The Use of Collagenase in the Treatment of Peyronie’s Disease

0022-5347 /85/1342-0280$02.00/0 Vol. 134, August

THE JOURNAL OF UROLOGY

Printed in U.S.A.

Copyright © 1985 by The Williams & Wilkins Co.

THE USE OF COLLAGENASE IN THE TREATMENT OF PEYRONIE'S DISEASE MARTIN K. GELBARD,* ARIE LINDNER

AND

JOSEPH J. KAUFMAN

From the Department of Surgery, Division of Urology, UCLA School of Medicine, Los Angeles, California

ABSTRACT

Purified clostridial collagenase was administered intralesionally in 31 men with Peyronie's disease. Within 4 weeks of treatment 20 patients showed an objective improvement. Pain was eliminated in 13 of 14 patients with this complaint at presentation within the same 4-week period. The ability to have intercourse was restored in 3 of 4 patients with this problem. Except for a small corporeal rupture at the site of injection in 1 patient, no significant untoward effects were noted. During the mean 9.8-month followup 1 recurrence of bending was noted. Peyronie's disease is diagnosed easily but its cause, prevalence and treatment are poorly understood. Patients with the disorder may present with findings ranging from an asymptomatic nodule to severe pain and deformity, which preclude sexual intercourse. The disease begins as inflammatory vasculitis and progresses to fibrosis, with the formation of a plaque or nodule involving the tunica albuginea of the corpus cavernosum. The lesions occur more often on the dorsal aspect than in a lateral or ventral location, may vary in length and thickness, and may be firm, rubbery or calcified in some cases. 1 The affected portion of the tunica does not expand normally during erection and as a consequence the penis may become bent and painful. Recent advances in the surgical management of the disorder have given urologists confidence that function can be restored in severely afflicted sexual cripples. 2 • 3 However, most patients do not demonstrate that degree of involvement. They are symptomatic men who are unhappy with their lot but wary of the risks and rigors of a reconstructive operation and, therefore, they usually seek medical treatment. Dissatisfaction with the results of the various forms of medical therapy currently administered for the disease prompted us to investigate the efficacy of a new agent for the disorder. In a previous study we showed that purified clostridial collagenase is active in vitro in dissolving plaque tissue without digestion of elastic tissue, vascular smooth muscle or the myelin sheath of axons. 4 Other investigators have reported that a low dose of the enzyme injected intradiskally relieved pain in patients with herniated lumbar disks,5 and topical collagenase facilitated the debridement of dermal ulcers. 6 We describe the first phase one clinical trial of intralesionally injected collagenase for the treatment of any localized fibrotic disorder. The study was designed to assess the value of injecting highly purified collagenase in lesions of patients with Peyronie's disease. An earlier study has shown that /3-aminopropionitrile does not reverse the deformity in the disorder7 but because of its demonstrated ability to blunt fibrosis in the collagen synthesis stage of wound healing8- 11 the drug was used as an adjuvant in our clinical trial of collagenase. This approach was adopted in an effort to maintain laxity in new collagen deposited following the action of the injected enzyme. MATERIALS AND METHODS

Between May 25, 1982 and June 1, 1983, 31 men 22 to 67 years old (mean age 55.5 years) with a history of Peyronie's Accepted for publication March 22, 1985. Read at annual meeting of Western Section, American Urological Association, Reno, Nevada, July 15-19, 1984. * Requests for reprints: 2701 West Alameda Ave., No. 406, Burbank, California 91505. 280

