Intralesional and topical treatments for Peyronie’s disease: a narrative review of current knowledge

Abstract

Peyronie’s disease (PD) presents a multifaceted challenge in contemporary urological practice, marked by penile deformity, pain, and the potential for erectile dysfunction. We meticulously explored the existing literature of intralesional/topical interventions, aiming to provide clinicians with a nuanced understanding of available options for comprehensive PD management. To conduct this review, we performed a systematic search using the PubMed, Scopus, and ScienceDirect databases, including the keywords of combination of the “Peyronie’s disease/plastic induration of the penis (PIP) and intralesional/topical treatments”. The study selection was based on adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, resulting in the inclusion of 16 articles. We delve into the effectiveness and safety profiles of collagenase Clostridium histolyticum (CCH), interferon, platelet-rich plasma (PRP), hyaluronic acid, botulinum toxin, stem cell, extracorporeal shock wave therapy (ESWT), and traction therapy, assessing their impact on penile curvature, length improvement, and patient-reported symptoms and outcomes. The best options evaluated are intralesional injections of CCH and penile traction devices, alone or in combination. Despite PD remains a challenge for urologists, the objective of this review is to contribute to the evolving landscape of PD management, fostering informed decision-making, and personalized care for individuals grappling with this challenging condition.

INTRODUCTION

Peyronie’s disease (PD) is a condition characterized by the development of fibrous plaques, consisting of a buildup of collagen fibers and other extracellular matrix components, within the tunica albuginea (TA) of the penis, leading to inelastic penile deformities.1 The most credited hypothesis in the literature concerns microvascular trauma and abnormal wound healing with accumulation of fibrotic tissue in response to cytokine stimulation (transforming growth factor beta 1 [TGF-β1] and platelet-derived growth factor [PDGF]); the other theory includes genetic predisposition, as there are reports that associate this condition with Paget’s disease of bone, Dupuytren’s disease, and some specific human leukocyte antigen (HLA) subtypes.1 This condition was initially described by François de la Peyronie in 1743; nonetheless, the pathogenesis is remaining a subject of ongoing research.2,3 Two different phases may be distinguished in the clinical history of the PD. During the acute phase, which can last up to 18 months following onset, inflammatory changes occur in the TA due to repeated microtrauma during sexual activity that bring inadequate activation of fibrinolysis and heightened fibroblast activity, contributing to rapid plaque growth. During this period, patients typically experience pain in both flaccid and erect status, along with palpable nodules and the development of penile curvature. As PD advances into the chronic phase (“quiescent” state), the plaque is stabilized with persistent penile curvature and potential shortening of penile length, whereas the pain typically subsides, but a curvature of the penis (20°–100°) remains.4 This may lead to discomfort and anxiety, resulting in emotional and psychosocial effects on sexual performance of patients, associated with erectile dysfunction.5,6 Although notable advances have been gained in the surgical field, especially for severe and intricate cases of curvature, topical and systemic medical treatments for mild–intermediate PD have yielded mixed results, with outcomes varying depending on the specific approach and timing of intervention.7 Nowadays, several types of treatments are available for PD; nevertheless, the choice depends on the severity of the condition, symptoms, and the preferences of the patient.8 The common therapeutic options include oral drugs (pentoxifylline, colchicine, nonsteroidal anti-inflammatory drugs [NSAIDs], and phosphodiesterase 5 inhibitors [PDE5is]), intralesional/topical treatments (verapamil, collagenase Clostridium histolyticum [CCH], interferon α-2b [IFN-α2b], hyaluronic acid, and botulinum toxin), penile traction devices (PIDs), shock wave therapy (SWT), and vacuum erection devices.9 Despite notable progress in intralesional/topical treatment interventions, an unequivocal gold standard procedure remains elusive.10 For these reasons, we performed a narrative review of the last 5 years of literature inherent to intralesional/topical treatments, with a specific focus on their application across various phases of PD, in order to discern efficacious and well-rounded strategies in the current panorama.

