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European Urology - Systematic Evidence-Based Analysis of Plaque Injection Therapy for Peyronie's Disease

Thursday, 01 March 2007

Volume 51, Issue 3, Pages 640-647 (March 2007)

1. Introduction

Peyronie's disease, an acquired disease of the tunica albuginea surrounding the corpora cavernosa of the penis, affects approximately 3% of the male population with an average age at onset of 57 yr [1], [2], [3]. The etiology of Peyronie's disease remains unknown, but one theory involves traumatic inflammatory changes to the septal fibres of the erect penis from either blunt penile injury or repeated microtrauma associated with sexual activity [4]. Microvascular penile injury leads to fibrin deposition, which in susceptible patients, who may be predisposed to aberrant wound healing, can lead to formation of fibrotic plaques in the tunica albuginea [4], [5], [6], [7]. These plaques can result in a focal loss of elastin with subsequent reduction in penile elasticity, causing penile curvature, pain, decreased length, distal softening, and hourglass deformities [8]. Erectile dysfunction due to loss of tumescence arises when cavernosal fibrosis disturbs the normal veno-occlusive mechanism needed to maintain penile tumescence [9], [10].

A wide variety of treatment options are available for symptomatic Peyronie's disease. Oral medications, including vitamin E, potassium para-aminobenzoate (Potaba), colchicines, tamoxifen, and acetyl-l-carnitine, have been used, usually with little proven effect [11], [12]. Transdermal medications such as verapamil have been used, but testing has shown minimal absorption within the plaque without concomitant electromotive treatment [13], [14]. Noninvasive surgical techniques (e.g., extracorporeal shock wave therapy [ESWL], radiation therapy) have been attempted with questionable success [15], [16]. More invasive procedures (e.g., plaque incision or excision with grafting) have been used successfully for many years in patients with good erectile function [17], [18]. Graft materials have included autologous, synthetic, preserved cadaveric, and bovine/porcine tissue. Patients with Peyronie's disease and poor erectile function often benefit from penile prostheses, which usually succeed in addressing the curvature and erectile function complaints [18].

Because a palpable plaque is commonly found with Peyronie's disease, many treatments have focused on disrupting or removing this tunical scar tissue. Injection of different potentially fibrinolytic drugs directly into the plaque has been used for >50 yr in the treatment of symptomatic Peyronie's disease. Despite this method's rationale, many urologists avoid this practice due to the perception that positive outcomes are lacking or that morbidity (e.g., discomfort, bleeding) outweighs the reported benefits. This study evaluated peer-reviewed urology literature and assessed the quality of Peyronie's plaque injection studies in terms of rigorous evidence-based medicine criteria.

2. Methods

The Medline database was searched for peer-reviewed literature on trials of intraplaque injections for treatment of Peyronie's disease, including trials of corticosteroids, collagenase, interferon α2-β (IFN), and verapamil. Studies combining plaque injections with another form of local or systemic therapy were excluded [19]. The identified studies were then evaluated using the Oxford Centre for Evidence-Based Medicine criteria (www.cebm.net), which use study design and data quality to grade studies as level 1 (meta-analysis or narrow confidence interval randomised, controlled trials), level 2 (randomised, controlled trials with low power or <80% follow-up/retention or good-quality, randomised, prospective, cohort studies), level 3 (case-control studies), level 4 (case series or poor-quality cohort or case-control studies), or level 5 (expert opinion without explicit critical appraisal).

3. Results

The Medline search, using keywords “Peyronie's” and “injection,” produced 77 hits. Non-English papers were excluded. A review of the remaining papers and studies referenced therein identified 19 studies exclusively on plaque injection monotherapy for Peyronie's disease. The other 58 studies involved animal models or were review papers. These 19 studies measured a variety of treatment outcome parameters including degree of angulation, erectile function, plaque size, and penile pain and used a wide range of techniques and scales to measure outcome parameters. Of the 19 studies, 17 (90%) showed subjective or objective (or both) improvement in outcome parameters with plaque injection therapy.

Six studies using injectable corticosteroids were identified, all of level 4 quality according to the Oxford criteria. All six showed positive outcomes from treatment. Table 1 shows study design, number of patients, Oxford criteria rating, and any perceived benefit with treatment for each study.

Table 1.

