Intralesional interferon-[alpha]-2B injections for the treatment of Peyronie's disease.

Background: Intralesional therapies provide an alternative to surgical treatment of Peyronie's disease (PD). This study examines the efficacy of intraplaque injections of interferon-[alpha]-2B (IFN-[alpha]-2B) in the treatment of PD.

Methods: Twenty-five patients were enrolled in the study with 21 completing the study. The average age of the study participants was 55.8 years, with 10 of the 21 having diabetes, hypertension, or both. Seven patients received placebo injections using 10 ml saline bi-weekly for 6 weeks before interferon therapy, and all 21 patients received biweekly injections of 2 X 1[0.sup.6] U IFN-[alpha]-2B for 6 weeks before reevaluation. Patients were evaluated with duplex Doppler ultrasonography to assess penile curvature and blood flow.

Results: The International Index of Erectile Function questionnaire was completed by 14 of 21 men to assess severity of erectile dysfunction (ED) before and after treatment. Improvements of 20% or more in penile curvature occurred in 14 (67%) of 21 men. Penile pain decreased in eight (80%) of 10, and plaque size decreased subjectively in 15 (71%) of 21 participants. The International Index of Erectile Function questionnaire showed significant improvement of ED in five (71%) of seven men with baseline moderate to severe ED. Peak systolic blood flow improved in three (43%) of seven men with baseline hemodynamic impairment, and veno-occlusive disease resolved in three (18%) of 17 individuals. IFN-[alpha]-2B injections led to significant improvements in penile pain and curvature caused by PD.

Conclusion: Results of intralesional IFN-[alpha]-2B injections in improving ED are encouraging. The study findings warrant further investigation of the effectiveness of IFN-[alpha]-2B injections for treatment of PD.

Key Words: interferon-[alpha]-2B, intralesional, nonsurgical, Peyronie's disease

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Peyronie's disease (PD), which was named after Louis XIV's personal physician Francois Gigot de la Peyronie after his publication on this condition, is characterized by an inelastic, fibrous scar involving the tunica albuginea of the corpus cavernosa. This condition affects approximately 3.7% of men aged 40 to 70 years, with numerous reports of younger individuals affected. (1) A palpable plaque, painful intercourse, and penile curvature are common manifestations of PD. In addition, approximately 30 to 40% of patients complain of significant erectile dysfunction (ED). Altogether, these symptoms can lead to a significant decrease in quality of life and adverse psychological effects in as many as 77% of patients. (2) Recent theories propose that PD results from penile trauma and injury to the tunica albuginea during sexual intercourse. The microinjury and bleeding in the tunica albuginea leads to fibrin deposition and cytokine release as the healing process is initiated. In PD, evidence suggests that the tunica albuginea displays a disordered wound-healing process--an imbalance between scar formation and remodeling. As a result, there is prolonged and aberrant healing that leads to plaque formation.

Intralesional injection of Peyronie's plaques has been a focus of nonsurgical therapy in the treatment of PD for many years. In the 1950s steroid injections were reported to reduce both plaque size and penile pain but were also associated with local tissue atrophy and fibrosis that hindered any further surgery. (3) Controlled studies with intralesional collagenase demonstrated significant benefits in penile curvature in patients with less severe forms of PD. (4) Recently, intralesional injections of calcium-channel blockers have gained popularity. By blocking calcium, an essential component for the extracellular transport of collagen, uncontrolled studies with verapamil have shown improvement in penile curvature in 60% of PD patients with few adverse effects. (5) However, the benefits of this treatment have been limited to patients with minimally calcified plaques and penile deviation of less than 30 degrees. (6)

