Are patients undergoing intralesional collagenase Clostridium histolyticum injection therapy for Peyronie’s disease compliant? A 7-year analysis from a tertiary care men’s health center

Abstract

Background

Peyronie’s disease (PD) involves the formation of fibrous scar tissue in the penis, causing pain, deformity, and significant psychological and sexual distress. Intralesional injection of collagenase Clostridium histolyticum (CCH) has emerged as a promising non-surgical treatment, though patients may experience complications and require multiple clinic visits.

Aim

This study aims to evaluate patient compliance with CCH therapy, compare outcomes between compliant and non-compliant groups, and identify reasons for non-compliance.

Methods

This IRB-approved retrospective study analyzed patients with PD between 2017 and 2023. Patients were evaluated by a fellowship-trained andrologist. Patients who elected to have intralesional CCH were initially offered four cycles of treatment, with compliance defined as completing at least four cycles or achieving satisfactory results with fewer cycles.

Outcomes

Data on demographics, disease characteristics, treatment modalities, compliance, and outcomes were extracted from electronic medical records, and causes of non-compliance were identified. Outcomes and complications were compared between compliant and non-compliant groups.

Results

Two hundred and ninety-two PD patients elected to have an intralesional injection of collagenase CCH. Among these, 51.4% completed four treatment cycles, 14.7% received more than four cycles, and 33.9% received fewer than four cycles. The overall compliance rate for injection therapy, including those satisfied with fewer cycles, was 70.89%. Mean pre-treatment curvature for 292 patients was 46.77 ± 14.26 degrees. Compliant patients showed a greater percent of curvature reduction (median 44.44 (IQR 34.17) vs 33.33 (IQR 44.17), P = .034) and less post-treatment curvature in degree (median 25.00 (IQR 17.02) vs 30.00 (IQR 23.75), P = .032) compared to non-compliant patients. Common reasons for incomplete treatment included adverse effects (15.1%), early satisfaction with results (14.1%), and unknown factors (45.4%).

Clinical Implications

Compliance with CCH therapy for PD significantly impacts treatment outcomes. Healthcare providers should address factors contributing to non-compliance. Qualitative studies are recommended to gain deeper insights into non-compliant patients.

Strengths and Limitations

This study analyzed compliance in a large cohort of PD patients and compared outcomes between compliant and non-compliant groups. However, missing data in the non-compliant group and the bias between compliant and non-compliant patients in this retrospective study are major notable limitations.

Conclusion

Overall compliance rate for CCH injection therapy was 70.89%. Greater curvature reduction was demonstrated in compliant patients. Common reasons for incomplete treatment included adverse effects (15.1%), early satisfaction with results (14.1%), and unknown factors (45.4%). However, missing data and bias from retrospective design are major limitations.

Peyronie’s disease, penile curvature, collagenase Clostridium histolyticum

Introduction

Peyronie’s disease (PD) is characterized by the formation of fibrous scar tissue within the tunica albuginea of the penis, causing pain, functional impairment, and cosmetic deformity.^1,2 This condition can severely impact quality of life, leading to psychological distress and sexual dysfunction.^3-5 The etiology of PD remains unclear, but it is believed to involve penile trauma, genetic factors, and abnormal wound healing, resulting in fibrotic plaque and penile deformity.^6,7

Various treatments have been investigated for managing PD, ranging from conservative to invasive approaches. These include oral medications, intralesional injections, mechanical stretching devices, extracorporeal shockwave therapy, stem cell therapy, platelet-rich plasma injections, and surgical interventions.^8-11 Among these, intralesional injection with collagenase Clostridium histolyticum (CCH) has gained popularity in the United States as a promising non-surgical treatment option.¹²

CCH is an enzyme that specifically targets and degrades collagen, the primary structural component of fibrous plaques. By enzymatically breaking down collagen, CCH facilitates the reduction of penile curvature and improves overall penile function.^13,14 The treatment, which involves a series of intralesional injections administered directly into the fibrous plaques, has shown an average curvature reduction of approximately 35% in men with stable-phase PD.

Despite achieving a lesser degree of curvature correction,¹⁵ the patient satisfaction rate is comparable to that of surgical treatments.¹⁶ However, its lengthy treatment regimen requires multiple visits over several months,¹³ increasing the risk of early discontinuation and loss to follow-up compared to other treatments. Several factors also influence patient compliance with CCH therapy, including the perceived effectiveness of the treatment,¹³ the occurrence of adverse effects,¹³ the higher cost of treatment compared to other modalities,¹⁵ and patients’ expectations regarding the treatment process and outcomes.¹⁷ Non-compliance with the treatment regimen can result in suboptimal outcomes, wasted healthcare resources, and diminished patient satisfaction. Furthermore, incomplete treatment may negatively impact the reputation of CCH therapy as an effective management option for PD.