SEARCH STRATEGY

In August 2023, a literature search was carried out using PubMed, Scopus, and ScienceDirect databases to identify studies published in English between January 2018 and June 2023. The search followed the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and all relevant items from the PRISMA checklist are explicitly addressed.11 The search included the following keywords: “plastic induration of the penis [Mesh term] and medical therapy [Mesh term]”; “plastic induration of the penis [Mesh term] and medical treatment [Mesh term]”; “plastic induration of the penis [Mesh term] and non-surgical treatment [Mesh term]”; “plastic induration of the penis [Mesh term] and non-surgical therapy [Mesh term]”; “la peyronie disease [Mesh term] and medical therapy [Mesh term]”; “la peyronie disease [Mesh term] and medical treatment [Mesh term]”; “la peyronie disease [Mesh term] and non-surgical treatment [Mesh term]”; “la peyronie disease [Mesh term] and non-surgical therapy [Mesh term]”; “PIP [Mesh term] and medical therapy [Mesh term]”; “PIP [Mesh term] and medical treatment [Mesh term]”; “PIP [Mesh term] and non-surgical treatment [Mesh term]”; “PIP [Mesh term] and non-surgical therapy[Mesh term]”; “PIP [Mesh term] and PRP [Mesh term]”; “la peyronie disease [Mesh term] and PRP [Mesh term]”; “PIP [Mesh term] and ESWT [Mesh term]”; and “la peyronie disease [Mesh term] and ESWT [Mesh term]”.

INCLUSION AND EXCLUSION CRITERIA

Only papers written in English between January 2018 and August 2023 were considered for inclusion, while “in vitro” or “animal models” studies, meeting or conference abstracts, letters to the editor, case reports and case series, editorials, and previous reviews were excluded.

In order to ensure comprehensive and rigorous selection, we included only studies with a minimum of 40 patients and a minimum follow-up period of 3 months, providing detailed data upon PD parameters as comprehensive reports of the clinical outcomes.

SCREENING AND SELECTION PROCESS

Using Mendeley Ltd. for narrative review (a software company based in London, UK), four independent authors divided into two groups (AM and GR; AT and AI) conducted a comprehensive screening of all the records obtained. When conflicts arose about differences of opinion or conflicting information, a discussion involving two senior authors (LC and FE) was held to resolve the issue and reach a consensus. The full texts of the screened papers were further evaluated for eligibility by two authors (AM and LC), and those meeting the criteria were included in the present review. A third author (FE) further reviewed those qualifying papers for which there was not an agreement and selected some that were finally included in the review.

DATA EXTRACTION AND SYNTHESIS

Extracted data included study characteristics, patient demographics, details of PD and intralesional/topical treatment interventions, and relevant clinical outcomes. A narrative synthesis approach was used to summarize the findings due to the heterogeneity of the included studies.

The literature search yielded 957 studies. First, 403 duplicate studies were excluded. After screening titles and abstracts of the remaining 554 studies, we additionally discarded 495 studies which did not meet the inclusion criteria. Thereafter, we assessed the full texts of the remaining 59 studies for eligibility and 14 studies met the predefined inclusion criteria. After review of qualifying papers, we identified 2 additional papers. In a total of 16 studies, 6 prospective studies, 8 retrospective studies, and 2 randomized controlled trials were encompassed, each contributing valuable insights to the review (Table 1). Additionally, Figure 1 provides a graphical representation of the literature search and screening process.

Table 1.

