Intralesional injection therapies for peyronie’s disease
In addition to oral treatments for Peyronie’s disease (PD), another option for therapy that has become more popular over the last 10-20 years is injection of pharmacologically active agents directly into penile plaques.
One advantage of intralesional treatment compared with oral treatment is localized delivery of a particular agent, which provides higher concentrations of the drug than might be tolerated if given systemically. Several drugs have been used to treat penile plaques with varying degrees of efficacy, including corticosteroids, verapamil, interferon-α-2a or -2b, and collagenases.
Corticosteroids are candidates for treatment of PD because of their anti-inflammatory effects via inhibition of phospholipase A2 and suppression of the immune response (Tranchant et al, 1989).
The first documented use of intralesional corticosteroids for PD (Bodner et al, 1953) reported a decrease in plaque size and penile pain following dexamethasone injection. A second study (Winter and Khanna, 1975) of 21 patients with PD conducted in 1975 failed to confirm these earlier findings, even though a high percentage of the patients who had previously failed other therapies noted decreased pain and plaque size. Investigators concluded that the results of intralesional corticosteroid injections did not differ significantly from what would be expected from the natural history of the disease.
Because of the lack of conclusive evidence showing benefit and because of the adverse effects experienced with long-term use of corticosteroids (eg, local tissue atrophy, thinning of skin, immune suppression), corticosteroid injections are not currently advocated as an intralesional therapy for PD.
Verapamil is a calcium channel antagonist that is thought to selectively inhibit calcium ion flux in both cardiac muscle and cells responsible for intracardiac conduction, as well as in coronary and systemic arteries. The rationale for its use in the intralesional treatment of patients with PD is based on in vitro data that demonstrate transport of extracellular matrix molecules that include collagen, fibronectin, and GAGs as a calcium-dependent process (Roth et al, 1996). In addition to resulting in decreased intracellular calcium, verapamil has been shown to increase collagenase activity, affect cytokine expression associated with early inflammation and wound formation, and inhibit in vitro fibroblast proliferation in PD plaques (Roth et al, 1996; Mulhall et al, 2002).
Use of intralesional injections of verapamil in patients with PD was popularized in a nonrandomized, uncontrolled study (Levine et al, 1994) of biweekly injections of verapamil 10 mg given over a 6-month period that led to subjective decreases in penile narrowing (reported by 100% of patients) and curvature (among 42% of patients) and objective decreases in plaque volume of ≥50% demonstrated in 30% of patients. Patients also reported benefits with respect to plaque softening and erectile function.
There has only been 1 randomized, placebo-controlled, single-blinded study of verapamil (Rehman et al, 1998). This study included 14 patients with PD and consisted of weekly injections of verapamil or placebo for 6 months with pretreatment and posttreatment PDDU used to objectively measure results. Comparing verapamil with placebo, the data obtained showed statistically significant improvements in mean plaque-associated penile narrowing, statistically significant subjective improvements in mean erectile function (42.87% vs 0%, respectively) and subjective softening of plaques in verapamil-treated patients. The mean change in penile curvature with verapamil was not statistically significant (reduction from 370 at baseline to 290; P < .07).
In patients with PD, adverse effects of the therapy that have been reported thus far include nausea, lightheadedness, penile pain, and ecchymosis. No cardiovascular events have been documented, and the adverse effects of verapamil are generally considered to
be mild. Because only 1 study evaluating the efficacy of verapamil has included a placebo arm, additional studies are required to more fully document the benefit of verapamil in terms of altering the natural history of PD.
Phase II Interferon-α-2a or -2b
Interferons are a class of endogenously produced, low-molecular-weight cytokines that function to regulate the normal immune response to foreign antigens. Currently, 3 types of natural interferons have been identified: α, β, and γ. The first suggested use of interferons for the treatment of PD was initiated in a study (Duncan et al, 1991) that treated cultured fibroblasts derived from PD plaques with a human recombinant interferon. Results showed that although the α, β, and γ forms of interferon led to inhibition of fibroblast and collagen production, interferon-γ also caused an increase in GAG and fibronectin production. From these data, the authors hypothesized that interferon-α and -β were reasonable agents for use as intralesional therapies for PD.