Summary of studies


Study	Agent	Study type	No. of patients	Oxford level	Benefit with treatment?
Winter 1975 [45]	Corticosteroid	Retrospective	21	4	Yes
Desanctis 1967 [46]	Corticosteroid	Retrospective	28	4	Yes
Teasley 1954 [47]	Corticosteroid	Retrospective	24	4	Yes
Williams 1980 [48]	Corticosteroid	Prospective	45	4	Yes
		Nonrandomised
Toksu 1971 [49]	Corticosteroid	Prospective	5	4	Yes
		Nonrandomised
Furey 1957 [50]	Corticosteroid	Prospective	13	4	Yes
		Nonrandomised
Gelbard 1985 [34]	Collagenase	Prospective	31	4	Yes
		Nonrandomised
Gelbard 1993 [20]	Collagenase	Randomised	49	2	Yes
		Double-blind
		Placebo-controlled
Levine 2002 [22]	Verapamil	Prospective	156	4	Yes
		Nonrandomised
Levine 1997 [21]	Verapamil	Prospective	46	4	Yes
		Nonrandomised
Rehman 1998 [2]	Verapamil	Randomized	14	2	Yes
		Single-blinded
		Placebo-controlled
Levine 1994 [51]	Verapamil	Prospective	14	4	Yes
		Non-randomized
Hellstrom 2006 [24]	Interferon	Randomized	117	1	Yes
		Single-blinded
		Placebo-controlled
Brake 2001 [52]	Interferon	Prospective	23	4	No
		Nonrandomised
Ahuja 1999 [53]	Interferon	Prospective	21	4	Yes
		Nonrandomised
Wegner 1995 [54]	Interferon	Prospective	25	4	Yes
		Nonrandomised
Wegner 1997 [55]	Interferon	Prospective	94	4	No
		Nonrandomised
Judge 1997 [56]	Interferon	Prospective	13	4	Yes
		Unclear if randomised
Polat 1997 [57]	Interferon	Prospective	15	4	Yes
		Nonrandomised

A summary of all reviewed Peyronie's plaque injection studies listed by author, injected agent used, study report type (prospective versus retrospective, randomisation type, blinding type, single versus multicentre), number of patients enrolled in study, the Oxford Centre for Evidence-Based Medicine criteria evidence level, and summary of treatment benefit as assessed by the authors.

Two studies using injectable collagenase were identified: one level 4 and one level 2 study. Both had positive treatment outcomes. The level 2 study by Gelbard et al. was designed in a prospective, randomised, placebo-controlled fashion with a crossover retreatment arm of the control group [20]. Patients were randomised to receive a single intraplaque injection of either collagenase or saline. Parameters assessed included plaque size as measured by calipers, degree of penile curvature as assessed by vacuum-chamber photography, and degree of erectile impairment as assessed by a non-validated questionnaire. Positive response to treatment was defined as improvement in these three parameters as per the patient's subjective opinion that was then confirmed via the objective tests above. Overall, 36% of patients who had collagenase injections reported a positive response as opposed to only 4% in the control arm. When the controls received the collagenase injection in the crossover retreatment part of the study, 56% had a positive response. In patients with a positive response to therapy, the maximum degree of penile angulation improvement was 15–20°.

Four studies evaluating the use of verapamil injections into the plaque showed positive results, including three level 4 and a single level 2 study [21], [22], [23]. The level 2 study, by Rehman et al., was a single-blinded, placebo-controlled study in which 14 patients received weekly intraplaque injections of either verapamil or saline for 6 mo [2]. Parameters evaluated included plaque size as measured by ultrasound or calipers, erectile function as evaluated by a non-validated questionnaire, and degree of penile curvature change as measured by an unspecified physical examination evaluation. Plaque volume decreased in 57% of patients in the treatment arm versus 28% in the control arm. Mean plaque volume in the patients treated with verapamil dropped from 1.42cm3 before treatment to 0.63cm3 after treatment. Improvement in erectile function was reported in 43% of the verapamil patients and 0% of the control group. A total of 28.6% of the men treated with verapamil noted a decrease in penile curvature, with an average decrease from 37.7° to 29.6° following treatment. In contrast, none of the control patients noted such an improvement.

