Collagenase clostridium histolyticum (CCH), marketed as Xiaflex® (Endo Pharmaceuticals, Inc., Malvern, PA, USA) [1], was first isolated and purified from the bacterium Clostridium histolyticum in 1953 by Mandl et al [2]. CCH is comprised of a heterogeneous group of seven different enzymes that were found to demonstrate remarkable specificity to digestion of specific protein domains within type I and type III collagen fibers under physiological conditions. Commercially, CCH is available as a mixture of AUX-I collagenases, which cleave the N- and C-terminal ends of triple-helical collagen, and AUX-II collagenases, which hydrolyze internal peptide domains with higher affinity than AUX-I [34]. Furthermore, preclinical studies have demonstrated that AUX-I and AUX-II enzymes are not immunologically cross-reactive and work synergistically to breakdown collagen plaques [5]. The specificity of CCH makes it an attractive therapeutic option for patients with Peyronie's disease (PD), a fibroproliferative condition characterized by the formation of penile plaques composed largely of type I and type III collagens [6].

Studies have demonstrated that CCH exerts pleotropic effects on the development and progression of PD. One in vivo study found that CCH could degrade the collagen fibers abundant in PD, as well as suppress cell adhesion and the maturation of fibroblasts. CCH accomplishes this by downregulating extracellular-matrix associated genes, cytokines and growth factors over-expressed in PD. CCH has also been shown to directly induce membrane leakage and decrease metabolic activity in fibroblasts, as well as reduce expression of alpha-smooth muscle actin, desmin, transforming growth factor beta-1 (TGF-β1), and fibronectin [7]. Furthermore, CCH demonstrates no activity against elastin, keratin, albumin, or hemoglobin [8]. One important feature of CCH is that it does not exhibit activity against type IV collagen fibers, which are heavily expressed in the basal lamina of arteries and veins, and the perineurium of peripheral nerves [8]. Its poor activity against type IV collagen was supported by pre-clinical studies, which demonstrated that CCH did not cause significant degradation of blood vessels, nerves, and epithelium following local injection [91011]. In summary, CCH selectively targets type I and III collagen fibers that generate the pathological curvature in PD, but spare type IV collagen that are important components of normal vascular anatomy of the penis. In 2013, the United States Food and Drug Administration approved CCH for the non-surgical management of PD in men with dorsal or lateral penile curvature >30° with or without a tangible penile plaque [1]. CCH has since become the gold standard in the minimally invasive treatment of PD.

To test the safety of CCH in humans, 19 patients received a single cycle of intralesional injection of CCH (two injections at a dose of 0.58 mg separated by 24~72 hours). Plasma AUX-I and AUX-II levels in subjects with quantifiable levels of the two enzymes were minimal and short-lived. Within 10 minutes of intralesional injection, maximal plasma concentrations of AUX-1 and AUX-II were less than 29 ng/mL and 71 ng/mL, respectively. All subjects had undetectable levels of AUX-I and AUX-II in their plasma within 30 minutes of injection [1213].

Each AUX-I and AUX-II molecule requires fusion of catalytic and collagen-binding domains in order to possess the catalytic activity necessary to degrade collagen. In-vivo studies found that the enzymes require both calcium and zinc to act as cofactors to facilitate proteolysis, as zinc is necessary for activation at the catalytic site, and calcium maintains the appropriate structure of the collagen-binding site to accept the triple-helix structure of the collagen fibrils. When collagenase is injected intralesionally in patients with PD, it specifically targets the collagen within the plaque, which has an abundant amount of type I and III collagen. These enzymes lyse the cord's collagen structure to make it more susceptible to rupture following manual manipulation [914].