This study aims to evaluate the compliance rate among patients undergoing intralesional CCH injection for PD at a tertiary care men’s health center over a 7-year period. Additionally, the study seeks to compare clinical outcomes between compliant and non-compliant patient groups and to identify the reasons for non-compliance.

Methods

An Institutional Review Board (IRB)-approved retrospective study was conducted (IRB number #20173746). Patients diagnosed with PD who visited the clinics between the years 2017 and 2023 were included in the data collection process.

Patients were evaluated by a fellowship-trained andrologist in a tertiary care university hospital setting in an urban area. Penile deformity assessment was performed following artificial erection, and penile duplex ultrasound was utilized to evaluate plaque and deformity. Curvature was measured using a goniometer, with degrees recorded in two planes (left to right and dorsal to ventral). In cases where curvature presented in multiple planes, a composite curvature was calculated using Pythagorean theorem to add two or more vectors. Patients were instructed that a minimum of three months of stable deformity was required before considering any invasive treatment. Those with a curvature of at least 30 degrees were offered CCH injection therapy as a treatment option, regardless of the severity or complexity of the curvature. However, patients with erectile dysfunction unresponsive to non-surgical treatments or those with a history of CCH allergy were excluded from being offered CCH injection therapy. Treatment modality decisions were made based on discussion between the patients and the clinicians.

The intralesional CCH regimen consisted of two injections of 0.58 mg CCH into the primary plaque at the point of penile curvature, typically 24-72 hours apart (one cycle), for a total of four cycles, with a six-week period between each cycle. Patients underwent penile plaque modeling by the treating physician 24-72 hours after the second injection. Using the plaque as a fulcrum point, the treating physician applied firm, steady pressure to elongate and stretch the penis, holding in this position for 30 seconds. The procedure was repeated three times. Patients were instructed to perform standardized home penile modeling three times daily using a similar procedure during the six-week period between each treatment cycle. Patients were also encouraged to use a penile traction device as an adjunct treatment.

Post-treatment curvature assessment was performed following the completion of all four treatment cycles. Patients who underwent more than four cycles of injection received subsequent deformity evaluations, and those who discontinued CCH treatment before completing four cycles were also offered a deformity evaluation. In cases where multiple post-treatment evaluation results were available, the closest measurement to the time of treatment completion or discontinuation was used for statistical analysis.

Data were extracted from electronic medical records. Demographic variables, including age, weight, height, ethnicity, underlying diseases, sexual preference, and marital status, were recorded. Clinical data related to PD, such as disease onset, presence of pain symptoms, presence of erectile dysfunction, previous treatments for erectile dysfunction, results of deformity evaluations, penile duplex ultrasound parameters, treatment modality, and outcomes, were documented.

Compliance with intralesional CCH therapy was assessed in patients who received at least one injection of CCH. A compliant patient was defined as one who either received at least fours cycles (eight injections) of CCH treatment or received fewer than four cycles but had documented a satisfactory result. Patients who discontinued treatment before completing four cycles for any other reason were defined as non-compliant. Potential causes for non-compliance were identified from medical records without direct patient contact. If no potential reason was identified from the records, the reason was classified as an unknown cause. Post-treatment evaluation results and complication data were collected. Outcomes were compared between compliant and non-compliant groups, regardless of any additional treatments received. Demographic data were presented as mean ± standard deviation (SD) or median and interquartile range (IQR) as appropriate after using the Shapiro–Wilk (n < 50) or the Kolmogorov–Smirnov (n ≥ 50) test for normality. Comparisons of demographic data between compliant and non-compliant groups were analyzed using the t-test, Mann–Whitney U test, or Chi-square test as appropriate. Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 28.0 (IBM Corp, Armonk, NY).

Results

Between January 2017 and December 2023, a total of 573 patients visited the tertiary care men’s health clinics for the assessment of PD. Demographic data for the patient cohort are presented in Table 1. A total of 292 patients (50.9%) received at least one intralesional injection of CCH, and 83 patients (14.5%) underwent surgical correction, including 44 patients who received penile prosthesis surgery. Additionally, 43 patients (14.7%) reported using a penile traction device, and 214 patients (37.3%) did not receive any interventional treatment.

Table 1

Demographic data, pre- and, post-treatment evaluation.