disease for 2 to 60 months (mean 22 months) were enrolled in the study (see table). Informed consent was obtained from all patients according to guidelines established by the UCLA Human Subject Protection Committee. Investigational new drug numbers for all agents in the study were provided by the Food and Drug Administration. Pre-treatment assessment of each patient consisted of a complete history, physical examination, plaque measurements, tracings of the penis, urinalysis, routine blood studies and parameters measured by an SMA-12 panel. All but 1 patient had a history of pain with erection, followed by penile bending or circumferential constriction. Some subjects described the pain as "tension" or "pulling" around the plaque and those with asymmetrical disease said they occasionally felt pain throughout the side of the corpus affected by the plaque. In most cases the pain had resolved spontaneously but it continued to be a problem for 14 patients at the beginning of the study. The pain or deformity prevented intercourse in 4 patients and 3 who were able to perform sexually complained of a tendency of the erect penis to buckle at the site of the plaque upon insertion. Five subjects had decreased erection distal to the plaques. Ten patients had received previous treatment, including irradiation, intralesional corticosteroids, vitamin E, potassium aminobenzoate and ultrasound but no significant benefit was obtained. One patient had undergone unsuccessful excision of the plaque and grafting of the tunica albuginea, which resulted in graft fibrosis and contracture with exacerbation of the penile bending. Tracings of the erect penis on the vertical and horizontal planes were made at the beginning of the study and 4 weeks after treatment (see figure). One patient had massive bilateral ventral plaques with downward bending, 2 had circumferential contraction with no plaques and 28 had dorsal or dorsolateral plaques with corresponding erectile deviation. The plaques, measured manually, were small or impalpable (less than 8 mm.) in 6 of the 31 subjects, of moderate size (8 to 15 mm.) in 12 and large (greater than 15 mm.) in 13. Ultrasound imaging, previously used to determine plaque size, 7• 12 was not performed in this study because of the high cost to the patient. Lidocaine was infiltrated locally to anesthetize the injection site in the first 22 patients in the series. However, the method did not always establish total anesthesia in the area involved and tended to distort the tissue around the lesion; it also presented difficulty if a plaque was not palpable. Subsequently, a method described for administering local anesthesia during placement of penile implants was adopted. 13 The injection sites in our last 9 patients were anesthetized by means of lidocaine 0.25 per cent insufflation of the corpus cavernosum. We prefer this technique because it provides excellent regional anesthesia

USE OF COLLAGENL61'SE II\! TJ1EATZ\1El\fT

PEYRONm's DISEASE

Clinical findings before and after treatment ?t. No.-Age 1-67 2-59 3-59 4-58

Total Dose

1,260 506 1,595

5-57

470 520

6-57 7-63 8-53 9-60 10-44 11-59 12-56 13-34 14-52 15-65 16-22 17-23

470 1,739 2,021 1,820 2,246 2,246 2,246 2,204 4,850 2,524 2,730 2,730

18-63 19-59 20-59 21-60 22-62 23-61 24-58 25-55 26-50 27-62 28-55 29-63 30-62 31-65

2,730 2,730 3,640 2,730 2,730 2,730 3,640 2,730 2,730 2,730 2,730 2,730 2,730 2,730

Plaque Size (mm.)

Penile Bend (degrees)

Before

After

Before

20

12 0 6 65

60 45 25

12

45 20

0

8 65 20 16 8 6 9 9

16 8 0 6

9

0

0

8 6 18 16 8

8 2 10

6

18 18 20 10 80 11 12 25 10 8 16 68 8 0

2

8 0 18 18 20 10 80 11

12 10 10

8 10 60 0 0

and demonstrates clearly the area of deformity or curvature, regardless of the presence or absence of a palpable plaque. The collagenase was used in concentrations of 4 70 to 620 µ./ cc in the first 15 patients and then 910 µJee in the remainder. Injection was intralesional by applying firm, steady pressure to a LO cc tuberculin syringe with a No. 23 needle taped securely to the barrel. For patients without a palpable plaque the injection site was the point of maximum penile bending. Most of the injections were made directly through the neurovascular bundle. An effective dose of collagenase for intralesional administration has never been established, On the basis of experimental studies 4 and clinical precedent5 a dose of 470 Advance Biofactures units per injection on 3 consecutive days was proposed. 1 nanomole of leucine One Advance Biofactures unit equivalent released per minute in the stand(free amino ard assay for <,vc,u,,,aci,m measuring the liberation of free amino acids method. The first 6 ranging from 270 to 1,595 units rei;pclmies were noted and no untoward reactions occurred, the was increased gradually and the next 25 patients received 1,739 to 4,850 units (mean 2,695 units). The collagenase initially used in the study was suspended in aqueous buffer and frozen in the liquid state. Subsequently, it was lyophilized for shipment, stored at OC and reconstituted before injection with a diluent containing 0.294 mg./mL calcium chloride and 9.10 mg./ml. sodium chloride. Only collagenase injections were administered to the first 6 patients and although 4 improved after treatment 1 had recurrence 3 months later. Then, /3-aminopropionitrile fumarate was administered to the next 25 patients as an adjuvant in an attempt to prevent recurrences by increasing the laxity of collagen formed at the site of the enzymatic wounding. The effect of /3-aminopropionitrile on the mechanical properties of connective tissue is owing to its inhibition of lysyl oxidase, the enzyme that catalyzes collagen cross linkage. 9 - 11 We believed that the theoretical objection to its use, difficulty in interpreting the results of patients receiving both agents, was minimized by