Estimating the true prevalence of PD has been a challenge for researchers, given the heterogeneity of subpopulations and clinical settings in which studies have been carried out. Moreover, prevalence estimates may differ greatly by age, pre-existing comorbidities, and socioeconomic status [15161718]. Many clinicians have perceived PD to be a rare disease (<1% of adult males). This perception may be attributed to a 1991 study conducted by Lindsay et al [19] which found a PD prevalence of 0.39% in males ages 19 and older living in Rochester, Minnesota from 1950 to 1984. More recent studies have shown that a significant percentage of the adult population suffers from PD. A large cross-sectional study conducted in 1999 in Cologne, Germany found the prevalence of PD to be 3.2% among all study subjects age 30 to 80 years old, and as high as 6.5% in men over 70 years old [20]. In another study, conducted in 2004 and involving 534 men undergoing prostate cancer screening in the United States, palpable penile plaques were found in 8.9% of patients [21]. In 2011, Dibenedetti et al [22] found, using an open Internet survey, a prevalence of 13% among males 18 years and older who had been diagnosed, treated, or currently had penile symptoms consistent with PD. Unfortunately, many of the aforementioned studies lack consistency with regards to their definition of PD and their reporting methodology, making comparisons between populations difficult. To address this issue, Stuntz et al [23] conducted a cross-sectional study using the same parameters as the Dibenedetti et al [22]. The 2016 study conducted by Stuntz et al [23] found the prevalence of definitive and probable cases of PD in the United States to be 0.7% and 11%, respectively. The estimate of 0.7% for definitive cases is consistent with the 0.5% prevalence of definitive cases found by Dibenedetti et al [22].

Despite improvements in recent estimates, the prevalence of PD is still likely underestimated for a variety of reasons. First, patients may consider the disease to be embarrassing and, therefore, may be unlikely to approach their physician with complaints of penile deformities. Second, patients may also mistakenly consider the effects of PD to be a natural effect of aging. Lastly, the prevalence of PD may be underestimated due to the high rate of comorbid erectile dysfunction, as penile deformities are potentially less notable when the penis is flaccid.

PD is an inflammatory disorder that is characterized by aberrant collagen deposition in the tunica albuginea of the penis leading to fibrous, non-compliant plaques that can impede erection. The most widely accepted theory for the cause of PD is repeated tunical mechanical stress and microvascular trauma to the erect penis. During erection, the tunica albuginea is stretched thin (<0.5 mm) relative to its thickness during the flaccid state (5 mm), making it prone to traumatic injury. Trauma may be brought on by: 1) the woman on top generates upward pressure on the relatively weak septal tunica junction, 2) the man accidentally thrusts his penis against his partner's perineum, thereby fracturing the penis, or 3) aggressive manipulation of the penis during masturbation [24]. Trauma then results in fluid and fibrinogen deposition, which initiates a local wound healing response. Following infiltration of neutrophils and macrophages, cytokines such as TGF-β1 are produced, increasing the production and deposition of collagen by fibroblasts [25]. TGF-β1 has been described as a major driver of the fibroproliferative mechanism in PD. TGF-β1 promotes plaque formation by inhibiting collagenases and stimulating the production of reactive oxygen species (ROS). ROS increase oxidative stress leading to lipid peroxidation, collagen III deposition and possible calcification. In 30 patients with PD, increased expression of TGF-β1 (26/30 patients), TGF-β2 (7/30 patients), and TGF-β3 (5/30 patients) was observed, compared to only 1/8 patients in the Non-PD group [25]. A rat model of PD has also been developed using subtunical injections of cytomodulin, a synthetic peptide with TGF-β-like activity [26]. After six weeks of subtunical injections of cytomodulin, El-Sakka et al [26] found histological and ultrastructural alterations in the rat penis similar to those found in human PD. Using this rat model, Bivalacqua et al [27] demonstrated upregulation of nuclear factor kappa B, a regulator of adhesion molecules and inducible nitric oxide synthase (iNOS) following injection of TGF-β1 and injury to the rat penis. This study supports the notion that iNOS activity may correlate with a protective effect against the development of PD. Francisco et al [28] improved the durability of the rat model by injecting both TGF-β1 and tetradecyl sulphate, which yielded a stronger fibrotic response than TGF-β1 alone. While the precise mechanism of PD is still not fully understood, the interplay between trauma and the resultant expression of profibrotic cytokines continues to be a recurring theme.