Characteristics of the included studies

Reference	Study design	Patient (n)	Acute or chronic	Grade of curvature at diagnosis	Pain (yes/no)/PD questionnaire (PDQ) for symptoms	Treatment	Time of follow-up	Primary endpoint	Treatment efficacy assessment	Treatment effect	Quantitative results
Goldstein et al.14 2020	Post hoc analysis of 4 RCT	280	Chronic	Group 1 (no calcification): 52.3° (mean) Group 2 (stippled calcification): 53.7° (mean) Group 3 (calcificated plaque): 51° (mean)	Pain: not reported PDQ (pain domains) at baseline: Group 1, 8.2; Group 2, 10.4; Group 3, 7.0	CCH	60 months	5 years (curvature change and PDQ improvement in men with different grades of calcification)	Goniometric evaluation of the penile curvature after pharmacologic stimulation of the erection Post-operative PDQ assessment for symptoms evaluation	Curvature (mean [95% CI]): Group 1, -25.4° (-28.6° to -22.2°); Group 2, -26.9° (-36.8° to -16.9°); Group 3, -21.9° (-29.5° to -14.4°) PDQ (pain domains) change, mean (95% CI): Group 1, -5.8 (-6.9 to -4.6); Group 2, - 8.5 (-17.2 to 0.2); Group 3, -5.3 (-14.7 to 4.1)	Descriptive analysis
Nguyen et al.15 2017	Retrospective	914	Acute vs chronic	Mean±s.d.: Group 1, 48.9°±16.9°; Group 2, 48.1°±15.8°	Not reported both pain and PDQ	CCH up to 4 cycles	Up to 48 months	Comparison of curvature change and adverse events occurred	Penile curvature assessment is not reported TRAEs: complications that occurred as direct consequence of CCH administration	Curvature change (mean±s.d.): Group 1, 13.5° ± 13.7°; Group 2, 15.6° ± 13.2° TRAEs (mean): Group 1, 11.9%; Group 2, 9.9%	P=0.09 for curvature change P not reported for TRAEs
Sockhal et al.36 2018	Prospective	86	Not reported	Mean±s.d.: 34.8° ± 11.4°	Not reported both pain and PDQ	IFNα2b	3 months	Evaluation of the efficacy of this treatment	Goniometric evaluation of the penile curvature after papaverine and phentolamine administration VAS for pain assessment IIEF-5 for erectile function assessment	Penile curvature (mean±s.d.): 1 month, 24.6° ± 4.1°; 3 months, 18.6° ± 3.6° VAS score (mean±s.d.): before, 5.1±3.6; 1 month, 3.6±1.4; 3 months: 1.8±1.2 IIEF-5 (mean±s.d.): before, 13.8±4.2; 1 month, 19.3±3.6; 3 months, 21.2±2.7	P<0.0001 in terms of curvature
Longo and Longo44 2022	Randomized controlled trial	71	Chronic	Not reported	Not reported both pain and PDQ	Laser photobio modulation	24 months	Reduction of 50% of the fibrous plaque	Ecographic features of the plaque	Not reported	Not reported
El-Khatib et al.28 2020	Retrospective study	61	Chronic	Mean±s.d.: 48.9° ± 15.4°	PDQ (mean±s.d.): 10.5±1.7	CCH	20.7 months	Improvement in curvature and PDQ	Goniometric evaluation of the penile curvature during erection after pharmacological stimulation of the erection. Post-operative symptoms bother domain of the PDQ (last 6 questions of the questionnaire) assessment for symptoms evaluation	Mean±s.d.: GC, -19.2°± 8.3°; PDQ, 3.8±2.2	P=0.007, compared to baseline for GC P=0.002, compared to baseline for PDQ
Alom et al.41 2019	Prospective study	287	Chronic	Median (IQR): Group 1, 60° (45°–75°); Group 2, 61.5° (45°–75°); Group 3, 65° (50°–85°)	Not reported	Group 1 (CCH alone); Group 2 (CCH + any PTT device other than RestoreX); Group 3 (CCH + RestoreX)	Up to 60 months	Changes in penile curvature and length	Stretched penile length was obtained from the pubic symphysis to the corona of the glans penis Curvature assessments were performed using a protractor with the penis assessed in 2 planes, dorsal/ventral and lateral All curvature measurements were then summed to define a composite curvature	Group 3 (better outcomes), median (IQR): GC, 30° (25°–44.4°); length, 1.75 (1–3) cm	P=0.01, GC (goniometric change) vs baseline P=0.001, penile length change vs baseline
Moncada et al.40 2019	RCT	80	Chronic	Median (IQR): Group 1, 72.3° (61°–105°); Group 2, 68.7° (58°–102°)	Pain has been considered an exclusion criteria	Group 1: Penimaster PRO Group 2: noninterventional group	3 months	Change in penile curvature	Goniometric evaluation of the penile curvature after alprostadil administration	Median (IQR): overall change in curvature, -31.2° (15°–50°); less than 4 h per day usage, -19.7° (15°–25°); more than 6 h per day usage, -38.4° (20°–50°)	P<0.001
Cocci et al.27 2018	Prospective	135	Chronic	Median (IQR): 30.0° (30.0°–60.0°)	PDQ-PP: 3.0 (0–6.0)	CCH	3 months	To define predictors of success in penile curvature improvement	Goniometric evaluation of the penile curvature after alprostadil administration	PC change (median): 20.0° Percentage of improvement (median [IQR]): 44% (28.0%–67.0%) Baseline curvature, dorsal and base location of the plaque as the absence of calcification were found to be predictors of penile curvature improvement	P<0.01 for PC change P<0.01 for baseline PC P<0.01 for basal and dorsal plaque location (OR: 64.27) P<0.01 for low calcification (OR: 0.06;) and P<0.01 for high calcification (OR: 0.03)
Cocci et al.13 2018	Prospective	50 (after PSM)	Chronic	Mean±s.d.: Group 1 (CCH + sildenafil 25 mg b.i.d.), 51.6° ± 23.12°; Group 2 (CCH alone), 49.2° ± 21.58°	PDQ-PP domains (mean±s.d.): Group 1, 3.24±5.10; Group 2, 4.48±4.87	CCH + sildenafil or CCH alone	Up to 12 months	To define the role of sildenafil in CCH treated patients	Goniometric evaluation of the penile curvature after alprostadil administration IIEF-15 for sexual function evaluation PDQ for PD-related symptoms evaluation	Penile curvature change (mean±s.d.): Group 1, -25.6° ± 9.05°; Group 2, -17.4° ±6.63° IIEF-15 change after treatment (mean±s.d.): Group 1, 9.24±5.42; Group 2, 7.8±12.74 PDQ-PS change after treatment (mean±s.d.): Group 1, -2.12±2.06; Group 2, -2.44±2.24 PDQ-PP change after treatment (mean±s.d.): Group 1, -0.88±2.04; Group 2, -1.2±3.67 PDQ-SB change after treatment (mean±s.d.): Group 1, -4.16±4.45; Group 2, -4.16±3.41	P<0.01 for penile curvature and IIEF-15 P=0.26 for PDQ-PS P=0.05 for PDQ-PP P=0.69 for PDQ-SB