Seven studies evaluated the use of injected IFN, including six level 4 and one level 1 study. Five showed positive outcomes and two showed no significant benefit with treatment. The level 1 study, by Hellstrom et al., was designed in a single-blinded, multicentre, placebo-controlled manner [24]. All 117 enrolled patients had at least a 12-mo history of Peyronie's disease as well as a minimum penile curvature of 30°. Patients were treated with either IFN or saline intraplaque injections on a biweekly basis for 12 wk. Evaluated parameters included penile curvature as measured by a protractor, plaque size as measured by calipers, and erectile function as assessed by the International Index of Erectile Function (IIEF). Curvature improvements were seen in both the IFN and saline groups, but the percent change was greater in the IFN group (27%) than the controls (8.9%). The average absolute improvement in penile curvature for the patients in the treatment arm was 13.5°. Before they started plaque injection therapy, 60.3% of the patients had penile pain with erections. Of these patients, 67.7% of the IFN patients had resolution of their pain after injections versus 28.1% of the controls. Percent change in plaque size was seen in both patient groups, but was larger in the IFN-treated patients (54.6%) than the control group (19.8%). No statistically significant difference was seen in improvement of erectile function as measured by the IIEF when comparing the treatment versus control arms; 13.5% of men in the IFN group and 6.0% of men in the control group reported a subjective increase in their IIEF scores, with these patients showing only a modest average increase of 1–2 points in their IIEF scores.

In an attempt to focus attention on the potential merits of each injection drug, we listed the results of the few controlled studies for three outcome measures: plaque size, degree of curvature, and erectile function (Table 2, Table 3, Table 4). With regards to plaque size improvements, the two controlled studies have reasonably similar deceases in percent volume changes. Additionally, the three controlled studies have similar deceases in curvature change. The erectile function measures are not comparable between studies. Conclusions are not possible because of the wide variability in effect, lack of uniformity in response, and low numbers of subjects.

Table 2.

Plaque volume changes


	Plaque volume: % decrease with treatment	Plaque volume: % decrease in controls	Plaque volume: total decrease with treatment	Plaque volume: total decrease in controls
Collagenase (Gelbard 1993) [20]	Not reported	Not reported	Not reported	Not reported
Verapamil (Rehman 1998) [2]	57%^*	28%^†	1.4 cc^†	0.63 cc^†
Interferon (Hellstrom 2006) [24]	54.6%^‡	19.8%^‡	2.6 cc^§	0.9 cc^§

Plaque volume changes in the three placebo-controlled, level 1 and 2 studies.

^*Statistical analysis not performed.

^‡p<0.04, plaque volume after treatment with verapamil versus control group using the unpaired Student t test with 0.05 the level of significance.

^§ p<0.01, plaque volume after treatment with interferon versus control group as assessed by plaque density measured by a blinded observer using the unpaired Student t test with 0.05 the level of significance.

Table 3.

Curvature changes


	Curvature: % of patients with decrease or % decrease with treatment	Curvature: % of patients with decrease or % decrease in controls	Curvature: total decrease in curvature with treatment	Curvature: total decrease in curvature in controls
Collagenase (Gelbard 1993) [20]	Not reported	Not reported	Maximal improvements 15–20°	Not reported
Verapamil (Rehman 1998) [2]	28.6% patients noted change^*	0% patients noted change^*	37.7–29.6°^†	33.6–31.4°^†
IFN (Hellstrom 2006) [24]	27% change in curvature^‡	8.9% change in curvature^‡	49.9–36.4°^‡	50.9–46.4°^‡

Penile curvature changes in the three placebo-controlled, level 1 and 2 studies.

^* Statistical analysis not performed.

^†p not significant, penile curvature after treatment with verapamil versus control group using the unpaired Student t test with 0.05 the level of significance.

^‡p<0.01, penile curvature after treatment with interferon versus control group as assessed by blinded observer using the unpaired Student t test with 0.05 the level of significance.

Table 4.

Erectile function changes


	ED: % with increase in erectile function	ED: % with increase in erectile function	ED: decrease in total erection score	ED: decrease in total erection score
Collagenase (Gelbard 1993) [20]	Not reported	Not reported	Not reported	Not reported
Verapamil (Rehman 1998) [2]	43%^*	0%^*	5.7–7.4^†	6.3–6.3^†
Interferon (Hellstrom 2006) [24]	13.5%^‡	6.0%^‡	18.3–20.8^‡	18.0–19.1^‡

Erectile function changes in the three placebo-controlled, level 1 and 2 studies.