The classic signs and symptoms of PD are palpable nodules in the penis that can cause varying degrees of penile deformity and erectile dysfunction. These penile deformities may also manifest as abnormal penile curvature, indentation, hourglass narrowing, and penile shortening, which can have detrimental effects on quality of life. Classically, PD follows two distinct clinical phases: an acute, progressive phase and a chronic, inactive phase. The acute phase involves painful erections with worsening penile deformity that typically lasts between six months and two years [25]. In contrast, the chronic phase is often pain-free and patients have stabilization of penile deformities. In reality, the clinical course of PD is unpredictable, and the optimal time to initiate treatment remains unknown. Some studies have demonstrated stable disease in a majority of patients at 12 months following conservative management [29]. However, other studies have reported that more than half of patients have worsening of curvature at 12 months [30].

Of note, there are also several risk factors and comorbid conditions associated with PD. The most notable of which is Dupuytren's contracture, which mimics PD histologically and is observed in up to 21% of PD patients [3132]. The prevalence of PD in patients receiving radical prostatectomy (RP) has also been reported to be as high as 15.9%, with a mean time to develop PD after RP of 13.9±0.7 months [33]. Penile trauma, diabetes mellitus, Paget's disease, lipomas, the use of beta-adrenergic blockers, plantar fascial contractures, tympanosclerosis, urethral instrumentation, and gout have also been associated with PD; however, no causative link has been described [3435]. In addition, a family history of PD has been documented in 2% of patients [30].

There are myriad medical and surgical therapies available to urologists for managing PD. Topical, oral, and injectable pharmacological treatments along with non-pharmacological treatments such as electromotive drug administration (EMDA), penile traction therapy, and extracorporeal shockwave therapy have been investigated as initial treatment options for patients with PD. Unfortunately, many of the studies evaluating these therapies are underpowered and have failed to demonstrate significant clinical benefit.

The American Urological Association (AUA) does not recommend the use of oral treatments such as vitamin E, procarbazine, omega-3 fatty acids, colchicine, potassium para-aminobenzoate, tamoxifen, pentoxifylline, co-enzyme Q10, and carnitine in the treatment of PD [243637]. These therapies have failed to demonstrate clinical efficacy in reducing penile curvature, plaque burden, and pain compared to placebo. Although many of these therapies do not carry significant adverse side effects, using oral agents alone may postpone the use of other efficacious therapies, leading to delayed treatment and increased costs.

EMDA with verapamil has also failed to demonstrate clinical efficacy in the management of PD, and is thus not endorsed by the AUA [2438]. A randomized-controlled study using verapamil with EMDA (delivered at home) showed minimal improvement over placebo in terms of penile curvature, plaque size, erectile pain, and erectile quality in patients with PD [39]. However, a similar study found no statistically significant improvement in curvature versus placebo [40].

Like oral agents and EMDA, the use of extracorporeal shock wave therapy (ESWT) has been met with mixed results. ESWT is hypothesized to disrupt dense Peyronie's plaques and allow for resolution of penile deformity and pain; however, the exact mechanism has yet to be characterized [41]. Palmieri et al [42] found small non-significant decreases in curvature and plaque burden in patients treated with ESWT compared to placebo. However, several studies have demonstrated no effect on curvature or plaque size, and as such the AUA recommends against the use of ESWT, as well [244344]. Additionally, ESWT may be associated with penile fibrosis and erectile dysfunction, furthering limiting its clinical application [45].

Intralesional injections with interferon-alpha2b, verapamil, and CCH, have proven to be more effective than topical and oral medications in the treatment of PD. Interferon-alpha2b has been shown to inhibit fibroblast proliferation and upregulate collagenase activity, thereby reducing collagen formation [46]. Hellstrom et al [47] conducted the first multi-institutional randomized controlled trial of intralesional interferon-alpha2b in patients with PD >12 months (6 doses), with penile curvature >30°. Patients given 5 million units interferon-alpha2b every two weeks for 12 weeks were compared to placebo. Patients in the treatment arm had significant improvements in curvature (treatment=−13.5° vs. placebo=−4.5°), plaque burden (treatment=2.6 cm² vs. placebo= 0.9 cm²), pain (treatment=68% vs. placebo=28%), and penile blood flow as measured by duplex Doppler ultrasonography. Erectile function as measured by the International Index of Erectile Function (IIEF) did not significantly differ between the two groups. Interestingly, another randomized controlled trial evaluating intralesional interferon-alpha2b in patients within early stage PD (<6 months) did not demonstrate statistically significant improvements in curvature and pain compared to vitamin E alone. These seemingly contradictory findings suggested that interferons should be administered to patients with stable PD [48]. Interferon-alpha2b injections have a good safety profile, with the most common adverse events being self-limiting sinusitis, flu-like symptoms, and minor penile swelling. This can be reduced by administering pre-injection non-steroidal anti-inflammatory drugs. Intralesional verapamil is also believed to increase collagenase activity and decrease collagen production; however, studies have shown mixed efficacy. Although verapamil has demonstrated improvements in plaque size and penile curvature in some studies, other large randomized controlled studies did not show any significant improvement compared to placebo [49505152]. Intralesional verapamil commonly causes side effects such as penile bruising and swelling; however dizziness, nausea, sweating, loss of libido, and pain at the injection site has been noted in some cases [53]. The role of CCH in the treatment of PD will be reviewed in the succeeding section of this article.