Li et al.29 2023	Retrospective	229	Not reported	Mean±s.d.: 45.3° ± 15.5° at baseline	Not assessed	CCH	4 months	To define the usefulness of additional CCH treatments in improving the penile curvature	Goniometric evaluation of the penile curvature	Curvature improvement vs baseline (mean±s.d.): after 8 injections, 8.3°±12.8°; after 16 injections, 7.7°±11.7°; after 24 injections, 4.4°±9.2°	P<0.001, curvature improvement vs baseline after the first and second rounds of injections P=0.169, curvature improvement vs baseline after the third round of injections
Cocci et al.30 2018	Prospective	135	Chronic	Median (IQR): 30° (30°–60°)	PDQ-PP, median (IQR): 3.0 (0–6.0)	3 injections of CCH 0.9 mg administered once every 4 weeks	3 months	To define the efficacy of this novel protocol and its impact on the female partner assessed to the FSFI	Goniometric evaluation of the penile curvature during erection	Penile curvature improvement 4 weeks after the last injection, median (IQR): - 19.7° (-30.0°–15.0°) FSFI, median (IQR): baseline 35.0 (30.0–38.0); last FU: 3.94 (2.0–5.0)	P<0.01 for both penile curvature and FSFI
Achraf et al.46 2023	Prospective	65	Chronic	Median (IQR): Group 1, 31.8° (25°–35°); Group 2, 39.1° (35°–45°)	Pain assessed through VAS scale	A session every 15 days for two months, then at 3 months, 6 months, and 9 months	12 months	Primary outcome: to define the role of PRP in reducing penile curvature Secondary outcome: define the role of PRP in pain relief and erectile function improvement	Goniometric evaluation of the penile curvature after alprostadil administration IIEF-5 and VAS administration	Penile curvature change (mean±s.d.): Group 1, -16.88° ± 3.35°; Group 2, -17.27° ± 4.22° IIEF-5 change (mean): Group 1, 50%; Group 2, 61% VAS change (mean): Group 1, -34%; Group 2, -39%	Penile curvature change: Group 1, P<0.01; Group 2, P<0.01 IIEF-5 change: Group 1, P=0.0255; Group 1, P=0.021 VAS change: Group 1, P=0.0442; Group 2, P=0.0457
Karokose and Yitgin47 2023	Retrospective	159	Acute	Mean±s.d. (95% CI): Group 1 (vitamin E + colchicine + tadalafil), 22.4°±5.5° (15°–30°); Group 2 (Li-ESWT + PRP + tadalafil), 23.3°±4.8° (15°–30°)	Pain assessed through VAS scale	Control group (vitamin E 600 mg per day + colchicine 1.5 mg per day + oral daily 5 mg tadalafil) Intervention group (Li-ESWT + PRP + oral daily 5 mg tadalafil)	3 and 12 months after treatment	To evaluate to the efficacy and safety of the combination of Li-ESWT and PRP therapy in acute phase Peyronie’s disease.	Goniometric evaluation of the penile curvature after alprostadil administration IIEF-5 and VAS administration	Main plaque size (mean±s.d.): control group, 13.2±3.6 mm; intervention group, 9±2.7 mm Curvature degree (mean±s.d.): control group: 18.3°±5°; intervention group, 12.8°±4° IIEF-5 (mean±s.d.): control group, 19.3±2.2; intervention group, 21±1.8 VAS (mean±s.d.): control group, 4±1.2; intervention group, 3±1.1	P<0.01
Di Mauro et al.49 2019	Prospective	325	Chronic	Median (IQR): 30.4° (22.2°–35.4°)	Pain assessed through VAS scale	3000 pulses (1500 per side of the plaque) per week for 6 weeks.	3 months	To define the effect of ESWT on PD affected patients	Goniometric evaluation of the penile curvature after alprostadil administration IIEF-15 and PDQ assessment	Penile curvature, median (IQR): 3 months, 25.0° (20.2°–30.4°); baseline, 30.4° (22.2°–35.4°) IIEF-15 after treatment, median (IQR): 3 months, 26 (23–27); baseline: 14 (11–16) PDQ-PS, median (IQR): 3 months, 8 (6–12); baseline, 13 (11–17) PDQ-PP, median (IQR): 3 months, 4 (2–6); baseline, 7 (6–8) PDQ-BD, median (IQR): 3 months, 1 (1–3); baseline, 3 (3-4)	P<0.01 for all the domains
Spirito et al.50 2024	Retrospective	194	Acute	Mean: 18.3°	Pain assessed through VAS scale PDQ was not assessed	3000 pulses per week for 4 weeks	3 months and 12 months	To define the effect of ESWT on pain and on the other PD bother symptoms	VAS scale assessment for pain Goniometric evaluation of the penile curvature after alprostadil administration IIEF-5 assessment for erectile dysfunction	Penile curvature (mean): baseline, 18.3°; 3 months, 21.5°; 12 months, 28.6° Penile pain (mean): baseline, 6.5; 3 months, 3.1; 12 months, 1.0 IIEF-5: baseline, 14.5; 3 months, 17.9; 12 months, 18.5	Penile curvature: 3 months, P=0.023; 12 months, P=0.01 Penile pain: 3 months, P<0.01; 12 months, P=0.01 IIEF-5: 3 months, P=0.01; 12 months, P=0.082
Dell’Atti et al.43 2023	Prospective	214	Chronic	Not reported Group 1: ESWT Group 2: ESWT + LILIDT	Pain assessed through VAS scale	Not reported	3 months, 6 months and 12 months	To compare the efficacy of ESWT when associated to low intensity laser diode administration on penile plaque	Not reported	Pain resolution in 3 months: Group 1, 55.8%; Group 2, 78.6% Curvature degree in 3 months: statistically significant difference between the two groups IIEF 3 months: statistically significant difference between the two groups	P<0.03 for pain resolution P<0.002 for curvaure degree P<0.001 for IIEF