^* Statistical analysis not performed.

^† p<0.02, quality of erection after treatment with verapamil versus control group using the unpaired Student t test with 0.05 the level of significance. Note that evaluation scale was a non-validated one grading erection quality 1 through 10.

^‡ p is not significant, using the unpaired Student t test with 0.05 the level of significance.

^§ Quality of erection after treatment with interferon versus control group as assessed by International Index of Erectile Function.

4. Discussion

The complexity of Peyronie's disease makes treatment outcomes difficult. This difficulty is further compounded by the many phases through which the disease process evolves [25]. Studies are often unclear as to whether the patients under evaluation include those in the early inflammatory phase, the late fibrotic phase, or a combination of patients from both phases. Treatment in the early inflammatory phase can theoretically reduce the degree of inflammation and break the cycle of fibrin deposition and abnormal tissue remodeling [6], [7]. Treatment outcome evaluation initiated during the inflammatory phase, however, is fraught with problems because the natural history of symptoms during this phase is often one of evolution even in the absence of any intervention. Penile curvature typically changes during the course of the inflammatory phase and has even been noted to resolve entirely in a minority of patients [25], [26]. Penile pain usually resolves once the inflammatory phase has resolved. These natural changes make evaluating the impact of any treatments initiated during the inflammatory phase very difficult, making adequate control groups critical to any study of therapies for Peyronie's disease. Other difficulties in evaluating studies of patients with Peyronie's disease include the lack of consensus on the important outcomes parameters as well as the best way to measure these parameters [23]. For example, it has been noted that the size of a penile plaque is typically unrelated to the severity of a patient's symptoms [23]. Despite its dubious significance, however, change in plaque size is one of the most commonly evaluated treatment outcome parameters due to its ease and objective nature [23]. Add to this the fact that most studies of treatment for Peyronie's disease are uncontrolled and poorly powered, and it is not surprising that there is no general consensus on the best treatment options for this disease outside of more invasive surgical procedures for relatively severe disease, such as plication, grafting, or penile prosthesis placement. A review of the results of surgical therapies is beyond the scope of this study, but Kadioglu et al. recently published an excellent review of the surgical outcomes [27].

The Oxford Centre for Evidence-Based Medicine criteria provide a means of evaluating clinical studies according to strict objective criteria. The quality of clinical studies is ranked on the basis of levels of evidence assigned according to study design and implementation. Exact criteria for each of the levels of evidence can be found on the Web site of the Centre for Evidence-Based Medicine at www.cebm.net. The Oxford criteria have been used by such organizations as the World Health Organization in the systematic evaluation of levels of evidence for the treatment of such disease processes as erectile dysfunction [28].

Injections of pharmaceutical agents directly into the Peyronie's plaque have been used for >50 yr in the treatment of clinically significant Peyronie's disease. In that time, only 180 patients have been treated in controlled studies. Injectable agents have been used both alone (monotherapy) and in combination with other forms of treatment, including ESWL, propionyl-l-carnitine, and hyaluronidase [29], [30], [31], [32]. This review excluded any combination studies and focused only on plaque injection monotherapy.

Corticosteroids exhibit strong immunosuppressive and anti-inflammatory effects. If given during the inflammatory phase of Peyronie's disease, corticosteroids theoretically could alter the inflammatory response and reduce the fibrin deposition with potential improvement of pain and penile curvature. Indeed, all six reviewed corticosteroid injection studies did show subjective improvement in patient symptoms with treatment. Whether the injections detailed in these reports were given during the inflammatory phase is conjecture. However, when evaluated with the Oxford criteria, evidence for the use of corticosteroid plaque injections looks weak, with all studies only level 4 quality. Corticosteroid injections also carry the risk of tissue atrophy, which can make any subsequent open surgical repair more difficult [33]. Based on these findings, we would not currently recommend the injection of corticosteroids for treatment of Peyronie's disease.

