in the market, thanks to the ability to degrade the predominant collagen types found in PD plaques.7,8 The clinical benefits of intralesional therapy are secondary to the adequate drug penetration inside the plaque that may significantly slow, prevent, or reverse PD plaque formation.9 Intralesional injection therapy with CCH was approved by the US Food and Drug Administration for the treatment of adult men with PD with a palpable plaque and curvature deformity of at least 30 at the start of therapy. CCH studies, including the Maximal Peyronie’s Reduction Efficacy and Safety Studies I and II randomized clinical trials, showed significant improvement in both penile curvature deformity and PD-specific psychosexual aspects (ie, Peyronie’s Disease Questionnaire PD Symptom Bother domain score), when compared with placebo treatments.3,4 However, very few studies have been conducted with standardized methods in comparison to placebo or other drug regimens. Consequently, there is no meta-analysis in the literature comparing all regimens for PD. In this regard, network meta-analysis (NMA) may be helpful in synthesizing data from a network of trials involving more than 2 competing healthcare interventions. The integration of direct evidence (from studies directly comparing interventions) with indirect evidence (information about 2 treatments derived via a common comparator) increases the precision in the estimates and produces a relative ranking of all treatments for the studied outcome.10
Aim The aim of our NMA was to analyze the clinical efficacy of intralesional therapies for PD in randomized controlled trials in terms of improvement of penile curvature (PC) and erectile function.
METHODS This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses Statement.11 A PICO review protocol has been created by the authors, and the study was registered at PROSPERO (CRD42017077050).
Search Strategy and Selection Criteria The search was conducted using studies in Medline, Scopus, and Web of Science databases published until September 30, 2017, without restriction on year of publication and using the following search terms for each database: "Peyronie’s" OR "Peyronie’s disease" OR "penile curvature" and "medical therapy" OR "treatment" OR "intralesional" OR "intralesional therapy" OR "management." Additional relevant studies were also searched from reference lists of retrieved articles and reviews selected. Randomized controlled trials were also included, comparing at least 1 intralesional therapy with a placebo or with another drug in the treatment of PD. Any crossover trials, case-series studies, single-arm studies, open-label studies, and studies without sufficient data were excluded to construct the NMA. All intralesional therapies were considered: CCH, hyaluronic acid, verapamil, and interferon a-2b. In case of overlapping data on the same study protocol, the most complete report was chosen.
Outcome Measures and Data Extraction Data were extracted in duplicate by 2 researchers (G.C. and G.I.R.), and a third reviewer (E.S.) resolved any disagreements. Continuous data, including summary estimates per group (mean, changes in means) with measures of variability (SD, 95% CI), were extracted as available. The primary efficacy outcome of the study was represented by the change in PC from baseline to final follow-up. The secondary efficacy outcome was represented by the change from baseline to study end in the Erectile Function domain score of the International Index of Erectile Function (IIEF). The geometric plot of the comparison network for the included studies was constructed.
Quality of Evidence The quality of the evidence from direct evidence and NMA was assessed by using risk analysis, which is the recommended approach for assessing risk of bias in studies included in Cochrane reviews. There are 4 levels of quality of evidence: high, moderate, low, and very low.12 The quality of evidence for each outcome was based on 5 domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias.
Statistical Analysis The pooled data were analyzed for all treatments with random effects models, within a Bayesian framework, using Stata J Sex Med 2019;16:289e299
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Figure 1. PRISMA flowchart of included studies. Figure 1 is available in color online at www.jsm.jsexmed.org. software, version 14 (StataCorp LP, College Station, TX, USA). Summary effect sizes were calculated as weighted mean difference for PC (degree) and IIEF with 95% prediction intervals.13 The surface under the cumulative ranking curve (SUCRA) was also calculated for different treatments.10 This tool ranges from 0e100%, where 100% reflects the best treatment with no uncertainty and 0% reflects the worst treatment with no uncertainty.10 Publication bias was examined through visual inspection of the funnel plot.