PDQ: Pain Domain Questionnaire; RCT: randomized clinical trial; CCH: collagenase Clostridium histolyticum; CI: confidence interval; TRAE: treatment-related adverse events; VAS: Visual Analogue Scale; IIEF: International Index of Erectile Function; GC: goniometric change; PC: penile curvature; PTT: penile traction therapy; IQR: interquartile range; PDQ-PP: Pain Domain Questionnaire-Penile Pain; PDQ-PS: Pain Domain Questionnaire-Psychological Symptoms; PDQ-SB: Pain Domain Questionnaire-Symptom bother; OR: odds ratio; FSFI: Female Sexual Function Index; FU: follow-up; s.d.: standard deviation; b.i.d: twice a day ESWT: extracorporeal shockwave therapy; LILIDT: low-intensity laser diode therapy.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses: flow diagram for inclusion and exclusion of studies.

In regard to the details of the PD, all studies considered patients in acute or chronic/stable phase that had completed a penile duplex Doppler ultrasound before any intralesional/topical treatment in order to assess the characteristic of the plaque in terms of calcification and dimension; even more, no one had previously undergone surgical treatments. Moreover, for curvature assessment, patients received an intracavernosal injection with an erectogenic medication to gain the maximum rigidity. Afterward, a goniometer was adopted to measure the degree of deformity at the point of maximum curvature. Following treatments, outcomes collected were quantitative through objective examination (curvature assessments) and qualitative (symptoms) using questionnaires, such as Peyronie’s Disease Questionnaire (PDQ). Our analysis revealed a positive improvement in penile curvature for each of the explored treatments; however, some studies highlighted the importance of combination therapy including CCH,12,13 while others showcased that the number of series performed, as the features or the location of the penile plaque have had an impact on the therapy’s efficiency.14,15

