intralesional treatment in peyronie's disease

Intralesional Treatment: Is there a real breakthrough?

Ege Can Serefoglu, MD, FECSMBagcilar Training & Research Hospital, Istanbul, Turkey

NO…!!!

Financial and Other Disclosures Off-label use of drugs, devices, or other agents: None or FILL IN HERE; including your local regulatory agency, such as FDA, EMA, etc.

Data from IRB-approved human research is presented [or state: “is not”]

3

I have the following financial interests or relationships to disclose: Disclosure code

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Intralesional Treatment in PD

Definition & Epidemiology

Pathophysiology

Treatment

Intralesional Treatment

Intralesional Treatment in PD

Definition & Epidemiology

Pathophysiology

Treatment

Intralesional Treatment

Definition & Epidemiology of PD

Peyronie's disease (PD) is a fibrotic disorder of the tunica albuginea of the penis.

Naming has been attributed to François Gigot de la Peyronie(surgeon to king Louis XIV of France)Memoire sur quelques obstacles qui s'opposent d l'Ejaculationnaturelle de la semence (Memoires de l'Academie royale de chirurgie - 1743)

Definition & Epidemiology of PD

Scarring/plaque of the tunica albuginea with excessive abnormal collagen depositionPotential symptoms:• Curvature – 80-91%• Nodule – 15%• Pain – 3-22%• ED – 15-28%• Penile shortening – 14%

8-9% report preceding traumaMore common in white males (OR 8.47)

15-58% of patients are unaware of disease (incidental discovery)

Bella A. J Sex Med 2007; Kadioglu A, et al. J Uro 2002; Rhoden EL, et al. J Sex Med 2010; Kadioglu A, et al. IJIR 2004; Chung E, et al. BJUI 2012.

Definition & Epidemiology of PD

Prevalence varies:In the general population: 0.4-13%Among patients:

ED 7.9%DM 8.1%ED + DM 20.3%Post-RP 15.9%

4 – Rhoden EL, et al: 2001 IJIR.5– La Pera G, et al: 2001 Eur Urol.

6 – Mulhall JP, et al: 2004 J Urol.

1 – Lindsay MB, et al: 1991 J Urol.2 – DiBenedetti DB, et al: 2011 Adv Urol.

3 - Schwarzer U, et al: 2001 BJU Int.

Intralesional Treatment in PD

Definition & Epidemiology

Pathophysiology

Treatment

Intralesional Treatment

Pathophysiology: What Is Collagen?

• Primary extracellular structural component

• All collagens contain a triple helix:• Composed of three polypeptide chains• Contains Gly-X-Y motifs (X and Y normally proline or

hydroxyproline)

• The triple helix• Requires extensive post-translational modification (“hard to

make”)• Is extremely stable (“hard to break”)

Intralesional Treatment in PD

Definition & Epidemiology

Pathophysiology

Treatment

Intralesional Treatment

Treatment

• Spontaneous resolution

• Oral therapy: Vitamin E, POTABA, Colchicine, Tamoxifen…

• Intralesional injection therapy • Calcium channel blockers (Verapamil)• Interferon (IFN)• Collagenase (Xiaflex) – FDA approval Dec 6, 2013

• Surgical options• Plication of contralateral corpora (Nesbit principle) • Incision & grafting (I & G) procedures• Prosthesis option with modeling or ancillary procedures

Treatment

• Clinicians should NOT offer:• Vitamin E, tamoxifen, procarbazine, omega-3

fatty acids, or Vit E w/ L-carnitine• Electromotive therapy w/ verapamil• Shock wave therapy for curvature or plaque

size (may offer for pain)• Radiotherapy

Treatment

AUA Guidellines on PD 2015

Clinicians may administer collagenase w/ modeling for pts with:

• Stable disease• 30-90°• Intact erectile function w/ or w/o meds

Clinicians may offer intralesional interferon or verapamil

Treatment

AUA Guidellines on PD 2015

Intralesional Treatment in PD

Definition & Epidemiology

Pathophysiology

Treatment

Intralesional Treatment

Intralesional Treatment

• Interferon (IFN)• Calcium channel blockers (Verapamil)• Collagenase (Xiaflex)