RESULTS Figure 1 shows the flowchart of the search according to the PRISMA statement. In total, 1,721 articles were identified after the electronic search in PubMed (n ¼ 646), Scopus (n ¼ 629), and Web of Science (n ¼ 446). After the global assessment, 8 comparisons matched with the inclusion criteria, including 1,050 patients (Figure 1). Table 1 lists the characteristics of included studies. Figure 2 shows the geometric plot and the contribution plot of the comparison NMA for the included studies.14e20
Data Synthesis and Analysis The mean age range of patients tested with CCH, hyaluronic acid, verapamil, and interferon a -2b ranged from 52.0e58.2 years. The protocol of infiltration for CCH (0.58 mg) was 4 treatment cycles, each separated by 6 weeks, with 2 injections per cycle separated by approximately 24e72 hours, with the second injection of each followed 24e72 hours later by penile plaque modeling.15 The protocol for interferon a-2b was biweekly for 12 weeks17 or weekly for 6 weeks,18 with a dose of 5 106 U; once a week for 6 months,19 twice weekly for 12 weeks,20 or once a week for 12 weeks,14 with 10 mg of verapamil. Hyaluronic acid has 2 methods; for the first 12 weeks, every 5 days, J Sex Med 2019;16:289e299
and from week 13, every 7 days with the molecular weight of hyaluronic acid between 0.5e1.2 million Daltons 16 or weekly for 12 weeks with 0.8% highly purified sodium salt hyaluronic acid at 16 mg/2 mL.14 The mean follow-up ranged from 3e13 months. There was some heterogeneity between studies based on duration of protocol and follow-up. Figures 3 and 4 show the risk of bias according to the included studies. We found consistent heterogeneity between studies. With regard to PC improvement (degree), Figure 5 shows the forest plot for overall efficacy. The black solid lines represent the confidence intervals for summary mean between treatment, and the red dashed lines represent the respective predictive intervals. Table 2 lists the summary of mean changes for penile curvature and erectile function for all treatments. In detail, the mean efficacies vs placebo treatments were as follow: CCH 0.41 (95% CI 19.0 to 18.17), hyaluronic acid 6.25 (95% CI 13.56 to 6.06), verapamil 1.88 (95% CI 14.56 to 18.32), and interferon a-2b 0.50 (95% CI 18.47 to 17.47). For mean changes against CCH, hyaluronic acid and verapamil showed worse outcomes, 6.66 (95% CI 20.50 to 33.83) and 2.30 (95% CI 22.52 to 27.11), whereas interferon a-2b exhibited similar results (mean change: 0.09; [95% CI 25.94 to 25.76]). Compared with the mean changes against hyaluronic acid, verapamil and interferon a-2b showed better penile curvature improvement, 4.37 (95% CI 24.17 to 15.43) and 6.75 (95% CI 33.49 to 20.00), respectively. Finally, interferon a-2b showed better improvement than verapamil (mean change 2.38; [95% CI 26.74 to 21.97]). When considering the improvement of erectile function assessed through the IIEF questionnaire, the mean efficacies
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Table 1. Main characteristics of included comparative studies Study
Year Design
Number of Interventions patients
57.46 ± 10.19 (Ver); 55.14 ± 10.93 (HA) CCH vs 401 (CCH); 57.6 ± 8.5 Placebo 211 (CCH); (Placebo) 57.9 ± 8.3 (Placebo) HA vs 83 (HA); 81 56.59 ± 10.59 Control (Control) (HA); 56.33 ± 8.25 (Control) IFN a-2b 53 (IFN a-2b); Overall: 55.1 vs 50 years Placebo (Placebo) (range 30 to 75) IFN a-2b vs 19 (IFN a-2b); 56.80 ± 2.29 Placebo 20 (IFN a-2b); (Placebo) 54.60 ± 1.95 (Placebo)