On the basis of dermatologic in vitro fibroblast studies demonstrating inhibition of fibrosis by interferons, clinical research has focused on intralesional interferons for the treatment of PD. A number of clinical trials have demonstrated significant changes in penile curvature, plaque size, and penile pain. (7-9) Other studies have questioned the benefits of interferon therapy. (10), (11) Differences in technique or therapeutic regimen may have contributed to the different conclusions reached by these studies. The dosage of interferon and its frequency of administration may be an important factor in the efficacy of treatment. This study used a dose of 2 X 1[0.sup.6] U of interferon-[alpha]-2B (IFN-[alpha]-2B) in 10 ml of normal saline twice a week for a 6-week period. The dose of interferon and the dosing regimen of this study differ from that of other studies previously conducted by Tulane University, which used 1 X 1[0.sup.6] U of IFN-[alpha]-2B biweekly for 6 months and 4 X 1[0.sup.6] U of IFN-[alpha]-2B once a week for 10 weeks. (7), (9) In this clinical trial, we further report on the safety and efficacy of intralesional interferon therapy, and evaluate changes in vascular dysfunction and ED.

Patients and Methods

Twenty-five men with PD (mean age, 55.8 yr; age range, 30-73 yr), were enrolled in this clinical trial at Tulane University Medical Center in New Orleans, LA, with 21 men completing the study. The entry criteria for the trial required that the patients have PD for a minimum of 6 months with a penile curvature of at least 15 degrees. Individuals with severely calcified plaques and those currently taking oral ta-moxifen or Potaba were excluded. Of the 21 men in the study, five had received and failed treatment with both vitamin E and Potaba, and an additional four had used vitamin E only. Four patients had a prior history of significant genital trauma and one also had Dupuytren's contracture. Five subjects had been prescribed [beta]-adrenergic blockers, and three had taken oral calcium-channel blockers. Ten of the 21 participants had diabetes mellitus (DM), hypertension (HTN), or both. Of these 10, three patients had both DM and HTN, four patients had DM, and three other patients had HTN (Table 1).

Each patient was asked to complete the International Index of Erectile Function (IIEF) questionnaire before and after treatment. (12) An additional survey was also completed to assess their sexual histories, prior treatments, risk factors, and subjective perceptions of their disease. All participants were informed of the goals and techniques of the trial before giving their written consent. Full medical history, physical examinations, complete blood count, blood chemistries, and liver function tests were performed before treatment.

Baseline objective evaluations of penile rigidity and cavernosal blood flow were assessed by an intracavernosal injection with 10 to 15 [micro]g prostaglandin [E.sub.1] followed by duplex Doppler ultrasonography. (13) In addition, an objective measurement of penile curvature was obtained using a protractor (Bracco Diagnostics, Princeton, NJ). To ensure consistency, the same individual performed all diagnostic tests for every participant.

For each injection, a dorsal and circumferential anesthetic block of the penis was performed using 5 ml of 1% Xylocaine and 5 ml of 0.25% bupivacaine. In the control series, 10 ml of normal saline was injected through multiple sites using a 27-gauge needle into the plaque as described by Levine et al. (14) After completion of the series of control injections and a washout period of more than 1 month, the seven control patients crossed over and received 2 X 1[0.sup.6] U of IFN-[alpha]-2B in 10 ml of normal saline in a manner identical to that administered to the 14 noncontrol patients. For both the control and the interferon series, injections were given twice weekly for a total of 6 weeks. Before each injection, the patient was questioned about any adverse side effects to the interferon therapy and any subjectively perceived improvements in their symptoms. After completion of the protocol, each patient was scheduled for a 4-week follow-up appointment, in which he underwent penile duplex Doppler ultrasonography with intracavernosal prostaglandin [E.sub.1] and objective measurements of penile curvature. Each patient was asked to complete the posttreatment IIEF questionnaire.

Results

Twenty-one of 25 men who were enrolled completed the study. The remaining four patients dropped out of the study either because of concomitant health problems or dissatisfaction with the progress made. Seven patients received both series of saline control and interferon injections, and 14 received interferon injections alone. During the saline control phase, none of the seven control patients expressed any adverse side effects or subjective benefit in penile pain or curvature. Tables 2 and 3 summarize the results of the intralesional IFN-[alpha]-2B injections on penile curvature, plaque size, and pain.