70

30 30 40 10 25

30 10 85 30 35 35

Pain

After 10

0 25 70 25 30 25 30 20 10

25 30 10

20 10 35 10

45 30 45 45 180 30 60 45 30 40 30 70

45 30 36 30 180 6 60 45 30 25 24 35

30

24

30

8

Side Effects

Before

After

No No No No Yes No Yes Yes No No No No Yes Yes No No Yes

No No No No No No No No No No No No No No No

No No Severe Severe Yes Yes Yes Yes No Yes No Yes No No

No No No No No No No

No No Yes

No No No No No No

None Ecchymosis Ecchymosis Ecchymosis Ecchymosis Ecchymosis, pain Ecchymosis Ecchymosis Ecchymosis Ecchymosis Ecchymosis Ecchymosis Ecchymosis Ecchymosis, pain None Ecchymosis Ecchymosis, ruptured corpora None None None None Ecchymosis Ecchymosis None Ecchymosis Ecchymosis None Ecchymosis Ecchymosis None None

the demonstrated lack of effect of /3-aminopropionitrile when used alone. 7 Topical /3-aminopropionitrile fumarate suspended in dimethyl sulfoxide was administered to patients 7 through 13. All subsequent patients were maintained on 250 mg. oral /3aminopropionitrile fumarate 4 times daily. Both groups received the adjuvant on days 7 to 28 and were tested with an SMA-12 panel weekly while on the medication and 1 month after treatment. Paients given the drug in dimethyl sulfoxide were examined with an ocular slit lamp before and during treatment, a procedure recommended whenever there is prolonged exposure to dimethyl sulfoxide, and no lenticular opacities were observed. During the course of the ~v.«u,5 '°'·"''''" injections, patients were then weekly for 2 visits and at examined daily for 3 4 weeks. Results were recorded 4 weeks after the nn·rn·nnn of treatment. ranged from 4 to 15 months

RESULTS

Of the 31 patients treated intralesionally with collagenase 20 (65 per cent) had improvement, usually within 2 weeks. Plaques disappeared or were altered significantly in configuration in 4 patients and penile curvature decreased 20 to 100 per cent in the remaining 16. Objective relief of deformity occurred in 50 per cent of 6 patients with small or impalpable plaques, 75 per cent of 12 with moderate lesions and 65 per cent of 13 with large lesions. Pain during erection was eliminated in 13 of the 14 patients (93 per cent) with pain at entrance to the study. When questioned specifically most patients with painful erections replied that the collagenase distinctly reduced the feeling of tension or restriction at the plaque. Of the 4 men who were unable to have intercourse before treatment 3 regained the ability, and the 1 who failed had a massive plaque and a 180-degree penile bend. Plaque tenderness had disappeared in 2 of 3 subjects and decreased in the third.

282

GELBARD, LINDNER AND KAUFMAN

BEFORE

BEFORE

PATIENT #14 VERTICAL PLANE

PATIENT #23 HORIZONTAL PLANE

AFTER

BEFORE

AFTER

PATIENT #17 HORIZONTAL PLANE

BEFORE

PATIENT #31 VERTICAL PLANE

AFTER

AFTER

Penile tracings before and 4 weeks after treatment

Of the 3 patients who had complained of buckling with insertion 2 noticed a reduced tendency for buckling to occur but only 1 of the 5 with decreased erection distal to a plaque and none of 2 with circumferential constriction showed improvement after therapy. The patient with massive bilateral ventral plaques experienced considerable restoration of symmetry and functional capacity, and although he had received 4,850 units of collagenase in the periurethral area there was no hematuria or urethral symptoms. Untoward reactions. Generally, injection of collagenase at the dose ranges administered was tolerated well. Two patients had pain at the injection site and 21 had ecchymosis but none complained of numbness in the glans or referred pain, and none required any analgesic during the study. Corporeal rupture attributable to collagenase occurred in a 23-year-old patient who experienced pain and a popping sensation at the injection site during intercourse 2 weeks after treatment. Ecchymosis ensued and the patient was instructed to bandage the penis and avoid erection for 3 weeks. After healing the penis was straighter than before treatment, suggesting that the portion of the corporeal wall that tore was the diseased segment responsible for the original deformity. One of the 18 patients taking oral f:1-aminopropionitrile suffered a hypersensitivity reaction on day 6 manifested by fever, malaise, eosinophilia, and elevated alkaline phosphatase, bilirubin, lactin dehydrogenase, serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase. These parameters returned to normal following withdrawal of the drug and no clinical difficulties were noted at followup. Nonetheless, this patient benefited from treatment with a 50 per cent loss of the original bending and disappearance of the solitary dorsal midline plaque. All of the subjects receiving f:1-aminopropionitrile showed an

apparent increase in serum creatinine without an elevation of blood urea nitrogen. This previously reported observation is owing to the false chromagen activity of cyanoacetic acid, a metabolite of f:1-aminopropionitrile, in the Jaffe reaction for creatinine. 14 DISCUSSION