Favilla et al14
2017 Randomized Ver vs HA
Gelbard et al15
2013 Randomized
Gennaro et al16
2015 Prospective Controlled study
Hellstrom 2006 Randomized et al17
Kendirci et al18
2005 Randomized
Mean age (years)
69 (Ver); 63 (HA)
Baseline penile curvature
Baseline erectile function
Post-treatment erectile function
Post-treatment penile curvature
Followup
90.5 30 (Ver); 0.0 ± 0.0 (Ver); 19.22 (IIEF-5) ± 5.25 Changes: 1.16 4.60 ± 5.63 95.7% 30 (HA) (Ver); 19.44 ± 3.95 (IIEF-5) ± 1.94 (HA) (HA) (Ver); 1.78 ± 2.48 (HA) 50.1 ± 14.4 (CCH); 5.6 ± 2.4 (CCH); Changes: 1.0 ± 2.4 33.1 ± 16.8 (CCH); 49.3 ± 14.0 5.6 ± 2.5 (CCH); 0.4 ± 2.4 40.0 ± 16.2 (Placebo) (Placebo) (Placebo) (Placebo)
12 wks
13 wks
21.52 ± 7.27 (HA); 21.88 ± 11.16 (Control)
21.41 ± 3.54 (HA); 21.31 ± 4.02 (Control)
0.0 ± 0.0 Changes: 0 ± 1.24 (HA); 1.77 ± 2.77 (HA); þ15.37 ± 16.00 (Control) (Control)
49.9 ± 2.4 (IFN a-2b); 50.9 ± 2.5 (Placebo) 48.75 ± 4.41 (IFN a-2b); 47.75 ± 2.84 (Placebo)
18.32 ± 1.21 (IFN a-2b); 17.98 ± 1.33 (Placebo) 17.85 ± 1.67 (IFN a-2b); 17.65 ± 1.52 (Placebo)
20.80 ± 1.19 (IFN a-2b); 19.05 ± 1.32 (Placebo) 21.10 ± 1.56 (IFN a-2b); 19.05 ± 1.48 (Placebo)
36.4 ± 2.1 (IFN a-2b); 46.4 ± 2.2 (Placebo) 36.75 ± 4.53 (IFN a-2b); 44.10 ± 3.02 (Placebo)
52 wks
6 wks
6 wks
CCH ¼ collagenase Clostriudium hystoliticum; HA ¼ hyaluronic acid; IFN a-2b ¼ interferon a-2b; Ver ¼ verapamil.
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interferon a-2b (mean change 0.65 [95% CI 0.06e1.25]) showed a slight increase in mean efficacy with respect to CCH. Moreover, verapamil and Interferon a-2b showed slightly worse mean change when compared with hyaluronic acid, 0.62 (95% CI 1.38 to 0.14) and 1.74 (95% CI 2.52, 0.95), and interferon a-2b was worse than verapamil, 1.12 (95% CI 2.21, 0.02) (Figure 6).
Figure 2. Plot of the acute mania network (efficacy outcome) using colored edges according to adequacy of allocation concealment estimated as the level of bias in many of the trials and weighted according to the number of studies in each comparison. Figure 2 is available in color online at www.jsm.jsexmed.org.
compared with placebo treatments were as follow: CCH 0.61 (95% CI 1.01, 0.20), hyaluronic acid 1.78 (95% CI 1.31e2.43), verapamil 1.16 (95% CI 0.16e2.16), and interferon a-2b 0.04 (95% CI 0.39 to 0.48). When considering the comparison among active treatments, hyaluronic acid (mean change: 2.39 [95% CI 1.62-3.15]), verapamil (mean change 1.77 [95% CI 0.69e2.85]), and
Based on the SUCRA rankograms, interferon a-2b and CCH showed the highest scores, 56.9% and 56.3%, respectively, compared with other active treatments, 48.5% for verapamil and 30.7% for hyaluronic acid (Figure 7). The SUCRA is a numeric representation of the overall ranking and presents a single number associated with each treatment. The higher the SUCRA value, and the closer to 100%, the higher the likelihood that a therapy is in the top rank or 1 of the top ranks. The closer to 0 the SUCRA value is, the more likely that a therapy is in the bottom rank, or 1 of the bottom ranks, when using a placebo treatment as comparator. Finally, Figure 8 shows the net-funnel plot for all included studies, demonstrating diffused heterogeneity between comparisons.
