American Urological Association - Peyronie's Disease

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Home Guidelines Clinical Guidelines Peyronie's Disease (2015)

Peyronie's Disease

Published 2015

The purpose of this clinical guideline is to provide a clinical framework for the diagnosis and treatment of Peyronie's disease (PD).

Unabridged version of this Guideline [pdf]
Appendix A: Peyronie's Disease Treatment Algorithm [pdf]

Panel Members

Ajay Nehra, Ralph Alterowitz, Daniel J. Culkin, Martha M. Faraday, Lawrence S. Hakim, Joel J. Heidelbaugh, Mohit Khera, Kevin T. McVary, Martin M. Miner, Christian J. Nelson, Hossein Sadeghi-Nejad, Allen D. Seftel, Alan W. Shindel, and Arthur L. Burnett

Executive Summary

Purpose

The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of Peyronie's disease (PD).

Methods

A systematic review of the literature using the Pubmed, Embase, and Cochrane databases (search dates 1/1/1965 to 1/26/15) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of PD. The review yielded an evidence base of 303 articles after application of inclusion/exclusion criteria. These publications were used to create the guideline statements. If sufficient evidence existed, then the body of evidence for a particular treatment was assigned a strength rating of A (high quality evidence; high certainty), B (moderate quality evidence; moderate certainty), or C (low quality evidence; low certainty); evidence-based statements of Strong, Moderate, or Conditional Recommendation, which can be supported by any body of evidence strength, were developed based on benefits and risks/burdens to patients. Additional information is provided as Clinical Principles and Expert Opinion when insufficient evidence existed.

Guideline Statements

Diagnosis

1. Clinicians should engage in a diagnostic process to document the signs and symptoms that characterize Peyronie's disease. The minimum requirements for this examination are a careful history (to assess penile deformity, interference with intercourse, penile pain, and/or distress) and a physical exam of the genitalia (to assess for palpable abnormalities of the penis). (Clinical Principle)

2. Clinicians should perform an in-office intracavernosal injection (ICI) test with or without duplex Doppler ultrasound prior to invasive intervention. (Expert Opinion)

3. Clinicians should evaluate and treat a man with Peyronie's disease only when he/she has the experience and diagnostic tools to appropriately evaluate, counsel, and treat the condition. (Expert Opinion)

Treatment

4. Clinicians should discuss with patients the available treatment options and the known benefits and risks/burdens associated with each treatment. (Clinical Principle)

5. Clinicians may offer oral non-steroidal anti-inflammatory medications to the patient suffering from active Peyronie's disease who is in need of pain management. (Expert Opinion)

6. Clinicians should not offer oral therapy with vitamin E, tamoxifen, procarbazine, omega-3 fatty acids, or a combination of vitamin E with L-carnitine. [Moderate Recommendation; Evidence Strength Grade B(vitamin E/omega-3 fatty acids/Vitamin E + propionyl-L-carnitine )/ C( tamoxifen/procarbazine)]

7. Clinicians should not offer electromotive therapy with verapamil. (Moderate Recommendation; Evidence Strength Grade C)

8. Clinicians may administer intralesional collagenase clostridium histolyticum in combination with modeling by the clinician and by the patient for the reduction of penile curvature in patients with stable Peyronie's disease, penile curvature >30° and <90°, and intact erectile function (with or without the use of medications). (Moderate Recommendation; Evidence Strength Grade B)

9. Clinicians should counsel patients with Peyronie's disease prior to beginning treatment with intralesional collagenase regarding potential occurrence of adverse events, including penile ecchymosis, swelling, pain, and corporal rupture. (Clinical Principle)

10. Clinicians may administer intralesional interferon α-2b in patients with Peyronie's disease. (Moderate Recommendation; Evidence Strength Grade C)

11. Clinicians should counsel patients with Peyronie's disease prior to beginning treatment with intralesional interferon a-2b about potential adverse events, including sinusitis, flu-like symptoms, and minor penile swelling. (Clinical Principle)

12. Clinicians may offer intralesional verapamil for the treatment of patients with Peyronie's disease. (Conditional Recommendation; Evidence Strength Grade C)

13. Clinicians should counsel patients with Peyronie's disease prior to beginning treatment with intralesional verapamil about potential adverse events, including penile bruising, dizziness, nausea, and pain at the injection site. (Clinical Principle)

14. Clinicians should not use extracorporeal shock wave therapy (ESWT) for the reduction of penile curvature or plaque size. (Moderate Recommendation; Evidence Strength Grade B)

15. Clinicians may offer extracorporeal shock wave therapy (ESWT) to improve penile pain. (Conditional Recommendation; Evidence Strength Grade B)

16. Clinicians should not use radiotherapy (RT) to treat Peyronie's disease. (Moderate Recommendation; Evidence Strength Grade C)

17. Clinicians should assess patients as candidates for surgical reconstruction based on the presence of stable disease. (Clinical Principle)

18. Clinicians may offer tunical plication surgery to patients whose rigidity is adequate for coitus (with or without pharmacotherapy and/or vacuum device therapy) to improve penile curvature. (Moderate Recommendation; Evidence Strength Grade C)

19. Clinicians may offer plaque incision or excision and/or grafting to patients with deformities whose rigidity is adequate for coitus (with or without pharmacotherapy and/or vacuum device therapy) to improve penile curvature. (Moderate Recommendation; Evidence Strength Grade C)

20. Clinicians may offer penile prosthesis surgery to patients with Peyronie's disease with erectile dysfunction (ED) and/or penile deformity sufficient to prevent coitus despite pharmacotherapy and/or vacuum device therapy. (Moderate Recommendation; Evidence Strength Grade C)

21. Clinicians may perform adjunctive intra-operative procedures, such as modeling, plication or incision/grafting, when significant penile deformity persists after insertion of the penile prosthesis. (Moderate Recommendation; Evidence Strength Grade C)

22. Clinicians should use inflatable penile prosthesis for patients undergoing penile prosthetic surgery for the treatment of Peyronie's disease. (Expert Opinion)

Purpose

This guideline's purpose is to provide direction to clinicians and patients regarding how to recognize Peyronie's disease (PD), conduct a valid diagnostic process, and approach treatment with the goals of maximizing symptom control, sexual function, and patient and partner quality of life (QoL) while minimizing adverse events and patient and partner burden. The strategies and approaches recommended in this document were derived from evidence-based and consensus-based processes. There is a continually expanding literature on PD; the Panel notes that this document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient in the context of that patient's history, values, and goals for treatment. As the science relevant to PD evolves and improves, the strategies presented here will be amended to remain consistent with the highest standards of clinical care.