Escalation to surgical management is indicated in patients with PD symptoms for at least 12 months and stable penile curvature for at least three months. Surgical techniques used for penile reconstruction include, but are not limited to, tunical plication, tunical incision/excision with grafting, and implantation of a penile prosthesis [24]. It is important for clinicians to consider factors such as the length of the penis, the severity of curvature, nature of the deformity, and degree of erectile dysfunction when selecting a surgical modality. Tunical plication is the most common surgical technique for PD and has demonstrated improvement in penile curvature in >90% of cases. This technique is particularly beneficial for patients with curvatures <60° and normal erectile function (or respond to oral medication or vacuum pump therapy) [5455]. For patients with severe curvature (>60°) or atypical deformity (narrowing or hinge) with normal erectile function, incision/excision and graft placement is employed [56]. Lastly, in patients with severe erectile dysfunction, insertion of an inflatable prosthesis is often recommended.

The treatment of active phase PD remains controversial, as the vast majority of data evaluating CCH's efficacy was conducted using patients with stable disease. Notably, the “Investigation of Maximal Peyronie's Reduction Efficacy and Safety Studies (IMPRESS)” clinical trials required at least one year of stable disease prior to initiation of CCH injections. Given the dearth of studies evaluating CCH in the acute phase, the AUA recommends against treatment until the plaque and curvature no longer demonstrate progression [24]. Fortunately, post-approval studies of CCH are beginning to incorporate patients who meet the acute phase criteria and have been met with positive results.

Yang and Bennett [57] were the first to report the outcomes of patients treated with CCH in the acute phase of PD. The authors included 12 patients with acute phase disease near the time of first injection and found a mean curvature decrease of 20° after treatment compared to a 13.9° curvature decrease in patients treated in the chronic phase (p<0.0001). Despite the small sample size, this study supports the authors claim that CCH may alter the course of PD if intervention occurs during the acute phase. Anaissie et al [58] conducted a retrospective study in 77 patients with heterogeneous forms of PD, 21 of which met criteria for acute phase disease. The authors of this study found that patients with acute phase PD had an overall decrease in penile curvature of −16.2°±16.3°, which was comparable to the change in curvature observed in those with stable PD (−14.9°±11.5°; p=0.702). While this study fails to demonstrate superiority over stable phase intervention, it does provide further support that CCH use in acute phase PD is both safe and efficacious. Future post-approval studies of CCH should continue to incorporate patients with acute phase disease to better characterize these findings. If CCH can be given to patients before severe curvature deformity develops, clinicians may be able to modify the physical and psychosocial impact of this disease.

The efficacy of CCH in the management of stable phase PD has been evaluated through numerous clinical trials and post-approval studies over the past few years. Although the formulation of CCH has remained constant, the protocol in which it is administered has been in continual flux. This section will highlight the efficacy of CCH in the context of a constantly changing protocol.