Demographic	Overall (n = 292)	Compliant (n = 207)	Non-compliant (n = 85)	P-value
Age (year)	57.74 + 11.18	57.88 + 11.30	57.4 + 10.95	0.734
Weight (kg)	87.02 + 14.85	86.87 + 15.45	87.37 + 13.34	0.794
Height (cm)	179.07 + 7.79	178.98 + 7.75	179.28 + 7.93	0.769
Onset (month)	12.00 (18.00)	10.00 (12.00)	12.00 (30.00)	0.003
Number of injections	7.38 + 3.18	8.80 + 2.39	3.94 + 2.01	<0.001
Pre-treatment curvature (degree)	46.77 + 14.26	47.08 + 14.57	46.02 + 13.54	0.572
Pain or history of pain (%)	114/292 (39.04)	82/207 (39.61)	32/85 (37.65)	0.755
Erectile dysfunction on initial visit (%)	160/292 (54.79)	110/207 (53.14)	50/85 (58.82)	0.376
Post-treatment	Overall (n = 202)	Compliant (n = 178)	Non-compliant (n = 24)	P-value
Post-treatment curvature (degree)	25.00 (20.00)	25.00 (17.02)	30.00 (23.75)	0.032
Degree improvement	20.00 (20.00)	20.00 (15.86)	15.00 (26.05)	0.225
Curvature reduction (%)	42.86 (34.29)	44.44 (34.17)	33.33 (44.17)	0.034

Data are presented as mean + SD, median (IQR).

P-value are calculated using t-test for mean, non-parametric independent sample median test for median or Chi-square-test for proportion.

Among the 292 patients treated with intralesional CCH therapy, 150 patients (51.4%) completed four cycles, 43 patients (14.7%) received more than four cycles, and 99 patients (33.9%) received fewer than four cycles. Based on the study definition, by combining patients who received at least four cycles of injection and 14 patients who received less than four cycles but were satisfied with the results, the compliance rate for CCH therapy was 70.89% (207/292).

The mean number of CCH injections in the compliant group was 8.80 + 2.39, compared to 3.94 + 2.01 in non-compliant group. Mean pre-treatment curvatures were not statistically different between compliant and non-compliant groups 47.08 + 14.57 vs 46.02 + 13.54 degree. The number of patients who had post-treatment curvature assessment was 178 from 207 (86.0%) in compliant group and 24 from 85 (28.2%) in non-compliant group. Median post-treatment curvature and percent of curvature reduction were more favorable in compliant group, 25.00 (IQR 17.02) vs 30.00 (IQR 23.75) degree and 44.44 (IQR 34.17) vs 33.33 (IQR 44.17) percent, respectively (Table 1). Pre-treatment composite curvature, treatment outcomes, and compliance rate based on curvature direction are stratified in Table 2.

Table 2

Pre-treatment curvature, curvature improvement, and compliance rate stratified by curvature direction.

Curvature direction	N	Mean pre-treatment composite degree curvature + SD	Median curvature improvement in percent (IQR)	Compliance rate (%)
Ventral	21	41.11 + 8.84	33.57 (51.67)	14/21 (66.67)
Dorsal	124	48.66 + 14.76	50.09 (31.06)	86/124 (69.35)
Left	69	41.27 + 13.35	46.63 (41.65)	50/69 (72.46)
Right	20	38.57 + 9.29	49.04 (26.19)	12/20 (60.00)
Ventrolateral	9	59.67 + 10.47	50.72 (56.92)	8/9 (88.89)
Dorsolateral	49	56.08 + 15.06	42.89 (37.64)	37/49 (75.51)
Total	292	46.77 + 14.26	42.86 (34.29)	207/292 (70.09)

The most common reasons for incomplete four treatment cycles were treatment-related adverse effects (15.1%), satisfaction with outcomes before completion of four cycles (14.1%), and unknown reasons (45.4%) (Table 3).

Table 3

Reasons for incomplete four cycles of intralesional injection for treatment of Peyronie’s disease.

Reasons for incomplete four treatment cycles	N	%
Adverse effect (including 4 suspected penile fracture)	15	15.1%
Satisfied with outcome (classified as compliant patient)	14	14.1%
Active comorbidity	9	9.1%
Lack of improvement	7	7.1%
Insurance policy change	6	6.1%
Change to surgery before four cycles	3	3.0%
Unknown	45	45.5%
Total	99	100%

Discussion

This study provides a comprehensive evaluation of patient compliance with intralesional CCH therapy for PD in 292 patients over a 7-year period at a tertiary care men’s health center. The findings offer valuable insights into the factors influencing patient adherence and the clinical implications of compliance on clinical outcomes.