As shown in Table 3, 14 (67%) of the 21 men showed significant changes in penile deviation with improvements of greater than 20%. The average improvement in penile angulation of the 21 study participants was 25%. Ten men experienced 20 to 40% improvements; one had a 40 to 60% improvement. Three subjects with penile curvatures of 30, 15, and 15 degrees had complete resolution of this problem. Three men reported minimal improvements of less than 20%, whereas one patient had no change in penile deviation. The remaining three patients exhibited worsening of penile curvature at the end of the study, with a mean increase in angulation of 44 degrees. Of the 10 men who had penile pain before the treatment, eight reported significant alleviation of this complaint. Although two patients did not perceive any subjective improvement in penile pain, neither man indicated any worsening of this symptom. In addition, 15 (71%) of the 21 participants noted subjective softening or decreasing size of their penile plaques. The only side effects of the interferon injections were local penile tenderness or bruising at the injection site and a few hours of mild flulike symptoms--fevers, chills, sinusitis, and arthralgias--which were effectively treated with an over-the-counter nonsteroidal anti-inflammatory agent.

The IIEF questionnaire was also incorporated into the study to further assess any changes in erectile function of the participants. The questionnaire was completed by 14 (67%) of the participants. The remaining seven men did not fill out the posttreatment questionnaire. The method developed by Cappelleri et al, (15) which uses the erectile function domain to identify ED, was adopted for our study. Before the interferon therapy, seven (50%) of the 14 had normal erections or mild ED, and the other seven (50%) had moderate to severe ED. After completion of the study, five (71%) of the seven patients with moderate to severe ED showed significant improvement (increase >5) from their baseline score. The results of the IIEF questionnaires are shown in Tables 4 and 5.

Table 6 shows the results of penile duplex Doppler ultrasonography studies performed on the 21 patients. Adopting the standard measurements used by several other studies, a peak systolic velocity greater than 30 cm/s was indicative of normal cavernosal arterial hemodynamic integrity. A velocity falling between 25 to 30 cm/s suggested mild hemodynamic impairment, and measurements less than 25 cm/s were indicative of impaired penile arterial inflow. At the beginning of this study, penile blood flow was normal in 14 participants, mildly reduced in four men, and significantly impaired in the remaining three men. After completion of the intralesional interferon injections, the follow-up duplex showed that two men with minimal impairment had regained normal hemodynamic function, another worsened into the severe range, and the last remained unchanged. Of the patients with severe hemodynamic impairment on the baseline duplex, one exhibited improved cavernosal blood velocities to normal levels, whereas the remaining two men showed no improvements.

Duplex ultrasonography was also useful in analyzing veno-occlusive disease. Using an end-diastolic velocity of 5 cm/s or less to denote normal vascular function, duplex scans revealed abnormal vascular leakage in 17 patients (81%). Before initiation of the study, the mean blood flow in these affected men was 10.5 cm/s. After completion of the interferon protocol, the vascular leakage component resolved completely in three men (18%). However, the end-diastolic velocity remained abnormal in the other 14 men with a mean end-diastolic velocity of 9.8 cm/s.

Discussion

Interferons are low molecular weight proteins and glycoproteins that are an important component of the immune system because of their antiproliferative and antitumorigenic effects. In 1991, in vitro studies on PD-derived human fibroblasts by Duncan et al (16) demonstrated that interferons hinder fibroblast production, decrease collagen synthesis, and up-regulate collagenase activity. Follow-up studies by Ahuja et al (17) documented that the presence of IFN-[alpha]-2B diminishes collagen production in corpora cavernosal-derived myofibroblasts.