The early studies evaluating the efficacy of CCH followed a protocol designed by Gelbard et al [3], in which patients were given one or two intralesional injections of CCH and observed for improvements in penile curvature, plaque burden, and penile pain. In this protocol, no penile modeling was performed by the patient or clinician. Gelbard et al [3] conducted the first of these studies involving 31 patients with stable PD. Within 4 weeks of first injection, the authors found that 20 patients (64.5%) had an objective improvement in their PD. PD was eliminated in four patients and penile curvature decreased between 20% to 100% in 16 patients (51.6%). Furthermore, CCH was shown to relieve penile deformity more effectively in patients with greater initial plaque burden. Of the 14 patients who began the study with penile pain, 13 patients (92.9%) reported complete resolution of pain within 4 weeks of treatment. Additionally, three of the four patients who reported erectile dysfunction regained full erectile function following treatment. Despite this success, patients with circumferential plaques and those with decreased erectile rigidity distal to the plaque failed to show improvement of symptoms following treatment [3]. The second of these studies, also conducted by Gelbard et al [59], was a prospective, randomized, placebo controlled, double-blind phase IIa study involving 49 men with stable PD. Patients were assigned different doses of CCH based on curvature and plaque size at presentation (Group 1: ≤30° and/or plaque size <2 cm; Group 2: 30°~60° and/or plaque size 2~4 cm; Group 3: >60° and/or plaque size >4 cm). Patients in Groups 1, 2, and 3 received intralesional CCH at doses of 0.35 mg, 0.58 mg, and 0.81 mg, respectively. When the treatment Groups 1, 2, and 3 were analyzed together for patient-reported improvement of curvature, CCH demonstrated statistically significant benefit compared to placebo (36% vs. 4%, p=0.007). However, when assessing the three treatment arms individually, only the patients treated in Group 2 had statistically significant improvement of curvature. As a result, future clinical studies would go on to adopt the Group 2 dose of CCH (0.58 mg) [59]. The last study to evaluate the efficacy of CCH without modeling in stable PD was Jordan [60], who reported results from a phase IIb trial data on a 9-month, open-label study involving 25 patients. Participants were given three injections of CCH with a total dose of 0.58 mg administered over 7 to 10 days, with repeat injections delivered every three months for three cycles. Interestingly, the greatest reduction in penile curvature and plaque size was observed after a single treatment cycle (at three months). Within the first three months, over 50% of patients experienced decreased curvature and 94% experienced decreased plaque size. Furthermore, patient questionnaires given at each follow-up point demonstrated significant improvements in subjective patient sexual function and quality of life.

The next generation of studies standardized the treatment regimen to include three 6-week cycles of CCH injections coupled with intermittent penile modeling therapy. Each treatment cycle consisted of two injections of CCH (0.58 mg) or placebo with an interval of 24 to 72 hours between the injections. Between 24 and 72 hours after the second injection of each treatment cycle, either the clinician or the patient performed gentle stretching of the flaccid penis for 30 seconds in the opposite direction of the curvature. Gelbard et al [61] was the first to incorporate modeling therapy in tandem with CCH injection in a phase IIb, randomized, double-blind, placebo controlled study that involved 147 patients. In this study, patients in the CCH plus modeling arm had a mean decrease in penile curvature of −17.5°±15.3° (32.4% per patient), which was clinically superior to the mean decrease in curvature observed in both the CCH without modeling arm (−15.0°±14.0° or 27.1% per patient) and the placebo arm receiving modeling without CCH (−5.4°±13.8° or 11% per patient; p<0.001). The promising results from this and other phase I and phase II trials provided the framework with which two large phase III clinical trials, titled “IMPRESS I and II” would be based. These studies were identical prospective, 1-year, double-blinded, randomized, placebo-controlled studies that enrolled a combined 832 men from 64 sites across the United States and Australia [62]. The protocol of the IMPRESS trials mirrored that of Gelbard's phase IIb study [61]; however, in addition to penile modeling by the investigator, patients were instructed to perform home modeling three times per day between each injection cycle. The mean baseline curvature for IMPRESS I and II was 50.1°±14.4° and 49.3°±14.0° in men in the CCH and placebo arms, respectively. Patients in the CCH arm had statistically significant greater reduction in penile curvature when compared to those receiving placebo (−17.0°±14.8° or 34% vs. −9.3°±13.6° or 18.2%, respectively; p<0.0001). Patients in the CCH arm also experienced improvement in the Peyronie's Disease Questionnaire (PDQ) symptom bother domain compared to placebo (p<0.003). All PDQ domains other than penile length and penile pain showed statistically significant improvements in the CCH arm versus placebo. Treatment-related adverse events were observed in 464 patients (84.2%) compared to 102 patients (36.3%) receiving placebo. However, the most common adverse events, such as penile bruising, swelling, and pain were self-limited and 79% resolved without intervention within 14 days. Six patients experienced serious adverse events requiring intervention, including three corporal ruptures and three penile hematomas [62]. Levine et al [63] reported results of another phase III multi-institutional clinical trial involving 347 patients, which utilized the same protocol and endpoints as the IMPRESS trials. Mean penile curvature in the treatment arm decreased by − 18.3°±14.02° (34%) after 36 weeks. Similar to the IMPRESS trials, the CCH arm also demonstrated a statistically significant improvement in mean PDQ symptom bother domain from baseline to week 36 when compared to placebo. The improvements in both curvature and PDQ bother score were evident in patients in the treatment arm irrespective of baseline penile curvature severity. Patients treated with CCH also demonstrated statistically significant improvement in penile plaque firmness, IIEF overall satisfaction score, and penile pain [63].