Intralesional Interferon Alpha-2b

1 RCT, 1 randomized study (w/o placebo), 8 observational studies

Single-blind, multicenter, placebo controlled, parallel arm

N=103, age 55, PD >12 mo, curvature > 30°

Bi-weekly x 12 injectionsCurvature reduction: 13.5° (IFN) vs 4.5°

Plaque size reduction: 2.6 cm2 (IFN) vs 0.9 cm2

Pain improvement: 67.7% (IFN) vs 28.1%

Hellstrom WJ, et al: 2006 J Urol.

Intralesional Interferon Alpha-2b

Role in men w/ Stable disease

Curvature >30°

Non-calcified plaque

ventral curvatures, penile pain

Pts should be informed regarding expected average curvature reduction of 13.5 degrees (only 9 degrees different than placebo)

Clinicians should counsel pts prior to tx about potential adverse events

sinusitis, flu-like symptoms, and minor penile swelling. AUA Guidellines on PD 2015

Intralesional Verapamil2 RCTs, 8 observational studies1. 10 – 27 mg intralesional verapamil weekly for 6 months1

N=14

Randomized, single-blind, placebo controlled

significant decrease in plaque length, width, and volume in the verapamil group (but not in the placebo group)

2. 10 mg verapamil, twice weekly for 12 weeks2

N=80,

Randomized, single-blind, placebo controlled

No significant differences in curvature, pain, plaque size, or sexual function

1- Rehman J et al. Urology 1998

2 – Shirazi M, et al. Int Urol Nephrol. 2009

Intralesional Verapamil

Clinicians who consider the use of intralesionalverapamil as a treatment for symptoms of PD should fully consider the weakness of the evidence demonstrating its efficacy.

Clinicians should counsel pts prior to tx about potential adverse events,

penile bruising, dizziness, nausea, and pain at the injection site.

AUA Guidellines on PD 2015

2014 – The Year of Collagenase Clostridium Histolyticum

Surgical specimens of excised plaque & normal tunica Injection into dorsal tunica (400 U clostridial collagenase in 0.2 mL) Incubation for 24 h before tissue processing Localized complete lysis of collagen (note sharp demarcation from normal tissue)

Gelbard MK, et al. Urol Res 1982

Hematoxylin & eosin stain(collagen = dense pink stain)

Van Gieson’s stain(collagen = dark red stain)

CCH injection into the Plaque

Amino acid release to buffer (ninhydrin) after CCH injection into the plaque

Gelbard MK, et al. Urol Res 1982

Complete disruption of plaque collagen

• Surgically excised plaque bisected:• Half was treated with collagenase (400 U in 0.1 mL)• Half was injected with saline (0.1 mL)

• Incubation for 24 h before tissue processing• Note difference in size & morphology (both are same magnification)

Saline Collagenase

Gelbard MK, et al. Urol Res 1982

Dupuytren’s Contracture Starkweather KD, et al. J Hand Surg Am. 1996.

Peyronie’s Disease Gelbart M, et al. J Urol. 1993

CCH in PD

Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies (IMPRESS I + II)

2 large double-blind, randomized, placebo controlled phase 3 studiesConducted at 64 sites in the U.S. and Australia417 + 415 subjects with penile curvature deformity from 20 to 90o

Randomized to receive up to 8 injections of XIAFLEX 0.58 mg or placebo in 2:1 ratiomaximum of 4 treatment cycles, each separated by 6 weeks

Gelbart M, et al. J Urol. 2013

CCH Improved Penile Curvature Deformity over 52 Weeks

20

25

30

35

40

45

50

55

XIAFLEX Placebo XIAFLEX Placebo

BaselineEOS

37.6%

21.3%15.2%

30.5%

Deg

rees

of C

urva

ture

Def

orm

ity

P=0.0005 P=0.0059

IMPRESS I IMPRESS II

N=199 N=104 N=202 N=107

CCH Improved Penile Curvature Deformity over 52 Weeks

Baseline curvature deformity – 48o

End of study curvature deformity – 28o (38% improvement)