The compliance rate of 70.89% observed in this study indicates that the majority of patients adhered to the CCH treatment regimen as defined by the study criteria. This rate is comparable to the compliance reported in the IMPRESS trials, where 78.8% (434/551) of patients completed four cycles of CCH treatment. A literature review by Amighi et al. reported discontinuation rates ranging from 13% to 56% across various studies.¹⁸ Given the intensive nature of CCH therapy, which requires multiple clinic visits and injections, this compliance rate is encouraging. Notably, 51.4% of patients completed all four cycles, while an additional 14.7% underwent more than four cycles.

The notable proportion of patients (33.9%) who received fewer than four cycles of CCH therapy, however, raises concerns about barriers to full adherence. Understanding these barriers is critical, as non-compliance can result in suboptimal outcomes. Our study demonstrated a significantly lower percent curvature improvement in the non-compliant group compared to the compliant group (33.33% (IQR 44.17) vs 44.44% (IQR 34.17), P = .034). These results partially align with findings from Anaissie et al., who reported that CCH injections improved penile curvature up to the third cycle, with diminishing therapeutic benefit thereafter.¹⁹

The reasons for non-adherence to four cycles, as outlined in Table 2, provide further insights into patient behavior and decision-making. While adverse effects are expected with any therapy, they may have contributed to patient non-compliance. Discomfort from injections, along with potential side effects such as penile pain and swelling, may have discouraged patients from completing the full course of treatment. Additionally, some patients may have had unrealistic expectations regarding the speed and extent of curvature correction, leading to dissatisfaction and early discontinuation of therapy. The financial burden associated with CCH injections, which may not be fully covered by insurance, could also have been a significant deterrent for some patients. Despite these factors, the reasons for non-compliance in 45.4% of patients remained unidentified, warranting further investigation.

As a retrospective study, this research has several limitations, one of which is its inherent nature. The disparity in the number of patients who underwent post-treatment curvature assessments between the compliant (86.0%) and non-compliant (28.2%) groups, as well as the potential bias between patients in each group in this retrospective study, are major limitations. However, the higher follow-up rate in the compliant group suggests greater patient engagement, likely leading to better outcomes. This is supported by the higher mean number of injections received by the compliant group, which correlated with more favorable treatment results. These findings underscore the critical role of adherence in achieving optimal clinical outcomes. Conversely, the lower follow-up rate in the non-compliant group suggests a disconnect between these patients and their healthcare providers, which may have contributed to poorer outcomes. Additionally, the absence of data on adjuvant treatment, post-treatment sexual-related quality of life, and patient satisfaction also impacted the completeness of this study.

Implications for clinical practice

The findings of this study highlighted the need for healthcare providers to proactively address the factors contributing to non-compliance among patients undergoing CCH therapy for PD. A qualitative study should be employed to provide detailed insight into non-compliant patients. Strategies to enhance patient adherence should include comprehensive education about the treatment process, realistic management of patient expectations, counseling on potential side effects, and exploration of financial assistance options.

Additionally, a more personalized approach to treatment, which takes into account individual patient preferences, financial constraints, and tolerance for side effects, could improve compliance rates. Strengthening the patient-provider relationship and ensuring that patients feel supported throughout their treatment journey may help optimize outcomes for men with PD.

Conclusion

This study highlighted the challenges and successes of patient compliance with CCH therapy for PD in a real-world clinical setting. The overall compliance rate for CCH injection therapy in this study was 70.89%. Greater curvature reduction was demonstrated in compliant patients. The significant number of non-compliant patients and the associated lesser curvature improvement underscored the importance of addressing the barriers to adherence. Common reasons for incomplete treatment identified in this study included adverse effects (15.1%), early satisfaction with results (14.1%), and unknown factors (45.4%). However, missing data and bias from the retrospective design remain major limitations.

Acknowledgments

None.

Author contributions

S.L.: Conceptualization-Equal, Data curation-Lead, Formal analysis-Lead, Methodology-Lead. H.N.: Data curation-Supporting. M.A.M.H.: Data curation-Supporting. E.A.C.: Data curation-Supporting. F.A.Y. Conceptualization-Equal, Methodology-Equal, Project administration-Equal.

Funding

None declared.

Conflicts of interest

FY: Coloplast: Advisory board, speaker; Endo: Advisory board; Haleon: Advisory board; Halozyme: Advisory board, speaker; Masimo: Intellectual property; Softwave: Advisory board; Sprout: Consultant; Vertica: Research investigator; Xialla: Advisory board.