The first placebo-controlled study involving interferon-α-2b (Judge and Wisniewski, 1997) examined the effects of interferon 1.5 x 106 units administered intralesionally 3 times weekly over a 3-week period in 13 patients with PD of ≥12 months’ duration. These investigators found that 6 of 10 patients achieved complete resolution of erectile discomfort and significant improvements in penile deformity (mean improvement 200), with those presenting with smaller initial plaque lengths (<4 cm) showing the greatest improvements.
One interesting study that employed magnetic resonance imaging (MRI) to quantitatively assess plaque size in patients with PD prior to and following treatment with interferon-α-2a supported the finding that interferon therapy was more likely to benefit patients presenting with smaller plaques (Polat et al, 1997). Among subjects classified as having plaques 0.5–1 cm in length, complete resolution (at least below the resolution capacity of MRI) was seen, whereas those with plaque lengths of 1.5 and 2 cm achieved mean plaque reductions of 90% and 83.3%, respectively.
The most scientifically definitive study to date on the efficacy of intralesional interferon- α-2b in PD is a singleblinded, multicenter, placebo-controlled, parallel study involving 117 patients published in 2006 (Hellstrom et al, 2006). Fifty-five patients were given interferon-α-2b 5 6 106 units at 2-week intervals over a period of 12 weeks, and each patient was evaluated for penile curvature, plaque characteristics (size, density), penile pain, erectile function, and penile hemodynamics using color flow duplex Doppler and IIEF questionnaires. Significant improvement was seen in actively treated patients compared with placebo (intralesional injection of the same volume of saline) for mean penile curvature (reduction from 49.9u to 36.4u in the interferon group vs 50.90 to 46.40 in the placebo group), mean penile plaque size (reduction from 4.8 to 2.2 cm2 in the interferon group vs 4.5 to 3.6 cm2 in the placebo group), mean plaque density (reduction from 2.29 to 1.52 in the interferon group vs 2.07 to 1.84 in the placebo group [range 0–3 for both groups]), pain resolution (67.7% of patients in the interferon group vs 28.1% of patients in the placebo group), and penile blood flows, whereas mean IIEF scores were not significantly different before and after treatment (interferon 18.3 to 20.8 vs placebo 17.9 to 19.0). These results provide the best efficacy evidence to date supporting the use of intralesional interferon in patients with PD.
Collagenase is a physiological enzyme (also classified as specific matrix metalloproteinase 1, 8, and 13) that is capable of degrading interstitial collagens, such as type II collagen. The first examination (Gelbard et al, 1980) of the effect of collagenase on PD plaques took place in 1985. These investigators utilized highly purified clostridial collagenases (PCCs) to test their effect on various human tissues in vitro, including human pericardium, human corpus cavernosum, tunica albuginea, and PD plaques. Results from these experiments demonstrated a considerable reduction in the size of the PD plaque, along with microscopic fraying and dispersal of collagen bundles, when compared with plaques injected with normal saline. Predictably, elastic fibers, vascular smooth muscle, and axonal myelin sheaths were not affected by collagenase application.
Following up on these in vitro results, this research team performed an in vivo pilot study that involved injecting intralesional PCC (mean dose 2328 units) in 31 men with PD (Gelbard et al, 1985). After 4 weeks of treatment, 65% of patients exhibited objective improvement, 93% reported elimination of pain, and the ability to have intercourse was restored in 75% of patients.
Additionally, the researchers noted that penile plaques were either altered significantly or absent in 4 patients and reduced by 20%–100% in 16 others.
Interestingly, a study evaluating the presence of IgG antibodies to collagenase in healthy men vs those with PD found that antibodies were present in 34% of healthy men vs 58% of men with PD (Hamilton et al, 1986). These data suggest the possibility that collagenase activity is up-regulated in patients with PD or that effective collagenase activity is decreased because of an autoimmune response against the protein.