DISCUSSION In this NMA, we have provided, for the first time, evidence about the efficacy between different intralesional therapies for the treatment of PD. For those patients, prioritizing efficacy of PC,
Figure 3. Contribution plot for the network meta-analysis. The size of each square is proportional to the weight attached to each direct summary effect (horizontal axis) for the estimation of each network summary effects (vertical axis). The numbers re-express the weights as percentages. Hyal ¼ hyaluronic acid; Interf ¼ interferon a-2b; Pla ¼ placebo; Ver ¼ verapamil. Figure 3 is available in color online at www.jsm.jsexmed.org. J Sex Med 2019;16:289e299
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Figure 4. Panel a shows a risk of bias graph. Review authors’ judgments about each risk of bias item presented as percentages across all included studies. Panel b shows a risk of bias summary. Review authors’ judgments about each risk of bias item presented as percentages across all included studies. Figure 4 is available in color online at www.jsm.jsexmed.org. J Sex Med 2019;16:289e299
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Figure 5. Network meta-analysis for penile curvature improvement for different treatment effects. Hyal ¼ hyaluronic acid; Interf ¼ interferon a-2b; Pla ¼ placebo; Ver ¼ verapamil. Figure 5 is available in color online at www.jsm.jsexmed.org. CCH and IFN a-2b seems to be the best treatment of choice. On the other hand, for men wishing to receive benefit in terms of erectile function, hyaluronic acid shows better clinical outcomes. Many conservative treatment options have been tried, including extracorporeal shockwave therapy; iontophoresis; and intralesional, topical, and oral agents.21 However, among all literature data, no meta-analysis has been performed because of the lack of large and well-designed clinical trials. In this context, new drugs have been introduced in the market, but no direct comparisons with previous empirical protocol have been performed. We should also consider that some treatment could be considered historical. In a recent survey by Bole et al,22 53% (86 of 162) of men had tried at least 1 therapy for their PD, whereas 20% (32 of 162) had tried 2 treatments. Surprisingly, nearly half of the men (47%; 76 of
162) elected never to pursue treatment for their PD. Among those who chose to pursue treatment, vacuum erection devices were the most commonly used modality (50%, 43 of 86), followed by oral medications (34.9%, 30 of 86) and surgery (33.7%, 29of 86). However, details on characteristics of drugs were lacking. Recently, CCH (Xiapex, Swedish Orphan Biovitrum AB, Stockholm, Sweden; Xiaflex, Endo Pharmaceuticals, Malvern, PA, USA) is the first treatment approved by the US Food and Drug Administration and the European Medicines Agency for the non-surgical management of PD. CCH is an intralesional drug injected into the Peyronie’s plaque in men with stable disease and a curvature of 30 to 90 .23,24 The only 2 clinical trials included in the present NMA that analyzed CCH are the Maximal Peyronie’s Reduction Efficacy
Table 2. Summary of results for penile curvature and erectile function after the network meta-analysis for all treatments Erectile function†
Penile curvature (degrees)* Drug
CCH
IFN a-2b
HA
Verapamil
CCH
IFN a-2b
HA
Verapamil
CCH IFN a-2b HA Verapamil
— 0.09 þ6.66 þ2.30
þ0.09 — þ6.75 þ2.38
6.66 6.75 — 4.37
2.30 2.38 þ4.37 —
— þ0.65 þ2.39 þ1.77
0.65 — þ1.74 þ1.12
2.39 1.74 — 0.62
1.77 1.12 þ0.62 —
CCH ¼ collagenase Clostriudium hystoliticum; HA ¼ hyaluronic acid; IFN a-2b ¼ interferon a-2b. *Minus sign () means a greater decrease in penile curvature for the drug on the left side; plus sign (þ) means a worse penile curvature for the drug on the left side. † Minus sign () means a worse erectile function for the drug on the left side; plus sign (þ) means a greater increase in erectile function for the drug on the left side. J Sex Med 2019;16:289e299
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Figure 6. Network meta-analysis for IIEF-5 improvement for different treatment effects. Hyal ¼ hyaluronic acid; Interf ¼ interferon a-2b; Pla ¼ placebo; Ver ¼ verapamil. Figure 6 is available in color online at www.jsm.jsexmed.org.
Figure 7. Plots of the surface under the cumulative ranking probability for all treatments in the Peyronie’s disease network. The area under the curve represents the cumulative rank probability of each treatment (the larger the better). Figure 7 is available in color online at www. jsm.jsexmed.org.
