In the meantime, we are left with a good deal of ‘voodoo’ being practiced by our patients as they seek answers on the Internet. We also find that many physicians are reluctant to offer any treatment due to the misconception that this disorder has a reasonable likelihood of spontaneous resolution. In fact, the most current natural history studies on Peyronie's disease suggest that no more than 5–13% of men will have spontaneous resolution of their curvature and that up to 50% will have progression until the disease stabilizes [1], [2], [3]. Over the past 10–15 yr, intralesional therapies with verapamil and more recently interferon α-2b have emerged as the most scientifically sound treatments to stabilize or even reduce the deformity [4], [5], [6], [7], [8]. The rationale for using verapamil comes from work done many years ago that demonstrated that collagen production and secretion by fibroblasts is a calcium-dependent process [9]. In vitro experiments also revealed that when fibroblasts were exposed to a calcium channel blocker the protein secretion phenotype of the cells would change, such that they would stop making collagen, and in some cell models, fibroblasts would begin making and secreting collagenase [10]. This may explain the reason verapamil stabilizes the deformity and in responders stimulates remodeling or softening of the plaque with more tissue compliance. Interferon α-2b is also a biologic modifier and appears to work by a similar pathway to verapamil, although the details of how it affects the Peyronie's myofibroblasts is unclear. It has also been shown that when fibroblasts derived from Peyronie's plaques are exposed to verapamil or interferon there is a marked reduction in their proliferation rates [11]. All of these factors favor the use of these agents for treatment of the man with Peyronie's disease. It would also seem beneficial to offer nonsurgical therapy when the disease is most active to have the greatest potential of preventing progression. In addition, the patient with active disease is not a surgical candidate until the deformity is stable for a minimum of 6–9 mo. There may be other mechanisms as to how the intralesional injection of verapamil and interferon may result in improvement of penile deformity. The injection procedure itself may activate a remodeling process, but this has not been evaluated. Importantly, in the few studies in which saline was used as a control arm, negligible benefit was reported in the placebo group [5], [8].

The article in this month's journal entitled “Systematic Evidence-Based Analysis of Plaque Injection Therapy for Peyronie's Disease” by Russell, Steers, and McVary, attempts to assess the value of selected published manuscripts in the peer-reviewed English literature on intralesional therapy for Peyronie's disease [12]. The authors ranked the quality of these papers based on the Oxford Center for Evidence-Based Medicine Criteria. Not surprisingly, very few studies received a high grade based on these criteria. If the goal of this article was to draw attention to the weaknesses of the previously published studies on intralesional injection therapy, the authors have done so, but these weaknesses have been recognized for some time. On the other hand, if the goal of this article was to suggest that intralesional therapy should no longer be offered as a result of the Oxford Criteria ranking, I strongly disagree because we must look more carefully at the results of these published studies and the manner in which they were conducted. Clearly, the ultimate litmus test for any clinical trial in the modern era is a randomized, placebo-controlled, double-blind study. What is not discussed by these authors are the substantial limitations to performing this type of study on men with Peyronie's disease. This includes the fact that historically only a relatively small number of men with this disorder present to any one center, which limits the number of patients entering a trial. In addition, there is no established standard of care to use as a “control,” which when used would do no harm. The fact is, the typical patient with Peyronie's disease is reluctant to enter clinical trials when an invasive placebo is offered due to his fear of worsening the deformity. As a result, accrual to placebo-controlled trials has both practical and potential ethical limitations. Lastly, it is difficult for multicenter studies to be performed because there has been virtually no financial support from industry or government agencies. The authors do point out that verapamil is a generic drug, and as a result, there has been no pharmaceutical support for studying its use for Peyronie's disease. Although it is certainly possible to do a large-scale multicenter study on a non-supported agent, the realities of today's medicine are that these clinical trials are time-consuming and costly, making it difficult to accrue busy doctors at Centers of Excellence to perform the studies.

Several of the published studies on intralesional verapamil have attempted to address the issue of lack of a control arm by very carefully characterizing and measuring the subject's pretreatment and posttreatment erect deformity. When a double-blind, placebo-controlled trial cannot be performed, due to the lack of a viable control, then a recognized approach may be used known as a “quasi-experimental” design, which may provide useful although not perfect information [13]. In this circumstance, the patient can act as his own control as long as proper measurements are made both before and after treatment in a uniform and consistent fashion. Many of the studies on intralesional verapamil graded as a level 4 by the authors would qualify as quasi-experimental design studies because objective and subjective assessments were made and reported on each patient before and after completion of the trial [4], [5], [6], [7]. Many of the older studies on intralesional steroid or interferon injections did not include objective measures of deformity, which makes them non-interpretable.

The evaluation of the papers included in this article may be a commendable academic exercise with the hopes that it will result in a resounding call with better studies. But actually it is of little clinical benefit to the practicing urologist and may act as a disservice, if it persuades the physician to not offer a potentially beneficial treatment for men presenting with Peyronie's disease, with the notion that they will wait until more effective, proven treatments emerge. There is no doubt that having a control group is critical to any study on treatment for Peyronie's disease, but we should not ignore the lessons learned from the more recent non-controlled trials. My hope is that in time, with research into the pathophysiology of Peyronie's disease and the support of the pharmaceutical industry or government agencies (or both) that we will find more effective and reliable treatments of this distressing disorder.

At this time, it is my opinion that in our quest for an effective nonsurgical treatment for Peyronie's disease that the most sensible approach will be combination therapy which will provide a synergy between the chemical changes in the tissue as a result of oral, topical, or intralesional drugs and the application of mechanical stretching forces to the scar tissue. Studies examining vacuum therapy and penile extender devices will be necessary as independent treatments or in combination with drug therapy. We should also remember that not all patients are surgical candidates nor are many of the men with Peyronie's disease psychologically or physically ready to undergo surgical correction of their deformity. Therefore, until a reliable nonsurgical treatment is available, I will continue to offer intralesional verapamil or interferon based on the previously published literature despite the lack of high grades by the Oxford Criteria.

References

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