Methodology

Systematic review. A systematic review was conducted to identify published articles relevant to the diagnosis and treatment of PD. Literature searches were performed on English-language publications using the Pubmed, Embase, and Cochrane databases from 1/1/1965 to 1/26/2015. Data from studies published after the literature search cut-off will be incorporated into the next version of this guideline. Preclinical studies (e.g., animal models), commentary, and editorials were excluded. Additional exclusion criteria were as follows: patients constituted a mixed group among which most patients had congenital curvature rather than PD, and outcomes were collapsed across groups; article focused primarily on surgical technique with minimal or no patient information or outcomes reported; no outcomes reported or outcomes data not extractable; or duplicate report of data presented elsewhere. Review article references were checked to ensure inclusion of all possibly relevant studies. Multiple reports on the same patient group were carefully examined to ensure inclusion of only non-redundant information. The systematic review yielded a total of 303 publications relevant to preparation of the guideline.

PD Diagnosis and Treatment. The systematic review revealed insufficient publications to address PD diagnosis from an evidence basis. With regard to treatment, a total of 281 articles met the inclusion criteria; the Panel judged that these were a sufficient evidence base from which to construct the majority of the treatment portion of the algorithm (see Appendix A). Data on study type [(e.g., randomized controlled trial (RCT), controlled clinical trial (CCT), observational study], treatment parameters (e.g., type of treatment, dosing, follow-up), patient characteristics [e.g., age, symptom duration, penile deformity, plaque, pain, erectile dysfunction(ED)], outcomes (e.g., effects on deformity, plaque, pain, ED, QoL), and adverse events were extracted.

Quality of Individual Studies and Determination of Evidence Strength. The quality of individual studies that were either RCTs or CCTs was assessed using the Cochrane Risk of Bias tool.1 The quality of case-control studies and comparative observational studies was rated using the Newcastle-Ottawa Quality (NOQ) Assessment Scale.2 Because there is no widely-agreed upon quality assessment tool for single cohort observational studies, the quality of these studies was not assessed.

The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and includes not only individual study quality but consideration of study design, consistency of findings across studies, adequacy of sample sizes, and generalizability of samples, settings, and treatments for the purposes of the guideline. The AUA categorizes body of evidence strength as Grade A (well-conducted and highly-generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data). By definition, Grade A evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is evidence about which the Panel has a moderate level of certainty, and Grade C evidence is evidence about which the Panel has a low level of certainty.3

AUA Nomenclature: Linking Statement Type to Evidence Strength. The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, magnitude of benefit or risk/burdens, and the Panel's judgment regarding the balance between benefits and risks/burdens (see Table 1). Strong Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is substantial. Moderate Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is moderate. Conditional Recommendations are non-directive statements used when the evidence indicates that there is no apparent net benefit or harm or when the balance between benefits and risks/burden is unclear. All three statement types may be supported by any body of evidence strength grade. Body of evidence strength Grade A in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances and that future research is unlikely to change confidence. Body of evidence strength Grade B in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence could change confidence. Body of evidence strength Grade C in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence is likely to change confidence. Body of evidence strength Grade C is only rarely used in support of a Strong Recommendation. Conditional Recommendations also can be supported by any body of evidence strength. When body of evidence strength is Grade A, the statement indicates that benefits and risks/burdens appear balanced, the best action depends on patient circumstances, and future research is unlikely to change confidence. When body of evidence strength Grade B is used, benefits and risks/burdens appear balanced, the best action also depends on individual patient circumstances and better evidence could change confidence. When body of evidence strength Grade C is used, there is uncertainty regarding the balance between benefits and risks/burdens, alternative strategies may be equally reasonable, and better evidence is likely to change confidence.

For some clinical issues, particularly diagnosis, there was little or no evidence from which to construct evidence-based statements. Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinion with consensus achieved using a modified Delphi technique if differences of opinion emerged.4 A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence.

TABLE 1: AUA Nomenclature Linking Statement Type to Level of Certainty, Magnitude of Benefit or Risk/Burden, and Body of Evidence Strength
 Evidence Strength A
(High Certainty)
Evidence Strength B
(Moderate Certainty)
Evidence Strength C
(Low Certainty)

Strong Recommendation


(Net benefit or harm substantial)

Benefits > Risks/Burdens (or vice versa)


Net benefit (or net harm) is substantial


Applies to most patients in most circumstances and future research is unlikely to change confidence

Benefits > Risks/Burdens (or vice versa)


Net benefit (or net harm) is substantial


Applies to most patients in most circumstances but better evidence could change confidence

Benefits > Risks/Burdens (or vice versa)


Net benefit (or net harm) appears substantial


Applies to most patients in most circumstances but better evidence is likely to change confidence (rarely used to support a Strong Recommendation)

Moderate Recommendation


(Net benefit or harm moderate)

Benefits > Risks/Burdens (or vice versa)


Net benefit (or net harm) is moderate


Applies to most patients in most circumstances and future research is unlikely to change confidence