EVIDENCE SYNTHESIS

In the last decade, several treatment options, including nonmedical therapies, and pharmacologic and intralesional/topical treatments with various mechanisms of action, have been proposed for men with PD; however, there has not been unanimous consent on effective conservative management.10 The modification of penile curvature and deformity, and the relief from pain as the female partner’s sexual satisfaction are the goals of treatment.16 In the past, some intralesional therapies have been proposed, such as stem cell therapy, hyaluronic acid, and botulinum toxin. However, these treatments have not been taken hold, remaining isolated research experiences and no longer revived recently.14,15,16,17 Evaluating different types of interventions, intralesional verapamil has a recommendation Grade C in American Urology Association (AUA) guidelines and currently approved by the European Association of Urology (EAU) for the management of PD, despite weak and conflicting evidence, while intralesional IFN-α2b, an off-label treatment for PD, has a moderate recommendation.17,18,19 Concerning noninvasive therapy, extracorporeal shock wave therapy (ESWT) was first described in 1989 and nowadays is only recommended to treat PD-related pain in the AUA and EAU guidelines,9,17,20 while penile-traction therapy (PTT) is a efficacy and cost-effectiveness treatment to improve penile length, decrease curvature, and increase penile girth.21 However, larger cohorts in well-designed randomized control trials are required to further characterize its benefits in acute and chronic phases. To date, CCH, a mixture of a Class I clostridial collagenase (AUX-I) and a Class II clostridial collagenase (AUX-II), represents the only licensed drug approved by the USA Food and Drug Administration (FDA) for noninvasive PD intervention.22 Indeed, previous studies showed the safety and the efficacy of CCH in the management of penile curvature in both phases of PD, albeit with some side effects, such as acute low back pain.15,23,24 Recent evidence demonstrated how a multimodal approach seems to be more effective compared to monotherapy.25 Altogether, these findings suggest a need to clarify the role of these intralesional/topical treatments in the PD therapy’s panorama.

INTRALESIONAL/TOPICAL TREATMENTS

CCH

During the last 5 years, CCH has been surely the most explored intralesional therapeutic agent. Indeed, registration studies including Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies (IMPRESS) I and II recommend its administration for men >18 years old, affected by a chronic PD condition (>12 months history of PD with a stable curvature deformity of at least 3 months), without erectile dysfunction.26 A full round treatment of CCH consists of 4 cycles of injections, each one including two injections administered 48–72 h apart; each cycle has to be separated by 6 weeks from the former.

An attempt to best define those patients who best benefit by CCH administration has been done by Cocci et al.,27 who performed an analysis of a multi-institutional database of 135 prospectively included patients in order to define the predictors of success of this intralesional therapy; according to their findings, baseline curvature and dorsal and base location of the plaque as the absence of calcification are predictors of penile curvature improvement after CCH administration, empowering those recommendation given by the registration studies. However, the clinical debate on the possibility to manage atypical deformities through CCH injection is still open, even if as per label, its usage is not recommended when such deviations occur. Notwithstanding with that, the feasibility of this treatment has been described in a cohort of patients affected by atypical penile deformities due to PD achieving good clinical results both in terms of penile curvature improvement and in PDQ composite score.28 Interestingly, the clinical improvement is identical for all the subgroups of penile deformities with all of those benefiting from the proposed management.

The possibility of performing up to 2 additional rounds of treatment has been speculated recently and it has been found that a second full round treatment should positively impact on the penile curvature in patients who did not gain a clinical response to the first round.29 Furthermore, the value of a third round of CCH was questioned and it seemed not to produce clinical advantages in nonresponders to the second round. According to these results, an additional cycle of CCH should be avoided in nonresponders and a surgical approach should be promptly discussed with these patients.

The protocol above mentioned is not the only one explored in PD field. In 2018, another study confirmed the efficacy of a novel protocol, consisting of three intralesional injections of 0.9 mg of CCH performed at 4-week intervals at the point of maximum curvature, in terms of both penile curvature improvement and symptoms relief.30 Interestingly, in the same analysis, it was found that a better improvement in International Index of Erectile Function-15 (IIEF-15), sexual desire, and intercourse satisfaction domains seemed to be related to a better female partner satisfaction assessed with the Female Sexual Function Index (FSFI).

Discordantly to what has been speculated at the registration studies of CCH, a post hoc analysis of 4 randomized clinical trials (RCTs) conducted by Goldstein et al.14 in 2020 proved the same efficacy in terms of penile curvature modification in three groups of patients who had different grades of calcification of the plaque (Group 1: no calcification; Group 2: stippled calcification; and Group 3: calcificated plaque). Additionally, according to their findings, an identical trend is also found in all PDQ domains with no difference in terms of clinical advantage gained after the medical therapy among the same three groups. Real life analysis has to be conducted for a better definition of the impact of plaque calcification on the response to CCH therapy in PD affected patients. Indeed, contrary to what has been stated above, an higher mineral burden has impacted negatively on response to CCH in previous series stratified according to the degree of calcification. In these series, a rising grading of plaque calcification increased the risk of progression to surgery.31,32,33

To date, CCH prescription is recommended only during the chronic phase of PD when stabilization of the plaque as of the penile deformity has been achieved and disease is no longer progressing. Conversely, during the acute phase, physicians lack of disposable tools that may reverse or interrupt disease progression, but only palliative therapies as ESWT are available to alleviate symptoms.34 Nevertheless, safety and feasibility of CCH injection during the acute phase of PD have been recently speculated by Nguyen et al.15 who retrospectively assessed penile curvature improvement and adverse effects related to the therapy in two cohorts of patients differing from each other for the acute or chronic phase of the condition. Surprisingly, CCH provided similar results when administered both during the acute phase and the chronic phase of the PD, suggesting its adoption even at the onset of the condition, while a disease is progressing and a stable calcification has not yet been obtained.