Collagenase, a purified bacterial enzyme that attacks and breaks down collagen [34], has been used clinically in the treatment of severe burns and lumbar disk disease [1]. Only two studies evaluated intraplaque collagenase injections and both showed positive results. One study was a level 4 and the second was a level 2 according to the Oxford criteria. The level 2 study by Gelbard et al. was placebo-controlled, prospective, and randomised but used relatively small sample sizes (22 and 25 patients in the control and treatment arms, respectively) and failed to report on the mean change in curvature, plaque size, or erectile function over the course of treatment [20]. No hypersensitivity reactions were noted in these studies, and the injections seemed relatively safe, but further well-designed, more robustly powered studies are needed to prove their efficacy and safety.

Intracellular calcium levels play an important role in the metabolism and synthesis of collagen [35], [36]. Calcium channel blockers such as verapamil increase collagenase activity and decrease collagen secretion, although quite high tissue doses are needed for this [37]. Verapamil has been used clinically to treat burn scars and has been shown to decrease the formation of peritoneal adhesions in animal models [38], [39]. Four studies evaluated verapamil plaque injections for the treatment of Peyronie's disease, and all showed benefit with treatment. One study was level 2 according to the Oxford criteria, and the rest were level 4. The level 2 study was a single-blinded, placebo-controlled study, but the power of the conclusions was hampered by its small patient population: only 14 patients divided equally between treatment and control arms [2]. Verapamil injections seemed safe and well tolerated and appear effective in men with mild to moderate Peyronie's disease, but their efficacy needs to be verified with randomised, placebo-controlled trials. It must be acknowledged that expensive multicentre randomised trials will be more difficult to conduct because verapamil is a generic drug, making pharmaceutical industry support unlikely.

The IFNs, low-molecular-weight proteins involved in the normal functioning of the body's immune system [40], are known to inhibit the proliferation of myofibroblasts, decrease collagen production, and increase the activity of collagenase [40], [41]. IFN has been used clinically in the treatment of keloid and hypertrophic scar formation [42]. Recent publications suggest that expression and activity of Smad transcription factors of the transforming growth factor-β (TGF-β) pathway is increased in fibroblasts of patients with Peyronie's disease. Alterations in the TGF-β pathway seem to be a pathogenetic factor in the development of Peyronie's disease [43]. Intraplaque injections of IFN for Peyronie's disease were supported by the strongest level of evidence, with one well-designed study meeting level 1 Oxford criteria and showing positive results with treatment. Overall, five of the seven studies showed a benefit with therapy, whereas two (both level 4) did not. The level 1 study, a single-blinded multicentre, placebo-controlled study, enrolled 117 patients, with 55 and 62 patients in the treatment and control arms respectively, although 14 patients (9 controls and 5 in treatment group) dropped out secondary to other health problems, lack of perceived benefit, or discomfort with the injections [24]. The Hellstrom study is most interesting because of its power, the inclusion of a control group, and the use of validated measures such as the IIEF. IFN injections were a relatively safe form of therapy with only limited flulike side-effects in some patients [40]. Limited clinical evidence seems to suggest that intraplaque injections of IFN are a safe and effective treatment for mild to moderate Peyronie's disease, but these findings should be confirmed with further well-designed studies. The findings of this systematic review of level of evidence are supported by a recent review of nonsurgical therapies for Peyronie's disease [44].

5. Conclusions

Ninety percent of the studies published in the peer-reviewed literature over the last 50 yr regarding intraplaque injection therapy for Peyronie's disease have shown positive subjective or objective treatment outcomes. Unfortunately, most studies have not offered convincing evidence-based data as per the Oxford criteria, with only one positive study meeting level 1 criteria for clinical efficacy. Standardised outcome measures were not used, making comparisons difficult. Development of validated outcome measures and well-designed randomised, double-blind, controlled trials will help determine optimal therapeutic intervention for this debilitating disorder.

Conflicts of interest

Dr. Russell has nothing to disclose.

Dr. Steers is a Pfizer-investigator, a Novartis, Sanofi-Adventis-consultant, an investigator, and an Astellis-consultant.

Dr. McVary is a Pfizer, Lilly-ICOS, GlaxoSmithKline, Boston Scientific, Merck, Sanofi-consultant/advisor, investigator, meeting participant, lecturer.

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Shane Russell, William Steers, Kevin T. McVary

Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
Department of Urology, University of Virginia, Charlottesville, VA, United States

Accepted 17 October 2006 published online 7 November 2006.

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