We believe that refinements of the approach in this first clinical trial of intralesional collagenase will lead to an effective medical management of Peyronie's disease. Within 4 weeks of treatment, 65 per cent of our patients obtained objective improvement of deformity, and pain at erection was eliminated in 93 per cent. These results seem significant, especially in light of the deliberately cautious dose levels administered. The safety of intralesionally injected collagenase appears to be our most significant finding. None of our patients showed clinical or laboratory evidence of systemic side effects, skin ulceration, cold abscesses or neural damage, although most of the injections were made directly through the neurovascular bundle. Experimentally, collagenase does not appear to alter neural histology or physiology in vitro. 4 The only complication was a small rupture of the corporeal wall at the site of injection. This was not considered a side effect but rather the excessive local expression of the pharmacological effect of collagenase. The enzyme used in the study was a highly purified preparation with exceedingly low levels of nonspecific protease activity.15 We had no difficulty in administration but an effective high pressure syringe probably would facilitate injections. High pressure transcutaneous administration would not be practical, since transdermal delivery of collagenase would saturate dermal collagen and result in skin ulceration, as has been observed in laboratory animals.

283

USE G? COLLAGENASE

The .UHlWc!llUiCJ)',ll,ctl consequences of Lv.,w;;so,w,,s:; administration are unknown at this time. Therefore, to avoid possible hypersensitivity reactions, we limited exposure in our patients by injecting the enzyn1e on 3 consecutive Apparently, that period is insufficient for significant aucrn·v~ response and synthesis. We are studying the production of collagenase-specific immunoglobulins G and E in response to the doses and schedule used in the clinical trial. If vigorous antibody response does not occur we believe the efficacy of collagenase in the treatment of Peyronie's disease may be improved dramatically by administering repeat doses, possibly at higher levels. Our difficulty in restoring erection distal to a plaque raises the question of pathogenesis. If the phenomenon is due to penile constriction and reduced afferent blood flow, plaque dissolution should cause some degree of reversaL However, if the disease originates distally and proximal plaque migration leaves damaged corporeal matrix in its wake, an operation may be the only solution. We plan to investigate the pathogenesis of this abnormality questioning future patients about plaque migration. The tendency of the erect penis to buckle upon insertion appears more amenable to correction and seems to be owing to corporeal constriction at the site of the plaque. Rigidity in the erect penis is related to wall tension, which bears a simple geometric relationship to the radius in a cylindrical chamber. 16 With the decrease in radius of the corporeal lumen in Peyronie's disease, wall tension decreases independently of any pressure changes in the lumen. This effect produces a segment that tends to fail or buckle with axial loading. The problem may be eliminated injecting collagenase to dissolve the plaque thereby, increase the radius of the lumen at the restriction site. There is a wide variation in the severity of Peyronie's disease and regardless of refinements in the medical alteration of fibrotic tissue, there always will be a role for reconstructive surgery. We operated on 2 patients who failed to respond to collagenase injections. Although the effects of the enzyme make it slightly more difficult to mobilize the neurovascular bundle from the corporeal tunic, they do not impair the suitability of the patient for plaque excision and grafting, or plaque incision and stenting. Conversely, severely afflicted patients are suitable for an initial trial of collagenase therapy before an operation is recommended. The patient with massive bilateral ventral plaques had been told that an operation was his only recourse but he responded remarkably well to intralesional collagenase in our study. In the results of OUf clinical trial and the Of intralesionally administered 'vVHa,',c.cm,asc sive evaluation of this disease. Collagenase is the other agents currently used in the medical H1o1uo,;·cu,nn disease, since it is the against lesions in vitro. Our future for this agent include studies to determine the dose for use in u"'""'·""' the best method of and the immunological effects of this form of therapy.

7. 8. 9. 10.

lL 12. 18, 14.

15.