Gelbart M, et al. J Urol. 2013

CCH Improved PDQ BotherDomain Score over 52 Weeks

PD

Q B

othe

r Sca

le

P=0.0451 P=0.0496

IMPRESS I IMPRESS II

2.4(32.4%)

1.6(20.7%

)

N=199 N=104 N=202 N=107

Gelbart M, et al. J Urol. 2013

Most Common Adverse Events > 5%

ITT analysis/Preferred term listed

IMPRESS I IMPRESS II

XIAFLEX Placebo XIAFLEX Placebo

N = 277n (%)

N = 140n (%)

N = 274n (%)

N = 141n (%)

Any non-serious AE 256 (92.4) 81 (57.9) 252 (92.0) 88 (62.4)

Penile hematoma 171 (61.7) 19 (13.6) 165 (60.2) 22 (15.6)

Penile Pain 119 (41.2) 11 (7.9) 96 (35.0) 8 (5.7)

Penile swelling 114 (41.2) 1 (0.7) 95 (34.7) 2 (1.4)

Injection site pain 70 (25.3) 5 (3.6) 41 (15.0) 4 (2.8)

Penile hemorrhage 60 (21.7) 14 (10.0) 43 (15.7) 1 (0.7)

Injection site hematoma 45 (16.2) 14 (10.0) 61 (22.3) 16 (11.3)

Most Common Adverse Events > 5%

ITT analysis/Preferred term listed

IMPRESS I IMPRESS II

XIAFLEX Placebo XIAFLEX Placebo

N = 277n (%)

N = 140n (%)

N = 274n (%)

N = 141n (%)

Penile edema 45 (16.2) 1 (0.7) 40 (14.6) 0 (0.0)

Injection site swelling 30 (10.8) 0(0.0) 35 (12.8) 2 (1.4)

Contusion 28 (10.1) 0 (0.0) 27 (9.9) 1 (0.7)

Ecchymosis 26 (9.4) 0 (0.0) 12 (4.4) 0 (0.0)

Blood blister 9 (3.2) 0 (0.0) 17 (6.2) 0 (0.0)

Injection site hemorrhage 15 (5.4) 10 (7.1) 10 (3.6) 3 (2.1)

Serious Adverse Events

ITT analysis/Preferred term listed

IMPRESS I IMPRESS II

XIAFLEX Placebo XIAFLEX Placebo

N = 277n (%)

N = 140n (%)

N = 274n (%)

N = 141n (%)

Treatment emergent SAE 27 (9.7) 7 (5.0) 12 (4.4) 4 (2.8)

Treatment related SAE 3 (1.1) 0(0.0) 3 (1.1) 0 (0.0)

XIAFLEX Treatment Related SAEs

Hematoma 2 (0.7) 0 (0.0) 1 (0.4) 0 (0.0)

Corporal Rupture (penile fracture) 1 (0.4) 0 (0.0) 2 (0.7) 0 (0.0)

Conclusions of IMPRESS trials• CCH showed statistically significant improvements in

• penile curvature deformity (physical) [p-values of 0.0005 and 0.0059]

• PD bother (psychosocial) [p-values of 0.0451 and 0.0496]

• XIAFLEX is an effective FDA-approved biological therapy for the treatment of PD

• How many pts drop out the study??? (pain, hematoma, swelling, 8 mo tx)

• Is a mean curvature reduction of 17° is “functionally” significant for the patient?

• If the whole course of 8 injections is used, the cost would be >£8 000 (€11 200). (more than double compared with a tariff of £1 856 for a Nesbit procedure) (NHS England).

Conclusions

• PD is a common condition that can be both physically and psychologically devastating for men and their partners

• Intralesional interferon and verapamil treatment may be effective.

• CCH showed statistically significant improvements (17°) in penile curvature and PD bother

• It can be effective in PD patients with

• Dorsal curvature <50-60 degrees

• Without calcified plaque• Reducing the number of treatment cycles needed

would make the treatment significantly more cost effective.