Moreover, the efficacy of CCH has been tested also for combination regimens with other therapies that may empower its effect on deformity reduction and symptom relief. The assumption of 25 mg of sildenafil twice a day in addition to CCH injection was found to have a better impact on penile curvature improvement than CCH when administered alone; moreover, this combination therapy seems to have a better impact both in sexual function and in PD bother symptoms.13 These findings are relevant as they underline the possibility to conservatively manage PD in a larger percentage of cases that are otherwise referred to surgical treatment with a nonnegligible risk of erectile dysfunction or penile length shortening.

IFN-α2b

Other studies have focused on the role of alternative intralesional/topical therapies for the management of PD. In in vitro studies on PD-derived human fibroblast model and corpora cavernosa-derived myofibroblast model, IFN-α2b was found to be effective in inhibiting collagen production and increasing collagenase activity.35 Thereafter, IFN-α2b was proposed as therapy for many fibrotic conditions such as PD, keloid scars, and scleroderma. Based on these findings, Sokhal et al.36 found IFN-α2b to be effective in gaining a significant reduction in penile curvature and plaque volume as for sexual function and referred pain domains. This kind of therapy has to be more explored to empower current findings and make IFN-α disposable in everyday clinical practice.

PTDs

Although PTDs have been used for more than 1000 years, it has only recently been legitimized for various penile conditions,37,38 working on the principle of applying a controlled and gradual stretching and traction force to the entire surface of the penis, aiming to promote tissue expansion, but with the purpose to make the device more comfortable and better tolerated by patients.12 Recently, “Penimaster PRO” (MSP Concept, Berlin, Germany) has become available for medical use.39 Moncada et al.40 evaluated the Penimaster PRO, recommending that patients use it for a duration of 3–8 h per day, for a period of 12 consecutive weeks. However, they advised users to remove the device during sleep and take breaks every 2 h for 30 min or when experiencing discomfort or numbness. After 3 months of follow-up, they found a significant reduction in curvature in the Penimaster PRO group related to the number of hours of daily use. Specifically, an overall decrease of 31.2° (P < 0.001) compared to the baseline was proved with an increase of 5 points in the IIEF-15 score from the initial condition. However, mild adverse events (AEs) occurred in 43% of patients, as local discomfort and glans numbness. On the other side, the use of PTDs has been evaluated as an adjunctive therapy with verapamil, IFN-α2b, or CCH. Indeed, Alom et al.41 assessed the safety and efficacy of novel PTDs, called RestoreX (Pathright medical, Plymouth, MN, USA), plus CCH compared with CCH alone and CCH with other PTT devices. The device incorporates a new clamping mechanism with greater traction force and the ability to dynamically lengthen traction without removing it. Additionally, it has visible indicators of adequate traction, counter bends in 4 primary directions, and patients use it for only 30 min twice a day with 15 min of traction and 15 min of counterbalancing. According to their findings, RestoreX provides better results in terms of penile curvature (higher rates of ≥20%, and ≥50% improvement for CCH alone, CCH associated to other traction devices, and RestoreX associated to CCH, respectively), and length (≥1 cm length gain, and ≥20% length improvement) when compared to the other two subgroups. These findings are relevant in daily clinical practice as they proved that a less invasive device may warrant better clinical results than old generation tools for which the rate of discontinuation due to discomfort is so high.42

Laser therapy (LT)

Since 1980, LT has been successfully proposed for the treatment of plastic induration of the penis (PIP), although its adoption among physicians remains limited, with variations in dosage and procedure.43 With advancements in technology, higher-performance lasers are being considered for use, as their effects appear to involve the inhibition of fibroblast production and the flattening of scars. In a study by Longo and Longo,44 cycles of 20 sessions of irradiation were conducted for patients with PD, involving the sequential use of a diode laser at 810 nm, an neodymium Yttrium Aluminum Garnet (Nd-YAG) laser at 1064 nm, and a CO₂ laser at 10 600 nm. This type of laser photobiomodulation (PBM) demonstrated a high percentage of positive results (60% of excellent results both after one year and two years of follow up). If there was a reduction of <50% after the initial cycle, additional cycles were repeated using the same procedure, resulting in three cycles per year for each patient. Notably, adverse effects of high-energy laser exposure did not occur, the thermal relaxation time of the irradiated tissue was respected, preventing burns to the skin and other tissues.