Benefits > Risks/Burdens (or vice versa)


Net benefit (or net harm) is moderate


Applies to most patients in most circumstances but better evidence could change confidence

Benefits > Risks/Burdens (or vice versa)


Net benefit (or net harm) appears moderate


Applies to most patients in most circumstances but better evidence is likely to change confidence

Conditional Recommendation


(No apparent net benefit or harm)

Benefits = Risks/Burdens


Best action depends on individual patient circumstances


Future research unlikely to change confidence

Benefits = Risks/Burdens


Best action appears to depend on individual patient circumstances


Better evidence could change confidence

Balance between Benefits & Risks/Burdens unclear


Alternative strategies may be equally reasonable


Better evidence likely to change confidence

Clinical PrincipleA statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature
Expert OpinionA statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence

Limitations of the literature. The Panel proceeded with full awareness of the limitations of the PD literature. Some of these limitations derive from the fact that PD is characterized by symptoms that change over time and by some symptoms that may resolve in the absence of treatment (i.e.,Berookhim 2014; Grasso 2007; Mulhall 2006).5-7 The changing nature of PD symptoms and the possibility that improvement in some patients may be a consequence of the passage of time makes the study of treatment effects challenging. Some symptoms, such as pain, are highly susceptible to placebo effects. These characteristics of PD make it difficult to interpret studies that do not control for the natural history of symptoms or for placebo effects (e.g., observational studies). In addition, because patients may have highly variable courses with or without treatment, findings from studies that have small sample sizes – even well-designed studies – potentially lack generalizability because of the inherent instability of findings derived from small numbers of patients. Further, the quality of any empirical literature depends on its capacity for accurate measurement. An additional complexity of the PD literature is that many studies rely on patient perceptions of changes in deformity and penile dimensions as primary outcomes. This approach is problematic because studies that have compared objective and subjective measures of deformity and penile dimensions report limited or no correspondence between these two methods (e.g., Bacal 2009; Hudak 2013; Matsushita 2014; Taylor & Levine 2008).8-11 Additional limitations include highly variable inclusion criteria across studies in terms of symptom severity and symptom duration.

Process. The Male Sexual Dysfunction Panel was created in 2013 by the American Urological Association Education and Research, Inc. (AUA). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Co-Chairs who in turn appointed the additional panel members with specific expertise in this area. The AUA conducted a thorough peer review process. The draft guidelines document was distributed to 78 peer reviewers. The panel reviewed and discussed all submitted comments and revised the draft as needed. Once finalized, the guideline was submitted for approval to the PGC. Then it was submitted to the AUA Board of Directors for final approval. Funding of the panel was provided by the AUA; panel members received no remuneration for their work.

Background

Definition. The Panel defines PD as an acquired penile abnormality characterized by fibrosis of the tunica albuginea, which may be accompanied by pain, deformity, ED, and/or distress.

Epidemiology. Findings regarding prevalence rates depend on the methodology employed, the sample under study, how PD is defined, and how men are queried with ranges from 0.5% to 20.3% within specific populations. Using a population-based methodology in a U.S. sample aged 18 years and older, Dibenedetti (2011) reported a prevalence rate of 0.5% for men who had been formally diagnosed with PD, a rate of 0.8% for men who had been diagnosed or treated for PD, and a rate of 13.1% for men who had been diagnosed or treated or had any symptom of PD.12 Schwarzer (2001) conducted a community-based study among men in Cologne, Germany and reported a prevalence rate of 3.2% in men aged 31-78 years.13 Another population-based study in Italian men reported a prevalence rate of 7.1% among men aged 50-69 years.14 Among men older than age 40 years screened for prostate cancer in the U.S., a prevalence of 8.9% was reported.15 Men older than 50 years screened for prostate cancer in Southern Brazil had a prevalence rate of 3.7%.16 Rates may be higher among men who present with comorbidities. El-Sakka (2006) reported a prevalence rate of 7.9% among men who presented with ED.17 Arafa (2007) reported a rate of 20.3% among men who were diabetic with ED.18 Together, this group of studies suggests that prevalence rates historically have been under-estimated. The higher rates detected in more recent studies suggest a greater awareness of the disease and its symptoms.

Pathophysiology. PD is an acquired inflammatory disorder of the tunica albuginea. Microvascular trauma to the penile shaft associated with penile buckling in the erect or semi-erect state secondary to sexual activity is thought to be the most common inciting event; however, many patients do not recall an incident that preceded symptom onset. It is hypothesized, however, that repetitive minor trauma to the penis initiates a cascade involving significant extravascular protein deposition, fibrin trapping, macrophage recruitment, cytokine overexpression, and release of elastase leading to changes in the tunical collagen from type 1 to a predominant type 3.19-22 Additionally, trauma is associated with changes in elastin content of the tunica with subsequent inelasticity of the tunica leading to scarring.20,22 The natural degradation of fibrin may be altered secondary to proteins, such as transforming growth factor B1 and plasminogen activator inhibitor type 1, resulting in aberrant tunical healing.19,23,24