In 1995, the first clinical trials of intralesional interferon therapy were reported by Wegner et al. (18) After five injections with 1 X 1[0.sup.6] U of IFN-[alpha]-2B for a 5-week span, they demonstrated improvements in penile pain, curvature, and plaque size. These results were supported by a case-control study by Judge and Wisniewski, (19) who showed alleviation of penile pain in 60% of patients and a mean improvement in penile curvature of 20 degrees after using a regimen of 1.5 X 1[0.sup.6] U of IFN-[alpha]-2B three times a week for 3 weeks, but none in the saline controls. Likewise, in a study of 20 patients who were administered a biweekly dose of 1 X 1[0.sup.6] U of IFN-[alpha]-2B for 6 months, Ahuja et al (7) demonstrated a 65% improvement in penile curvature, an 85% decrease in plaque size, and 90% alleviation of penile pain. Further confirmation of these findings come from Astorga et al, (8) who reported improvements in penile angulation and pain in 47% and 94% of subjects, respectively, who were administered 10 X 1[0.sup.6] U of IFN-[alpha]-2B injections biweekly for 10 weeks. Also, Novak et al (9) showed decreased penile curvature in 39% of men and diminished plaque size in 38% of participants who were given 4 X 1[0.sup.6] U of IFN-[alpha]-2B once a week for 10 weeks. In contrast, Wegner et al (10) and Brake et al, (11) using regimens of three injections of 3 X 1[0.sup.6] U of IFN-[alpha]-2B for 3 weeks and nine injections of 2 X 1[0.sup.6] U of IFN-[alpha]-2B for 3 weeks, respectively, reported no significant improvements in penile curvature or plaque size with interferon therapy. The latter studies did not administer the agent intralesionally, but alongside the plaque. It is obvious that technique of administration is paramount to comparing results from different studies.

In this study, we used biweekly injections of 2 X 1[0.sup.6] U of IFN-[alpha]-2B for 6 weeks and demonstrated an improvement of 20 degrees or more in penile curvature in 14 (67%) of 21 men, a subjective improvement in plaque size in 15 (71%) of 21 individuals, and alleviation of penile pain in eight (80%) of 10 participants who complained of pain at the beginning of the study. Gelbard et al (2) have previously reported that in the untreated population with PD, penile pain disappears in approximately 44% of patients, and penile angulation improves in 13% of men. Even after accounting for the natural resolution of the disease, the results of this study still support the efficacy of interferon therapy in treatment of PD.

The most effective regimen for delivering interferon is unknown at this time. IFN-[alpha]-2B must first bind to extracellular receptors to suppress collagen synthesis and stimulate collagenase activity. Therefore, excessive dosing may not improve efficacy if all of the cell receptors are already saturated with interferon. It may be more important to maintain as minimal a dose as possible as the severity of the side effects are proportional to the dosage. (9) In addition, because the half-life of IFN-[alpha]-2B is only 2 hours, more frequent dosing may be more effective than merely once every week. Our clinical trial demonstrates that a dosage of 2 X 1[0.sup.6] U of IFN-[alpha]-2B delivered biweekly for 6 weeks yielded results comparable to those which used quantities of as much as 10 X 1[0.sup.6] U of IFN-[alpha]-2B for durations of as long as 6 months.

Our study also examined the impact of interferon therapy on ED. Results of the IIEF questionnaire showed that five (71%) of seven participants with moderate to severe ED had significant improvement (increase >5) in their erectile function domain from baseline scores after completion of the interferon protocol. There is no doubt that there are psychogenic overlays that may be involved in these assessments. However, systolic blood velocity improved in three (43%) of seven patients with previous hemodynamic dysfunction; veno-occlusive disease resolved in three (18%) of 17 men. Of course, these results are confounded by the fact that five of seven patients with impaired peak velocities and nine of 17 men with veno-occlusive disease also suffered from HTN or DM. These comorbidities may strongly contribute to vascular problems. It is well appreciated that venous leakage can also be caused by anxiety, and any improvement in an organic entity (eg, penile plaque) may reduce a patient's stress and anxiety. Although the moderate improvements in erectile function are documented, these may indirectly be caused by intralesional interferon and not necessarily any effects on vascular flow to and from the penis. It is obvious that more research is needed to examine this topic further.