The most recent generation of studies has continued to use the protocol outlined in the IMPRESS trials, with the caveat that patients perform the modeling themselves beginning on the first day of injections. The utility of home modeling is two-fold. Home modeling allows patients to be more involved with their care and limits manipulation performed by the clinician, which patients often find uncomfortable. Additionally, home modeling reduces the number of required office visits during treatment, thereby minimizing post-procedural costs. The efficacy of CCH with home modeling was first analyzed by Ziegelmann et al [64] in a prospective study involving 69 patients being treated for stable PD. In Ziegelmann's study [64], treatment cycles were administered in the same manner as the IMPRESS trials, but patients were instructed to perform the modeling themselves (rather than the clinician) beginning on the first day of the injection. This study was unique for several reasons. First, the authors utilize multiplanar (or composite) rather than uniplanar measurements of penile curvature, which more accurately characterizes baseline deformity and response to CCH treatment. Patients in the treatment arm had statistically significant improvements in both uni- and multi-planar curvatures after each successive cycle of CCH when compared to placebo. Those with multiplanar deformities demonstrated a 23° (38%) decrease in curvature, while those with uniplanar (purely dorsal or lateral) deformities demonstrated an 18° (33%) improvement (p<0.0001). Second, this study was the first to address the impact of CCH treatment on the need for surgery, which has been associated with erectile dysfunction, as well as decreased penile length and sensation [65]. Among those completing four cycles of CCH, 57% of patients believed that CCH negated the need for surgery, and 52% reported restoration of penetration. Overall, 81% of men perceived CCH treatment as meaningful and 88% reported subjective improvements after four cycles of injections. Seven patients developed penile hematomas (10%) without any reports of fracture or tunical rupture [64]. Yang and Bennett [57] reported the second prospective study involving 49 patients undergoing CCH injections with home modeling (after penile bruising and pain resolved). Patients in this study demonstrated a 15.4° curvature reduction (32.4%) following treatment. Similar to Ziegelmann et al [64], this study had a higher than expected rate of adverse events (10%). However, this may be attributed to more liberal patient selection than in the previous trials. Yang and Bennett [57] incorporated patients with active disease, as well as hourglass and ventral deformities, and placed no restrictions with regards to baseline curvature.

The standard protocol for administration of CCH is outlined in the IMPRESS trials. Using this protocol, each patient receives a total of eight injections split into four cycles of two injections (0.58 mg) given 24 to 72 hours apart from one another at six weekly intervals. During the 24 to 72 hour post-injection period, either the patient or the physician applies traction to the penis in the opposite direction of the curvature to enhance plaque disruption [62]. While this protocol has demonstrated clinical efficacy, there are several drawbacks. First, the standard protocol utilizes small concentrations of CCH, making it difficult to adequately distribute the drug over a wide area of the curvature apex. Second, intralesional injection of CCH causes a local inflammatory reaction that can make it difficult to palpate the plaque for the second injection after 24 to 72 hours. Furthermore, 24 to 72 hours may not be enough time for the inflammation at the injection site to subside before the next injection, potentially contributing to penile bruising and pain. Third, the standard protocol requires 14 patient visits over a 24-week period, which can be a significant burden on patients from a cost and time perspective [66].