16.

dermal cilcern with collagenase. Surg., Gynac. & Obst., 136: 281, 1973. Gelbard, M., Lindner, A., Chvapil, IVL and Kaufman, J.: Topical beta-aminopropionitrile in the treatment of Peyronie's disease. J. Urol., 129: 746, 1983. Peacock, E. E. and Madden, J. W.: Administration ofbeta-aminopropionitrile to human beings with urethral strictures: a preliminary report. Amer. J. Surg., 136: 600, 1978. Peacock, E. E., Jr.: Pharmacologic control of surgical scar tissue. Amer. Surg., 44: 693, 1978. Peacock, E. E., Jr.: Pharmacologic control of surface scarring in human beings. Aun. Surg., 193: 592, 1981. Moorhead, L. C.: Inhibition of collagen cross-linking: a new approach to ocular scarring. Curr. Eye Res., l: 77, 1981. Gelbard, M., Sarti, D. and Kaufman, J. J.: Ultrasound imaging of Peyronie's plaques. J. Urol., 125: 44, 1981. Kaufman, J, ,J.: Penile prosthetic surgery under local anesthesia. J. UroL, 128: 1190, 1982. Keiser, H. R. and Sjoerdsma, A.: Studies on beta-aminopropionitrile in patients with scleroderma. Clin. Pharm. Ther., 8: 593, 1967. Keller, S. and Mandi, I.: The preparation of purified collagenase. Arch. Biochem., 101: 81, 1963. Gelbard, M.: The disposition and function of elastic and collagenase fibers in the tunic of the corpus cavernosum. J. UroL, 128: 850, 1982.

EDITORIAL COMMENTS Despite an enthusiastic body of literature describing numerous innovative techniques to replace the corporeal defects and restore potency, most patients with Peyronie's disease and sexual dysfunction do not respond to anything short of a penile prosthesis. This large, weli monitored phase I study of a new coliagen digesting agent administered intralesionally appears promising. Of 31 patients 20 had some improvement and 13 of 14 had complete resolution of the pain with a followup of more than l year. Most of the patients who responded had done so within 2 to 4 weeks, which represents a new and effective medical treatment for this pathological condition, since most patients who achieve spontaneous resolution do so during 1 to 2 years. The historical information reflecting the inadequacy of prior remedies is sufficient to warrant continued use of this agent for a disease that in essence is not medically treatable to date. Although the authors do not describe any systemic effects from this agent, I have concerns that any intralesional enzyme injection, much like the spinal disk experience, eventually would cause serious anaphylaxis. However, the authors are to be complimented for the introduction of this unique pharmacological treatment for Peyronie's disease.

Leonard M. Zinman

vVHv•UCHV.U,

REFERENCES 1. Smith, B. H.: Peyronie's disease. Amer. J. Clin. Path., 45: 670,

1966. 2. Devine, C. J., Jr. and Horton, C. E.: Surgical treatment of Peyronie's disease with a dermal graft. J. Urol., 111: 44, 1974. 3. Raz, S., deKernion, J.B. and Kaufman, J. J.: Surgical treatment of Peyronie's disease: a new approach. J. Urol., 117: 598, 1977. 4. Gelbard, M. K., Walsh, R and Kaufman, J. J.: Collagenase for Peyronie's disease: experimental studies. UroL Res., 10: 135, 1982. 5, Sussman, B. J., Bromley, J. W. and Gomez, J. C.: Injection of collagenase in the treatment of herniated lumbar disc. Initial clinical report. J.A.M.A., 245: 730, 1981. 6. Varma, A. 0., Bugatch, E. and German, F. M.: Debridement of

Evaluation of various forms of therapy for Peyronie's disease has been coimphc,ated by the ten,o_ei1cy of natural processes to resolve the lesion any treatment at This paper presents an important new technique aimed at the !Jtlcnc11ui:1c,;i condition actually present, that is excessive deposition of collagen. Patients who still are capable of having satisfactory intercourse do not require surgical therapy but they would still like the situation to be better. In these 31 men only 4 were not able to have intercourse and the ability was restored in 3. These results are better than with any other method short of an operation but there are problems. In some patients the collagen in the tunica remained soft and elastic. However, at times it appeared that the injection softened the lesion but did not disturb the continuation of the disease. Natural processes then do not restore the collagen to a normal configuration and within a few weeks the situation is much as it was. Widespread clinical application of this treatment should await a longer term of observation of these patients and, as outlined in the last sentence of the paper, determination of the optimal dose, best method of delivery and immunological effects of this form of therapy. I hope that continued observation and experience uphold the promise of these results.

Charles J. Devine, Jr. Department of Urology Hague Medical Center Norfolk, Virginia