Conclusions

Intralesional interferon injections are an effective nonsurgical therapy for treating some men with PD. Interferon injections resulted in significant improvements in penile curvature, penile pain, and erectile function. A dose of 2 X 1[0.sup.6] U of IFN-[alpha]-2B delivered biweekly for 6 weeks proved to be equally as efficacious as higher doses administered for longer durations. Patients with PD requesting a nonsurgical alternative can be offered a short course of intralesional IFN-[alpha]-2B.

Table 1. Demographic data of 21 patients with Peyronie's disease

                                       No. of patients

Prior vitamin E and Potaba use                5
Prior vitamin E therapy                       4
History of genital trauma                     4
Dupuytren's contracture                       1
Prior use of [beta]-blockers                  5
Prior use of calcium-channel blockers         3
Diabetes mellitus (DM) alone                  4
Hypertension (HTN) alone                      3
DM and HTN                                    3

Table 2. Results of 21 patients with Peyronie's disease after
completion of biweekly intralesional injections of 2 X 1[0.sup.6] U of
INF-[alpha]-2B a 6-week period (a)

                                 No. with no
Peyronie's      No.       No.     significant    No.
symptom      affected  improved  improvement   worsened

Curvature      21        14          4            3
Plaque size    21        15          5            1
Pain           10         8          2            0

(a) Subjectively assessed by patient.

Table 3. Results of the intralesional interferon injection protocol
compared with baseline expressed as a percentage of objectively measured
curvature improvement

                Curvature
Patient no.  improvement (%)

 1                 50
 2                -22
 3                100
 4                 22
 5                100
 6                 17
 7                 33
 8                 25
 9                 33
10                -60
11                100
12                 25
13                 25
14                -50
15                 25
16                 11
17                 29
18                 11
19                  0
20                 33
21                 25

Table 4. Changes in the erectile function domain of the International
Index of Erectile Function index on 14 patients with Peyronie's disease
treated with biweekly INF-[alpha]-2B 2 X 1[0.sup.6] U for 6
weeks.

Erectile dysfunction  Theoretical domain   No. of patients before
status                   score range      INF-[alpha]-2B treatment

None                        26-30                    6
Mild                        22-25                    1
Mild to moderate            17-21                    2
Moderate                    11-16                    2
Severe                        <10                    3

Erectile dysfunction   No. of patients after
status                INF-[alpha]-2B treatment

None                             8
Mild                             1
Mild to moderate                 2
Moderate                         1
Severe                           2

Table 5. Individual results of the erectile function scale of the
international index of erectile function index on 14 patients with
Peyronie's disease treated with INF-[alpha]-2B x 2 x 1[0.sup.6] U
biweekly for 6 weeks (a)

         EF score before  EF score after
Patient  INF-[alpha]-2B   INF-[alpha]-2B
no.         treatment      treatment

 1             30               30
 2             25               24
 3             30               29
 4              3                2
 5             12               30
 6             26               27
 7             26               27
 8              5               20
 9              2               12
10             27               27
11             21               27
12             20                9
13             14               21
14             29               26

(a) EF, erectile function; INF, interferon.

Table 6. Comparative results of the penile duplex Doppler
ultrasonography on 21 patients with Peyronie's disease treated with
intralesional interferon

                                     No. with no
Vascular           No.       No.     significant    No.
impairment       affected  improved  improvement  worsened

Arterial             7        3           3          1
  insufficiency

Venous              17        3          14          0
  leakage

From the Department of Urology, Tulane University Health Sciences Center, New Orleans, LA.

Supported in part by an educational grant from Schering Corp.

Reprint requests to Wayne J.G. Hellstrom, MD, Department of Urology, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL42, New Orleans, LA 70112. Email: [e-mail]

Accepted November 18, 2002.

Copyright [C] 2004 by The Southern Medical Association 0038-4348/04/9701-0042

References

(1.) Carson CC III, Gelhard MK, Jordan GH. Peyronie's disease: New concepts in etiology, diagnosis, and treatment. Contemp Urol 1999;11(2):44-64.