In the aforementioned study, Anaissie et al [58] was the first to report findings examining the relationship between the number of treatment cycles and clinical efficacy. This study involved retrospective analysis of 77 patients treated at a single institution using the same treatment protocol as outlined in the IMPRESS trials. In their repeated measures model, penile curvature improved significantly following the first three treatment cycles, but not the fourth. These findings suggest that the four-cycle protocol set forth by the IMPRESS trials may be worth reevaluating. Interestingly, the authors found that patients who had a ≥20% final reduction in curvature had a significantly greater change in curvature following the first injection (−16.2° vs. 5.8°, p<0.001). Thus patients who have a strong response to the first cycle of CCH may be more likely to have a superior final reduction in penile curvature after completion of successive cycles of treatment. Equipped with this information, urologists can counsel patients who have a strong response to initial treatment to complete the CCH regimen. For example, patients who demonstrate a weak response to initial treatment can be told that they may still achieve significant clinical benefit from further cycles; however, final curvature improvement may be limited.

More recently, Abdel Raheem et al [66] evaluated the efficacy and safety of CCH administration using a modified and shortened treatment protocol in 53 patients at a single center. In their shortened protocol, each cycle consists of only one injection with a larger dose of CCH (0.9 mg; whole vial), rather than two injections of the dose (0.58 mg each) outlined by Gelbard et al [6596162] in earlier studies (Fig. 1). This method allows higher concentrations of CCH to be delivered to the plaque while limiting the inflammatory changes that occur with more injections. Furthermore, limiting the frequency of injections in the modified protocol and having patients complete the modeling themselves at home, allows patients to complete treatment in only four patient visits over a 12-week period (Table 1). This undoubtedly improves compliance and reduces costs associated with CCH treatment. More importantly however, this shortened modified protocol demonstrated a mean curvature reduction of −17.4° (−31.4%) from baseline. This is comparable to the results obtained in the IMPRESS trials, which yielded mean curvature reduction of −17° (−34%) from baseline [66]. Moreover, there was an improvement in each of the IIEF questionnaire domains, all 3 PDQ domains, and the global assessment of the PDQ.

Although the vast majority of patients with PD have dorsal and uniplanar curvature, roughly 10% of patients have atypical presentations of PD, including ventral curvature, hourglass narrowing, and multiplanar curvature. Patients with atypical PD often have a greater burden of disease when compared to those with more typical presentations, especially in regard to sexual dysfunction [6768]. Unfortunately, the IMPRESS trials excluded patients with ventral plaques and hourglass deformities due to concerns of urethral damage during injection and modeling therapy. Todate, only one report has been published analyzing the efficacy of CCH in the treatment of ventral plaques. Milam [69] administered four cycles of CCH to two patients with ventral plaques measuring 30° and 45° at presentation. There was a mean improvement of 32° (86%) between the two patients, and both reported marked improvement of symptoms without serious adverse events. This study suggests that ventral plaques can be managed with intralesional injection, and may reduce the need for surgical intervention. Furthermore, intralesional injection poses fewer risks (erectile dysfunction, hematoma, corporal rupture) than surgery, making intralesional injection an attractive option for this patient population. If CCH is not tolerated, patients with ventral plaques may also benefit from intralesional interferon-alpha2b. Stewart et al [70] compared the efficacy of intralesional interferon-alpha2b in the treatment of dorsal versus ventral plaques in a retrospective analysis involving 131 patients. Intralesional interferon-alpha2b reduced curvatures by more than 20° in over 90% of patients irrespective of plaque location. To-date, despite the aforementioned report, clinical trials have not evaluated the use of CCH in the treatment of ventral plaques; however, these studies challenge the framework that atypical PD must be managed surgically.

Similar to the management of ventral plaques, there is a paucity of studies evaluating the management of patients with rare presentations of PD, such hourglass deformity, penile shortening, or multiplanar curvature. A meta-analysis conducted by Yafi et al [68] concluded that surgical intervention using partial excision and grafting or plaque incision and grafting may be the best option for those with atypical presentations. However, for atypical presentations that can result in loss of adequate penile length, non-invasive approaches such as penile traction therapy and pharmacological management should be employed.