Natural History. PD is characterized by symptoms with a variable course, some of which may improve or resolve without treatment in some patients. Mulhall (2006) reported on 246 men newly-diagnosed with PD who had no medical treatment and were followed for at least 12 months.7 At follow-up, all patients who had reported pain at baseline indicated improvement in pain and most (89%) reported complete resolution of pain. Among men with curvature, 12% had improvement, 40% remained stable, and 48% had worsened curvature. Berookhim (2014) reported on 176 men with uniplanar curvature who opted for no treatment and were followed for at least 12 months.5 Sixty-seven percent experienced no change in curvature, 12% improved (mean 27 degree change), and 21% worsened (mean 22 degree change). Men who experienced no change were more likely to be older and to have had symptoms for greater than six months. Men who experienced improvement were more likely to be younger and to have had symptoms for less than six months. Paulis & Cavallini (2013) followed 82 patients who refused PD treatment for approximately 18 months.25 Among patients with pain, 26% had pain disappearance, 37% had pain improvement, 13% had worsened pain, and 26% had unchanged pain. Among patients with curvature, 7% had reduction (mean 5.8 degrees), 11% had no change, and 82% had curvature that worsened (men 12.3 degrees). Plaque volume increased in nearly all patients (96%) but increases were greater among patients < 45 years of age. Grasso (2007) followed 110 men annually for five years (mean follow-up 6.4 years).6 Approximately 68% of patients < age 50 years and 31.5% of patients > age 50 years experienced worsened curvature during follow-up. Significant predictors of worsened curvature were the presence of diabetes and, in contrast to Berookhim (2014), younger age. However, the two studies differ greatly in follow-up duration (>6 years in Grasso, 2007, compared to 12 months in Berookhim, 2014). Pain resolved in more patients > 50 years of age (69%) than in patients < 50 years old (20%). These data suggest that for many or most patients pain will resolve over time without intervention; curvature (or other types of deformity), however, is much less likely to improve and may require treatment if it compromises sexual function and/or is the source of patient or partner distress (see Impact on Psychosocial Functioning and QoL). These data also highlight the challenge to interpret studies that are not designed to control for the passage of time.

Impact on Psychosocial Functioning and QoL. The panel fully recognizes that PD can have a profound negative impact on men's QoL. Many men with PD experience emotional distress, depressive symptoms, and relationship difficulties.26 As many as 81% of men with PD indicate "emotional distress."27 More serious psychological sequelae can occur; one study reported 48% of men had clinically meaningful depressive symptoms (26% moderate, 21% severe) as assessed by the Center for Epidemiological Studies Depression (CESD) scale. It is important to note that these depressive symptoms remained consistently high over time, suggesting PD has a lasting psychological impact on these men.28 Additionally, the stress of PD often extends to men's relationships, and more than half (54%) of men report relationship difficulties as a result of PD.29 Men express concerns about the physical appearance of their penis and report PD negatively impacts their masculine self-image.30 Men with PD also indicate a reduction in sexual satisfaction. They report increased anxiety in a sexual situation, a decrease in sexual confidence, and a concern that they are not satisfying their partner.30 Lastly, men with PD report a sense of isolation as they find it difficult to communicate with their healthcare professionals or partners about PD.30 With these issues in mind, the Panel stresses the importance of assessing for distress in the PD patient before treatment begins and during treatment course.

Patient Presentation

Symptoms. PD is a symptomatic disorder characterized by a disorganized, excessive deposition of collagen that results in formation of a plaque within the penile tunica albuginea. The plaque may restrict tunica lengthening on the effected side during erection, which can lead to penile curvature, penile deformity, penile discomfort, penile pain, and/or ED. Changes in the appearance and function of the penis can be associated with emotional and psychosocial consequences, such as bother, depression, and relationship difficulties.

There are several potential patient presentation scenarios that are seen in clinical practice; some scenarios are more common than others. A most common presentation is the male in his mid-50s who presents with recent onset of penile curvature accompanied by mild to moderate penile pain. The patient usually does not recall a specific sexual or non-sexual event (e.g., an injury) that preceded onset of symptoms. Most often his penile erection is still firm enough for sexual intercourse. The penile curvature or pain, however, may either preclude intercourse or may make intercourse difficult for the patient and/or his partner. The patient and clinician usually cannot palpate any abnormalities on the penile shaft in the non-erect state. The recent onset of penile curvature and varying degrees of penile pain, without a palpable penile abnormality, in the non-erect state, may be considered diagnostic.

Less common presentations include younger men (i.e., in their 20s or 30s) who present with Peyronie's symptoms. This patient may recall a specific sexual event that preceded onset of penile curvature. This patient will have varying degrees of penile pain and may have a palpable penile plaque in the non-erect state. Another less common presentation will be of a middle-aged male patient with a more advanced degree of penile curvature, for example a dorsal and lateral curve with erection, or an indentation in the mid penile shaft with erection. A penile plaque may or may not be palpable in the non-erect state. Again, these conditions will be accompanied by varying degrees of penile pain. A PD patient also may present with ED as his primary complaint and may have undiagnosed PD. Potentially, the PD plaque and/or curvature may only become apparent during pharmacologic testing or at the time of surgery as a penile prosthesis is being inserted.

Active vs. Stable Disease. It is useful clinically to distinguish between the patient with active disease and the patient with stable disease because treatment type depends on whether the patient's symptoms are dynamic or stable.

Active disease. Active disease is characterized by dynamic and changing symptoms. Penile and/or glanular pain or discomfort with or without erection is the defining symptom of the active stage. Symptom onset may be associated with a history of penile buckling during intercourse. The patient may or may not manifest the presence of penile induration – a palpable plaque associated with painful penile deformity and possible curvature. Plaque(s) and penile deformities, including curvature (dorsal, lateral, ventral), shortening, indentation, hinge effect, narrowing, or hourglass deformity, may not be fully developed at this stage. Distress may be present in response to pain and to progressive deformity. Erectile function may be intact or may be compromised by pain and/or developing deformity.