(2.) Gelbard MK, Dorey F, James K. The natural history of Peyronie's disease. J Urol 1990;144:1376-1380.

(3.) Winter CC, Khanna R. Peyronie's disease: Results with Dermo-Jet injection of dexamethasone. J Urol 1954;72:400-403.

(4.) Gelbard MK, Walsh R, Kaufman JJ. Collagenase for Peyronie's disease experimental studies. Urol Res 1982;10:135-140.

(5.) Levine LA, Goldman KE, Greenfield JM. Experience with intraplaque injection of verapamil for Peyronie's disease. J Urol 2002;168:621-626.

(6.) Rehman J, Benet A, Melman A. Use of intralesional verapamil to dissolve Peyronie's disease plaque: A long-term single blind study. Urology 1998;51:620-626.

(7.) Ahuja S, Bivalacqua TJ, Case J, et al. A pilot study demonstrating clinical benefit from intralesional interferon [alpha] 2B in the treatment of Peyronie's disease. J Androl 1999;20:444-448.

(8.) Astorga R, Cantero O, Contreras D, et al. Intralesional recombinant interferon [alpha]-2b in Peyronie's disease. Arch Esp Urol 2000;53:665-671.

(9.) Novak TE, Bryan W, Templeton L, et al. Combined intralesional interferon [alpha]2B and oral vitamin E in the treatment of Peyronie's disease. J La State Med Soc 2001;153:358-363.

(10.) Wegner HE, Andressen R, Knipsel HH, et al. Local interferon-[alpha] 2b is not an effective treatment in early-stage Peyronie's disease. Eur Urol 1997;32:190-193.

(11.) Brake M, Loertzer H, Horsch R, et al. Treatment of Peyronie's disease with local interferon-[alpha] 2b. BJU Int 2001;87:654-657.

(12.) Rosen RC, Riley A, Wagner G, et al. The international index of erectile function (IIEF): A multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822-830.

(13.) Lee B, Sikka SC, Randrup ER, et al. Standardization of penile blood flow parameters in normal men using intracavernous prostaglandin [E.sub.1] and visual sexual stimulation. J Urol 1993;149:49-52.

(14.) Levine LA, Merrick PF, Lee RC. Intralesional verapamil injection for the treatment of Peyronie's disease. J Urol 1994;151:1522-1524.

(15.) Cappelleri JC, Rosen RC, Smith MD, et al. Diagnostic evaluation of the erectile function domain of the international index of erectile function. Urology 1999;54:346-351.

(16.) Duncan MR, Berman B, Nseyo UO. Regulation of the proliferation and biosynthetic activities of cultured human Peyronie's disease fibroblasts by interferons-[alpha], -[beta], and -[gamma]. Scand J Urol Nephrol 1991;25:89-94.

(17.) Ahuja SK, Sikka SC, Hellstrom WJ. Stimulation of collagen production in an in vitro model for Peyronie's disease. Int J Impot Res 1999;11:207-212.

(18.) Wegner JE, Anderson R, Knipsel HH, et al. Treatment of Peyronie's disease with local interferon [alpha] 2b. Eur Urol 1995;28:236-240.

(19.) Judge IS, Wisniewski ZS. Intralesional interferon in the treatment of Peyronie's disease: A pilot study. Br J Urol 1997;79:40-42.

RELATED ARTICLE: Key Points

* Peyronie's disease is a more prevalent condition than previously recognized, and now more so with the introduction of an effective oral erectogenic agent (ie, sildenafil).

* Intralesional injection of Peyronie's plaques is a minimally invasive treatment for this condition.

* A dose of 2 X 1[0.sup.6] U interferon-[alpha]-2B delivered biweekly for 6 weeks is equally as efficacious as the higher doses administered for long durations in improving penile curvature, penile pain, and erectile function in men with Peyronie's disease.

Gerald Dang, MD, Richard Matern, Trinity J. Bivalacqua, Suresh Sikka, PHD, and Wayne J.G. Hellstrom, MD