Peyronie's disease (PD), also known as penile fibrous cavernositis, is a benign chronic disease characterized by the formation of fibroids in the tunica albuginea (1), leading to plaque formation, penile malformation, penile pain, sexual dysfunction, and mental disorders (2). Recent epidemiological surveys have shown that the period of the PD onset is usually 40 to 70 years old, and its prevalence is 3 to 9%. However, due to its low recognition, the prevalence of PD may actually be higher (3–5).

At present, clinical treatment of PD is mainly concentrated on the acute phase of the disease, aiming to prevent disease progression and penile malformation. For patients in the acute phase, non-surgical treatment is the primary choice, and only patients who are in the stable phase or with serious problems are treated with surgery (1, 6). Non-surgical treatments, such as oral drug therapy, intralesional local injection therapy, iontophoresis, and vacuum mechanical traction therapy, have received extensive attention (7–9). However, there is no strong evidence to prove their therapeutic advantages (10).

Local injection therapy for lesions has been accepted recently, because of its rapid drug delivery, high local drug concentration, and ease of clinical operation (7, 11). Currently, drugs for the local injection are mainly CCH, verapamil, and interferon-α2b, of which CCH is the most widely used (9, 12, 13). Previous clinical trials focused on the effectiveness of CCH (14–16), but most of them were reviews or case reports, lacking evidence-based medical evidence, and there are still some clinicians who are concerned about its safety and efficacy. Therefore, we are the first to use meta-analysis to explore the efficacy and safety of CCH in the treatment of PD all over the world.

This present study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria (17).

The incidence of PD increases with the age, and it has been reported that 90% of patients with PD are between 50 and 59 years old (22). As a chronic benign disease, PD could cause erectile dysfunction, which seriously affects the life quality. Unfortunately, there is, currently, no ideal treatment for PD and, thus, made it a hot topic. The CCH, a mixture of AUX-I and AUX-II Clostridium collagenase with high selective hydrolysis activity on Type I and Type III collagen, can directly destroy collagen-based plaques without damaging surrounding elastic tissue and vascular smooth muscle. Gelbard et al. (18) first reported the application of CCH in PD, and they found that the therapeutic effect of CCH was superior to placebo in terms of plaque size and penile deformity. Subsequently, substantial evidence has shown that CCH is an effective non-surgical treatment for PD (13). However, the safety and efficacy of CCH in PD remain controversial. We, therefore, conducted a meta-analysis of the current data to provide a higher level of evidence. As far as we know, our study is the first meta-analysis worldwide that systematically illustrates the efficacy and safety of CCH in the treatment of PD.

The PCD is caused by the formation of fibrous plaques in the tunica albuginea, which may cause great trouble for patients with PD in penetrative intercourse. A clinical trial found that, after two CCH injections, 69 patients had a significant improvement in mean percent change for PCD, and the average reduction in curvature is 23° (23). Evidence synthesis in our meta-analysis also indicated that CCH can significantly reduce PCD in patients with PD compared with placebo (p < 0.001), which was consistent with the results of the previous studies (21, 24, 25). Also, the man who is most likely to get PCD improvement is supposed to have curvature between 30° and 60°, longer duration, an international Index for Erectile Function score >17, no calcification, and a set to receive all standard cycles (26). On the other side, however, the practical significance of this improvement remains doubtful and requires further pieces of research, as none of the included studies resulted in a final mean curve <30°, which has been deemed unlikely to inhibit intercourse. Furthermore, for patients with severe curves (>90°), extended curves are recommended to receive surgical management to obtain a superior result (9).

The PD is characterized by penile abnormalities, coital pain, and impaired sexual function, followed by secondary psychological problems. The PDSB and the penile pain score focus on these issues and reflect subjective indicators. Our results confirmed the conclusion from previous studies that CCH can alleviate the PDSB of patients (p < 0.001). Increased tissue compliance and positive psychological suggestions for receiving non-surgical therapy could account for this phenomenon (9). In addition, one researcher (27) considered that the reduction of PCD, penile shortening, and pain during sexual intercourse can alleviate PD-related bothers. However, compared with placebo, CCH was not effective in reducing the penile pain score (P = 0.39), which may be associated with its side effect, inducing penile pain and bruising (28).

Safety is one of the most important indicators of all doctors' and patients' concerns about CCH treatment. Several studies have examined this topic, but the results were not the same. Tsambarlis et al. believed that patients with PD had a higher incidence of TAEs after receiving CCH, and 80% of the patients expressed a certain degree of dissatisfaction during treatment after therapy (29). On the contrary, several Phase 3 clinical trials have proven that patients treated with CCH have higher TAEs, but they were all acceptable, which were similar to our results. Moreover, the most common complications, such as penile pain, penile edema, injection site pain, and contusion, were slight and could recover without intervention. The occurrence of TAEs is also related to doctors' technical and postoperative care and, therefore, the clinical application should always be treated with caution. It is worth mentioning that corporal rupture, a serious adverse event, must be carefully dealt with to prevent its occurrence, as 34% of the providers encountered at least one case, and 67% of them managed the rupture surgically (30).

This study is the world's first meta-analysis of the efficacy and safety of CCH, and, thus, some limitations could not be avoided. First, although more reliable than the previous form, PDSB and the penile pain score were subjective indicators and could be biased by psychologic status in patients. Second, only 4 studies were included in our study, resulting in inadequate statistical confidence, and 3 of them shared the same first author. However, all studies were randomized controlled trials with a high level of evidence and very low heterogeneity in all results, which could make up for this shortcoming.

The present meta-analysis demonstrated that CCH had a significant effect on treating PD. This method could relieve bothering symptoms and provide improvement in PCD and sexual function. Its adverse event rate was higher but acceptable. However, more RCTs with a larger sample size are needed to confirm our findings.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

LL and QW contributed to conception and design. DC and JL contributed to the acquisition of data and critical revision of the manuscript for important intellectual content. DC, JL, YL, YH, BC, ZC, and YS contributed to the analysis and interpretation of data. DC and JL contributed to the drafting of the manuscript. QW contributed to supervision. All authors read and agreed to the published version of the manuscript.

This study was funded by the National Natural Science Foundation of China (Grant No. 82000721), Post-Doctor Research Project, West China Hospital, Sichuan University (Grant No. 2019HXBH089), Health Commission of Sichuan province (Grant No. 20PJ036), and Programs from the Department of Science and Technology of Sichuan Province (Grant No. 2020YJ0054).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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