Stable disease. In the patient with stable disease, symptoms have been clinically quiescent or unchanged for at least three months based on either patient report or clinician documentation. Pain with or without erection may be present but is less common. Stable disease means that the deformity is no longer progressive. Curvature may be uniplanar or biplanar and may not be dependent on the size and magnitude of the plaque. Plaque(s) can be palpated or documented on ultrasound. The most common plaque location is on the mid-shaft dorsal aspect of the penis toward the penile hilum or distally retrocoronal. The typical patient presents with a dorsal, dorso-lateral, or ventral penile deformity. Rarely rotational deformities may occur. There may be additional manifestations in the stable phase, including difficulty in maintaining erectile function and inability to sustain intercourse. Erectile function may be compromised by pain and/or deformity or may be reduced because of symptoms of ED not related to deformity or pain. It is reported that ED may be present in up to 33% of PD patients with greater than 50% of patients reporting that ED predated the onset of PD symptoms. Distress is generally present, and the degree of distress will depend on the patient's perception of his symptom severity.

Differentiation. The differential diagnosis is limited. In the young patient, the presence of lifelong ventral penile curvature, no penile pain, no penile plaque, and varying degrees of ability to have intercourse suggest a diagnosis of congenital penile curvature; this presentation should not be mistaken for PD. A thrombosed or torn dorsal penile vein may cause acute onset penile ecchymosis, penile pain, and swelling. A penile fracture is an acute event characterized by a popping sound of the tunica during intercourse, accompanied by penile swelling and ecchymosis. Of note, these two conditions are very acute. Usually the patients present within hours or days, while the PD patient presents in a subacute time frame of weeks to months. Rarely, a primary penile cancer or a metastatic lesion to the penis can be mistaken for PD. Even rarer is a primary penile sarcoma, such as a penile epithelioid sarcoma, or a leiomyosarcoma, which are mistaken for PD.

Diagnosis

The Diagnostic Approach. Insufficient literature was identified to constitute an evidence base for diagnosis of PD in clinical practice. For this reason, the section titled Diagnosis is based on Clinical Principle or Expert Opinion with consensus achieved using a modified Delphi technique when differences of opinion emerged. This section is intended to provide clinicians and patients with a framework for determining whether a diagnosis of PD is appropriate; it is not intended to replace the judgment and experience of the individual clinician faced with a particular patient.

Guideline Statement 1

The clinician should engage in a diagnostic process to document the signs and symptoms that characterize Peyronie's disease. The minimum requirements for this examination are a careful history (to assess penile deformity, interference with intercourse, penile pain, and/or distress) and a physical exam of the genitalia (to assess for palpable abnormalities of the penis). (Clinical Principle)

Discussion


Guideline Statement 2

Clinicians should perform an in-office intracavernosal injection (ICI) test with or without duplex Doppler ultrasound prior to invasive intervention. (Expert Opinion)

Discussion


Guideline Statement 3

Clinicians should evaluate and treat a man with Peyronie's disease only when he/she has the experience and diagnostic tools to appropriately evaluate, counsel, and treat the condition. (Expert Opinion)

Discussion


Treatment

Issues to Consider. It is important to recognize that PD is a symptom complex that may compromise sexual function and QoL but does not appear to affect survival. Given this context in pursuing a treatment plan, the clinician should carefully weigh the potential benefit to the patient of a particular treatment against that treatment's risk for adverse events, the severity of adverse events, and the reversibility of adverse events. For some patients, thoughtful counseling regarding the nature of PD and the typical disease course may be sufficient to alleviate concerns, and a patient may choose not to pursue further treatment. After patient education on normal penile function, the risks and benefits of the various treatment alternatives, and agreement on realistic treatment goals (if the patient desires treatment and is willing to engage in treatment), then a shared decision regarding the treatment plan can be conducted. The guideline statements in this section are intended to provide a framework to assist the clinician in counseling patients and in developing an individualized treatment plan that optimizes sexual function and QoL.

To the Panel's knowledge, there is no agreed-upon minimum curvature necessary prior to intervention. In published studies across intervention types (e.g., oral, topical, intralesional, surgical) that reported average baseline curvature, the range is 10 to 90 degrees, and the median is approximately 48 degrees. Approximately half of studies, therefore, evaluated patients with mean curvature < 48 degrees, and many evaluated patients with mean curvature <30 degrees. Distress over symptoms, penile appearance, and penile function is an important component of the patient experience of PD. The patient's level of concern regarding his symptoms and his willingness to undergo various types of treatment should be fully considered in the treatment decision-making process in addition to objective measures of curvature and erectile function.

The Panel reviewed the evidence on all therapies for PD, including oral, topical, intralesional, mechanical, combination, and surgical therapies. The Panel had three major purposes in evaluating PD treatments. The first purpose was to ensure that patients are not offered treatments that clearly lack efficacy, particularly as the use of those treatments may preclude the use of other treatments that could improve symptoms and alleviate distress. The threshold for categorizing treatments as lacking efficacy was relatively low and was considered met when any single study or group of studies produced generally negative findings. The second purpose was to identify treatments that may have efficacy with regard to one or more PD symptoms. The threshold for efficacious treatments was high because of the need for studies that controlled for PD natural history and placebo effects, engaged in rigorous measurement procedures, were adequately statistically powered, and were replicated. Replication in a high-quality design or convergent findings from a group of sufficiently powered observational studies was considered essential for sufficient certainty that findings would generalize. The third purpose was to identify treatments that may be promising but for which insufficient evidence currently exists to support even a Conditional Recommendation. In the Panel's view, the treatments in this category, even if promising, are unproven until a larger and/or more rigorous evidence base is available. The treatments that fell into this category are discussed in a section that follows the guideline statements called Other Treatments.