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Figure 8. Comparison-adjusted funnel plot for the Peyronie’s disease network.The gray line represents the null hypothesis that the study-specific effect sizes do not differ from the respective comparison-specific pooled effect estimates. Different colors correspond to different comparisons. Figure 8 is available in color online at www.jsm.jsexmed.org.
and Safety Studies I and II, which are 2 large, randomized, controlled, phase III clinical trials investigating intralesional CCH injection in men with PD. The treatment protocol consisted of 4 cycles, 6 weeks apart, of intralesional CCH (0.58 mg), followed by investigator modeling of the penis. Interestingly, the authors demonstrated a mean 34% improvement in PC, compared with a mean 18.2% improvement in placebo-treated men (P < .0001), whereas the change of erectile function was not superior compared with placebo treatment when both trials were considered separately. The benefits of CCH are mainly due to the disruption of the collagen Peyronie’s plaque.25 Taking into consideration hyaluronic acid, preliminary results for improvement of plaque size, PC, and overall sexual satisfaction have been previously reported.26 Only 1 study by Gennaro et al16 showed a benefit of HA over placebo drugs, whereas 1 other study by Favilla et al,14 comparing HA vs verapamil, found advantages of HA only in terms of PC and patient satisfaction. In this context, the benefits of HA are hypothesized to be secondary to the decrease of oxygen-free radicals and inhibition of apoptosis, promoting cell survival and decreased concentrations of inflammatory proteins.27 Among the other compared drugs, interferon a-2b is thought to improve PC and reduce plaque size in PD,28 whereas verapamil is thought to modify the inflammatory response in the early phase of the disorder and the inhibition of fibroblast proliferation in the plaques.29 Although differences among all intralesional drugs should be taken into account when considering the clinical outcomes, no J Sex Med 2019;16:289e299
meta-analysis has been conducted up to now. Therefore, herein we provide direct and indirect comparisons between these drugs, offering both physicians and patients a tool for choosing the best relevant treatment for PD. Despite the lack of comparative clinical trials between CCH and hyaluronic acid, we postulate that the differences among clinical efficacies could be attributable to the different mechanism of action. However, we would also point out some limitations. Unfortunately, we were not able to compare all specific outcomes (ie, pain, plaque size, patients’ satisfaction) of PD, because of the lack of homogeneity across relevant studies. Moreover, because of the few included studies, a meta-regression analysis of predictive factors of treatment response was not calculated. For the efficacy analysis, we pooled 4 outcomes, because efficacy endpoints varied between studies, but all are clinically relevant. Finally, we did not analyze adverse effects of drugs because of the low number of reported events in the studies.
Implications for the Future On the basis of this NMA, empirical therapy for PD should be avoided to offer the patients the best treatment in terms of level of evidence. We agree that the low number of included studies may represent a limitation to draw definitive conclusions about intralesional therapies for PD. However, CCH and interferon a-2b proved to offer the best benefit for PC, whereas hyaluronic acid is best for erectile function, respectively. We recommend further placebo-controlled prospective clinical trials to confirm
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our findings and draw definite conclusions. Future research should develop new drugs acting against specific targets of the disease.
CONCLUSIONS Our data suggest that, among all treatments for PD, CCH and interferon a-2b offer the best benefit for PC, whereas hyaluronic acid is best for erectile function. Urologists should discuss medical therapy with patients before surgical correction, as well as the target of improvement that they expect to obtain. Corresponding Author: Giorgio Ivan Russo, MD, PhD, Urology Section—University of Catania, Via Santa Sofia 78, 95125 Catania, Italy. Tel: 39 0953782710; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Funding: None.
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Giorgio Ivan Russo (b) Acquisition of Data Giorgio Ivan Russo; Giovanni Cacciamani; Andrea Cocci (c) Analysis and Interpretation of Data Giorgio Ivan Russo Category 2 (a) Drafting the Article Giorgio Ivan Russo; Paolo Verze (b) Revising the Article for Intellectual Content Thomas M. Kessler; Giuseppe Morgia; Ege Can Serefoglu; Maarten Albersen; Paolo Verze Category 3 (a) Final Approval of the Completed Article Giorgio Ivan Russo; Giovanni Cacciamani; Andrea Cocci; Thomas M. Kessler; Giuseppe Morgia; Ege Can Serefoglu; Maarten Albersen; Paolo Verze
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