Because of its documented efficacy, intralesional collagenase (Xiaflex, Auxillium Pharmaceuticals, Philadelphia, PA) therapy was studied an is now an approved treatment in the United States.
In addition to oral and injection routes of drug delivery, topical and transdermal approaches to the treatment of PD have been investigated. Topical preparations of β-aminopropionitrile, hydrocortisone, and verapamil have been reported in uncontrolled trials to have effects ranging from none to significant reductions in pain, penile deviation, and size of PD plaques (Gelbard et al, 1983; Miller and Ardizzone, 1983). However, the true efficacy of topical preparations was called into question following a study (Martin et al, 2002) in which verapamil levels were measured in excised samples of tunica albuginea following 2 applications of topical verapamil. This study showed that verapamil was not present in any of the tunical samples obtained and was recovered in small amounts in the urine. Despite minimal systemic absorption, the lack of demonstrable verapamil in sampled tunica albuginea suggests that there is no scientific basis for its use. As such, topical therapies are not currently recommended by any credible erectile authorities in the treatment of PD.
However, a recent publication by Fitch et al (2007) suggests that long-term (9-month) therapy does provide benefit. Obviously a multicenter placebo-controlled study is needed.
To overcome limitations of topical therapies, emphasis has more recently been placed on testing modalities such as iontophoresis, which enhances the local uptake of drugs. Iontophoresis involves the application of an external electric force to induce further (electromotive) penetration of topical medication and has been evaluated to date with topical verapamil, dexamethasone, and orgotein (Schieroni et al, 1985). This is in contrast to a later study (Martin et al, 2002) that demonstrated no uptake of verapamil in tunica albuginea following topical application. A study (Levine et al, 2003) reported that 71.5% of excised tunica albuginea samples from 14 men who received iontophoresis and topical verapamil therapy prior to undergoing surgical treatment for PD were found to contain measurable levels of verapamil. A subsequent prospective, controlled study evaluated the efficacy of electromotive verapamil and dexamethasone vs electromotive lidocaine (lignocaine) in 96 men with PD (Di Stasi et al, 2004). Men were randomized to receive either verapamil 5 mg 6 dexamethasone 8 mg or 2% lidocaine with a 2.4-mA electric current for 20 minutes, 4 times weekly for 6 weeks. Compared with baseline, significant decreases in median plaque volume (reduction from 824 to 348 mm3) and penile curvature (reduction from 43u to 21u) were seen in the actively treated groups, whereas no changes in plaque volume or curvature were seen in the control group. Significant pain relief was experienced transiently in the control group and permanently in the treatment arm. These results support those of a previous uncontrolled study that reported plaque reduction in 82%, curvature decrease in 84%, and pain elimination in 88% of 49 men who received verapamil and dexamethasone treatment with iontophoresis (Di Stasi et al, 2003).
Intralesional injection therapies have become more popular over the last 2 decades and provide an additional minimally invasive modality for patients with PD. The intralesional approach allows for direct delivery of a particular agent at concentrations that might otherwise be toxic systemically. Use of corticosteroids or orgotein is not currently recommended, and there have been no randomized, placebo-controlled studies clearly documenting their efficacy. Verapamil has been shown in 1 placebo-controlled and numerous uncontrolled studies to have beneficial effects in PD. interferon-α-2a or -2b has been reported in peer reviewed multicenter placebo controlled studies to have efficacy in improving penile curvature, plaque size and density, and to reduce penile pain. Use of collagenase is supported by the results of studies that have revealed significant benefits for this therapy when employed early in the course of PD.
As the definitive pathophysiology of PD has yet to be elucidated, further research is required in this area. Intralesional therapy using various agents (eg, verapamil, interferon, and collagenase) is growing in clinical acceptance and popularity as a minimally invasive approach for the initial treatment of PD. As our scientific understanding of the underlying mechanisms of this perplexing condition increase we can anticipate the development of novel medical therapies for PD.