Guideline Statement 4

Clinicians should discuss with patients the available treatment options and the known benefits and risks/burdens associated with each treatment. (Clinical Principle)

Discussion


Guideline Statement 5

The clinician may offer oral non-steroidal anti-inflammatory medications to the patient suffering from active Peyronie's disease who is in need of pain management. (Expert Opinion)

Discussion


Guideline Statement 6

Clinicians should not offer oral therapy with vitamin E, tamoxifen, procarbazine, omega-3 fatty acids, or a combination of vitamin E with L-carnitine. [Moderate Recommendation; Evidence Strength Grade B(vitamin E)/ B( omega-3 fatty acids)/ B (Vitamin E + propionyl-L-carnitine )/ C( tamoxifen)/ C(procarbazine)]

Discussion


Guideline Statement 7

Clinicians should not offer electromotive therapy with verapamil. (Moderate Recommendation; Evidence Strength Grade C)

Discussion


Guideline Statement 8

Clinicians may administer intralesional collagenase clostridium histolyticum in combination with modeling by the clinician and by the patient for the reduction of penile curvature in patients with stable Peyronie's disease, penile curvature > 30° and &lt: 90°, and intact erectile function (with or without the use of medications). (Moderate Recommendation; Evidence Strength Grade B)

Discussion


Guideline Statement 9

Clinicians should counsel patients with Peyronie's disease prior to beginning treatment with intralesional collagenase regarding potential occurrence of adverse events, including penile ecchymosis, swelling, pain, and corporal rupture. (Clinical Principle)

Discussion


Guideline Statement 10

Clinicians may administer intralesional interferon α-2b to patients with Peyronie's disease. (Moderate Recommendation; Evidence Strength Grade C)

Discussion


Guideline Statement 11

Clinicians should counsel patients with Peyronie's disease prior to beginning treatment with intralesional interferon a-2b about potential adverse events, including sinusitis, flu-like symptoms, and minor penile swelling. (Clinical Principle)

Discussion


Guideline Statement 12

Clinicians may offer intralesional verapamil for the treatment of patients with Peyronie's disease. (Conditional Recommendation; Evidence Strength Grade C)

Discussion


Guideline Statement 13

Clinicians should counsel patients with Peyronie's disease prior to beginning treatment with intralesional verapamil about potential adverse events, including penile bruising, dizziness, nausea, and pain at the injection site. (Clinical Principle)

Discussion


Guideline Statement 14

Clinicians should not use extracorporeal shock wave therapy (ESWT) for the reduction of penile curvature or plaque size. (Moderate Recommendation; Evidence Strength Grade B)

Discussion


Guideline Statement 15

Clinicians may offer extracorporeal shock wave therapy (ESWT) to improve penile pain. (Conditional Recommendation; Evidence Strength Grade B)

Discussion


Guideline Statement 16

Clinicians should not use radiotherapy (RT) to treat Peyronie's disease. (Moderate Recommendation; Evidence Strength Grade C)

Discussion


Guideline Statement 17

Clinicians should assess patients as candidates for surgical reconstruction based on the presence of stable disease. (Clinical Principle)

Discussion


Guideline Statement 18

Clinicians may offer tunical plication surgery to patients whose rigidity is adequate for coitus (with or without pharmacotherapy and/or vacuum device therapy) to improve penile curvature. (Moderate Recommendation; Evidence Strength Grade C)

Discussion


Guideline Statement 19

Clinicians may offer plaque incision or excision and/or grafting to patients with deformities whose rigidity is adequate for coitus (with or without pharmacotherapy and/or vacuum device therapy) to improve penile curvature. (Moderate Recommendation; Evidence Strength Grade C)

Discussion


Guideline Statement 20

Clinicians may offer penile prosthesis surgery to patients with Peyronie's disease with erectile dysfunction (ED) and/or penile deformity sufficient to impair coitus despite pharmacotherapy and/or vacuum device therapy. (Moderate Recommendation; Evidence Strength Grade C)

Discussion


Guideline Statement 21

Clinicians may perform adjunctive intra-operative procedures, such as modeling, plication or incision/grafting, when significant penile deformity persists after insertion of the penile prosthesis. (Moderate Recommendation; Evidence Strength Grade C)

Discussion


Guideline Statement 22

Clinicians should use inflatable penile prosthesis for patients undergoing penile prosthetic surgery for the treatment of Peyronie's disease. (Expert Opinion)

Discussion


Other Treatments

The Panel identified the treatments reviewed below as possibly promising but for which insufficient evidence currently exists to support even a Conditional Recommendation for their use. In the Panel's view, the treatments in this category are unproven until a larger and/or more rigorous evidence base is available.

Oral Therapies

Colchicine. Five studies evaluated the effects of colchicine either alone or in combination with another oral treatment.271-275 One study was a randomized design with a comparison group administered ibuprofen (Prieto Castro 2003). Although studies generally reported that large proportions of patients exhibited improvements in curvature, plaque, and pain, without controls for the natural history of PD these data remain of uncertain utility.

Pentoxifylline. One randomized design without a placebo control66 and one observational study with a no treatment comparison group276 reported on the effects of pentoxifylline. Alizadeh (2014) compared oral pentoxifylline to intralesional verapamil and combined treatment. Similar proportions of patients in each group experienced curvature and plaque improvement. More patients in the combined group experienced pain reduction and ED improvement than in the pentoxifylline only group. This study is difficult to interpret, however, because only proportion data are provided (no data reflecting magnitude of change are reported) and the study lacks a control for PD natural history. Smith (2011) reported that 92% of the pentoxifylline group had plaque improvement or stabilization compared to 44% of the no treatment group. The Panel judged that some uncertainty remains regarding the efficacy of pentoxifylline given the limited evidence base; replication in a randomized design is needed before pentoxifylline can be recommended as a PD treatment.

Potassium aminobenzoate. One RCT with a high risk of bias277 and one observational study278 evaluated the effects of potassium aminobenzoate. Similar proportions of patients experienced curvature improvement in the active and placebo arms of the RCT but plaque volume decreased more in the active treatment arm than in the placebo arm. The Panel judged that the efficacy of potassium aminobenzoate is unproven given the limited evidence base and the fact that < 100 patients have been evaluated; replication in a high-quality randomized design is needed before it can be recommended as a PD treatment.