Platelet-rich plasma (PRP)

PRP therapy involves the administration of a supraphysiological concentration of platelets, which are known to be significant promoters of growth factors such as platelet-derived growth factor, transforming growth factor-β1 and -β2 (TGF-β1 and TGF-β2), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and epithelial growth factor (EGF).45 Recently, its usage has gained growing interest, particularly for managing urological conditions such as PD and erectile dysfunction. Recent evidence suggests the safety and efficacy of PRP for treating penile curvatures.46,47 In a study by Achraf et al.,46 PRP was administered every 15 days for 2 months, followed by treatments at 3 months, 6 months, and 9 months, demonstrating effectiveness in terms of deformity improvement, pain relief during sexual intercourse, and erectile function improvement. Notably, this benefit was observed in two groups of patients differing in the severity of curvature deformity.

Furthermore, the combined treatment of PRP, low intensity shock wave therapy (Li-SWT), and daily oral 5 mg PDE5i demonstrated remarkable effectiveness in improving erectile function recovery and reducing pain severity, as reported by Karakose and Yitgin.47 This efficacy was found to be superior to therapy involving vitamin E at a dosage of 600 mg per day plus colchicine at a dosage of 1.5 mg per day combined with daily oral 5 mg PDE5i.

SWT

SWT harnesses the regenerative potential of shock waves to stimulate tissue repair. In PD, this mechanism involves mechanical cell stimulation, leading to the synthesis of nitric oxide (NO) and VEGF, which induce neoangiogenesis in the penile cavernous tissues.48 Despite the effectiveness of SWT remains debated and it is not recommended as the sole treatment for penile curvature in PD, retrospective studies have demonstrated its efficacy in managing associated symptoms.34,43,49

For instance, a study by Di Mauro et al.49 reported significant improvements in plaque size, penile length, curvature, and pain evaluated by Visual Analog Scale 3 months after undergoing ESWT once a week for 6 weeks. Additionally, improvements were observed in each domain of the IIEF questionnaire and Peyronie’s disease assessment.49 The effects of ESWT typically manifest 3 months after treatment initiation and remain stable over time. However, while pain relief shows significant improvement, erectile function may either remain stable or worsen after 12 months.50 Furthermore, combining ESWT with low-intensity diode LT has shown superior outcomes compared to ESWT alone, resulting in greater pain reduction, improved curvature, and resolution of erectile dysfunction.43

LIMITATIONS

Our conclusions must be viewed in light of the inherent limitations within the studies included in this narrative review. It is crucial to acknowledge that the absence of a consensus on a gold standard procedure, particularly given the emergence of multimodal therapy, contributes to the complexities of synthesizing findings. A notable limitation lies in the restricted number of studies included and above all covering certain interventions, specifically the lack of additional comparative studies for laser and IFN-α2b therapies. This limitation underscores the need for further research to reduce the gaps of the existing literature regarding some therapies and to evaluate the comparative effectiveness of these specific interventions. Despite these acknowledged limitations, our study provides valuable insights into the current landscape of PD treatment, paving the way for more targeted investigations in the field of PD treatment.

CONCLUSIONS

CCH has emerged as a widely explored noninvasive treatment for PD in recent literature. Over the past 5 years, research has consistently demonstrated its effectiveness in improving penile curvature and alleviating symptoms. Notably, various administration protocols have been investigated, revealing positive outcomes. Despite the label indication restricting its prescription to chronic PD without plaque calcification, recent findings challenge this limitation. Comparable clinical results have been observed when administering CCH during the acute phase of the condition or in cases with a high calcium deposition over the plaque. Moreover, the integration of additional therapies, both medical interventions and traction devices, has shown enhanced clinical benefits compared to CCH alone. Beyond CCH, the exploration of alternative tools such as laser therapy, PRP, ESWT, and IFN-α2b has yielded promising results. Additionally, it would be beneficial to assess whether the combination of these intralesional/topical treatments can lead to significant clinical benefits, as reported by some of the aforementioned studies. However, to establish their efficacy in comparison to standard therapies and to create a standardized program, further studies, particularly comparative studies, are essential to assess a pivotal role in shaping the future of PD management.

AUTHOR CONTRIBUTIONS

AM, LC, and FP provided concept and study design, performed data analysis, and drafted the manuscript. AM, AI, AT, and GR performed data collection and interpretation. RP drafted the manuscript. MM and RMS provided data interpretation and a critical revision of manuscript. AM, FP, and FE provided concept and study design, data interpretation, and critical revision of manuscript. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.