Co-enzyme Q10. Co-enzyme Q10 was evaluated in one RCT.279 The authors reported that CoQ10 significantly reduced curvature and plaque size and increased IIEF-5 scores in the active treatment group compared to the placebo group. There were no effects on pain. The efficacy of CoQ10 is unproven given the existence of only one study and the fact that < 100 patients were administered CoQ10; replication in a high-quality randomized design is needed before it can be recommended as a PD treatment.

Topical Therapies

Magnesium or verapamil. Topical magnesium or verapamil were evaluated in comparison to placebo in one RCT.280 Topical verapamil improved curvature and reduced plaque compared to placebo. More patients experienced curvature improvement and plaque reduction in the verapamil group compared to the placebo group. The magnesium sulfate group had results comparable to the placebo group. In the open-label phase of this trial in which patients continued with topical verapamil, the improvements documented in the randomized phase continued. Uncertainty remains regarding the efficacy of topical verapamil given the existence of only one study and the fact that < 20 patients were administered verapamil; replication in a high-quality randomized design with a larger sample size is needed before it can be recommended as a PD treatment.

Topical liposomal recombinant human superoxide dismutase (LrhSOD). Two studies examined the effects of topical LrhSOD – one crossover trial281 and one observational study.282 Topical LrhSOD for four weeks significantly reduced pain compared to placebo. In the open-label phase of this trial, pain improvement continued. Effects on curvature and plaque were not evaluated in the randomized phase but curvature improvements were noted in 23% of patients and plaque reductions in 47% of patients in the open-label phase. In the observational study, 25% of patients reported curvature improvement, 56% reported plaque improvement, and 100% reported pain improvement. Uncertainty remains regarding the efficacy of topical LrhSOD given the small body of evidence, and the fact that < 60 patients were administered LrhSOD; replication in a high-quality randomized design with a larger sample size is needed before it can be recommended as a PD treatment.

Electromotive therapies

Electromotive verapamil + dexamethasone. Six studies, including two randomized designs without placebo control groups67,283 and four observational studies evaluated electromotive verapamil + dexamethasone.284-287 Di Stasi (2004) compared verapamil + dexamethasone electromotive to lidocaine electromotive. Mehrsai (2013) compared verapamil + dexamethasone electromotive to verapamil + dexamethasone intralesional. Verapamil + dexamethasone significantly reduced plaque volume and penile curvature compared to lidocaine electromotive (Di Stasi 2004). Pain improved in both groups but the verapamil + dexamethasone group had longer periods of pain relief. When compared to intralesional verapamil + dexamethasone, electromotive verapamil + dexamethasone reduced plaque volume more and improved IIEF scores to a greater degree, but these changes were not statistically significant.67 Electromotive treatment did, however, improve pain significantly more than did the intralesional treatment. The observational studies generally reported curvature improvements, plaque reductions, and pain improvement. These findings are suggestive that verapamil + dexamethasone may provide benefits to PD patients; however, the randomized designs evaluated < 100 patients and lacked placebo groups. Replication with larger sample sizes with a placebo group to control for placebo effects is needed.

Intralesional Therapies

Intralesional LrhSOD. Three observational studies evaluated the effects of intralesional LrhSOD.288-290 Given the absence of untreated controls, randomized designs, and/or placebo control groups, the studies cannot be interpreted because of the inability to account for change over time in disease state independent of treatment. Given the methodological limits of these studies, the small sample sizes, and the small number of studies, intralesional LrhSOD for treatment of PD remains unproven.

Other intralesional therapies. An additional group of studies examined other types of intralesional treatments. One small RCT291 (n = 32 in the active treatment group) evaluated the effects of nicardipine and reported significant improvement in pain, plaque size, and IIEF-5 scores compared to placebo; both groups exhibited similar curvature improvements. These findings require replication. Additional observational studies evaluated intralesional parathyroid hormone,292 intralesional dexamethasone,293 intralesional betamethasone + hyaluronidase + lidocaine,294 intralesional Iloprost,295 and intralesional verapamil with or without intralesional dexamethasone and with or without lidocaine electromotive.296 Most studies reported improvement in one or more signs and symptoms of PD. However, given the observational designs, small sample sizes, and lack of control for natural history of placebo effects, these findings require replication in randomized adequately-powered designs.

Combination Therapies

An additional group of studies evaluated combination therapies. These included: verapamil intralesional + oral L-carnitine;297 verapamil intralesional + oral tamoxifen;297 interferon intralesional + oral vitamin E;298 verapamil intralesional + oral l-arginine + oral pentoxifylline;299 verapamil intralesional + oral l-arginine + oral pentoxifylline + penile traction;299 oral vitamin E with or without ICI treatments (papaverine, phentolamine, PGE1) and with or without oral colchicine;300 and ultrasound + hydrocortisone.301 These one-of-a-kind studies had small sample sizes and reported a mix of findings. All require replication in appropriately-powered randomized designs.

Mechanical Therapies

Several studies evaluated the effects of therapies categorized as mechanical. Three observational studies reported on the effects of penile traction for 4.5 to 5.0 hours a day302-304 and reported curvature improvements. One observational study evaluated the use of the vacuum pump without the constriction ring305 and also reported curvature improvement. One randomized study assessed hyperthermia (39 to 40 degrees C for 30 min twice weekly; the comparison group received intralesional verapamil) and reported curvature improvement and plaque reduction.68 Sample sizes were small; these findings require replication in appropriately-powered randomized designs.

Future Direction

Given its prevalence and its significant psychosocial impact, better understanding of the pathophysiology of PD is greatly needed. In addition, this knowledge is critical to develop clinical therapies that are effective and safe. The absence of knowledge regarding what causes PD has two major consequences: it is not possible to advise men regarding risk factors and how the disease may be prevented and treatments remain focused on the alleviation of symptoms rather than on addressing causal mechanisms. Ideally, future treatments will be developed with full understanding of the scientific basis of the disease and that demonstrate consistent clinical effectiveness for most or all patients. Research endeavors in this field should continue to address multiple disciplinary areas including epidemiology, risk associations, pathophysiology, psychosocial assessment, diagnostics, clinical pharmacology and therapeutics, and health-related outcomes.

Basic scientific investigation effort should be geared toward elucidating the biologic mechanisms of PD. Current understanding of pathogenesis suggests the involvement of inflammatory factors, cytokines, growth factors and other molecular factors involved in tissue injury, fibrosis and abnormal wound healing. Ongoing scientific investigation that defines the molecular pathophysiology of this disorder can be expected to suggest molecular sites that can be targeted therapeutically. In acknowledgment of a likely genetic determinant or susceptibility for many individuals incurring PD, scientific focus should be intensified in discovering the genetic factors related to this condition. Investigative work involving gene expression profiles and describing gene mutations of cellular proteins involved in tissue fibrosis and plaque calcification is most relevant. Such work also may lead to establishing biomarkers that can be applied for disease evaluation and related diagnostic procedures (e.g., predictors of progression, spontaneous recovery, and possibly treatment response). Purpose in the basic scientific arena also may encompass the application of emerging technologies which, while grounded within advancements in the scientific basis of PD, may yield opportunities for implementing revolutionary therapeutics in the field. Besides such advances in pharmacotherapy, gene therapy, stem cell therapy and regenerative medicine may all be considered as having potential future roles in this condition.

Clinical research is also central and can be expected to involve a translational process flowing from basic scientific discoveries. New drugs or therapies with a scientific foundation will need to be brought forward while adhering to rigorous clinical assessment methodology. Several considerations merit emphasis for clinical therapeutic development in PD in view of widespread deficiencies that were found in studies of therapies for this disease state.

First, studies must be undertaken with full appreciation for the fact that PD is characterized by symptoms that change over time and that some symptoms will resolve in the absence of treatment. In the absence of a control for the natural history of PD, findings from observational studies are of limited value. Journal editors and article reviewers may want to consider whether studies that do not meet methodological thresholds for making a meaningful contribution to the PD body of knowledge merit publication.

Second, some PD symptoms – such as pain -- are highly susceptible to placebo effects. It is not possible to know with certainty whether a new therapy reliably decreases pain in the absence of a placebo control group. Reports of pain relief from studies that were not designed to control for natural history of symptoms as well as placebo effects cannot move the PD treatment literature forward clinically.

Third, because patients may have highly variable courses with or without treatment, findings from studies that have small sample sizes – even well-designed studies – potentially lack generalizability because of the inherent instability of findings derived from small numbers of patients. Replication of findings is critical before new therapies can be offered with confidence.

Fourth, the quality of any empirical literature depends on its capacity for accurate measurement. PD studies must use validated measures of objective and subjective outcomes. Objectively measured outcomes, such as degree of curvature or plaque characteristics or penile dimensions or ED, are critically important to establish that a therapy is effective in reducing these manifestations of PD. Without this information, it is difficult to counsel patients regarding what to expect from specific therapeutic choices and whether a particular therapy is suitable for a specific patient given that patient’s history, values, and treatment goals. A critical component of the patient experience of PD is subjective and includes pain and distress. Pain can be measured validly using visual analog scales. These scales provide reliable documentation of baseline symptoms and responses to treatment. At the time this guideline was created, measures of patient symptomatology and distress (i.e., the PDQ) were undergoing psychometric evaluation306,307 but were not yet fully validated for use in clinical settings. Until a validated measure of distress is available, the Panel emphasizes the need to query patients regarding distress as part of baseline evaluation and follow-up. In addition, patient perceptions of changes in deformity and penile dimensions are not reliable indicators of objective changes, with many patients overestimating the degree of curvature and the extent of penile shortening (e.g., Bacal 2009; Hudak 2013; Taylor & Levine 2008; Matsushita 2014). Importantly, although patient perceptions of deformity may not predict objective measures of deformity, and patient distress is poorly correlated with objective measures of deformity (Hellstrom 2013), patient perceptions of deformity correlate with distress. Therefore, documentation of objective outcomes is critical to provide patients with information regarding actual changes in curvature and penile dimensions. Additionally, the assessment of benefit for a proposed therapy should be based on establishing clinically meaningful change measures, whether they are objectively or subjectively measured.

Tools and Resources

Abbreviations

AEAdverse event
AMSAmerican Medical Systems
AUAAmerican Urological Association
CCTClinical controlled trial
CESDCenter for Epidemiological Studies Depression scale
cmCentimeters
CoQ10Co-enzyme Q10
EDErectile dysfunction
EMDAElectromotive drug administration
ESEvidence strength
ESWTExtracorporeal shock wave therapy
GyGray
ICIIntracavernosal injection
IIEFInternational Index of Erectile Function
IMPRESSInvestigation for Maximal Peyronie's Reduction Efficacy and Safety Studies
LrhSODLiposomal recombinant human superoxide dismutase
mgMilligrams
mJMillijoules
mlMilliliters
mmMillimeter
MRIMagnetic resonance imaging
MUMillion units
NOQNewcastle-Ottawa Quality Assessment Scale
NPTNocturnal penile tumescence
PDPeyronie's disease
PDDUPenile duplex Doppler ultrasound
PDE5Phosphodiesterase type 5 inhibitor
PDQPeyronie's Disease Questionnaire
PGCPractice Guidelines Committee
PSVGeak systolic velocity
QoLQuality of life
RCTRandomized controlled trial
RTRadiotherapy
SPLStretched penile length
SWsShock waves
UUnits
VASVisual analog scale

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