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”]

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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



Pathophysiology

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)

Presenter

Presentation Notes

Although the naming of the disorder has been attributed to François Gigot de la Peyronie, surgeon to king Louis XIV of France, descriptions in the literature consistent with the disease can be found as early as 1265 Journal: Memoires de l'Academie royale de chirurgie.(1743)


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.


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.



Pathophysiology

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”)

Presenter

Presentation Notes

Collagens are the primary structural components of the extracellular matrix. There are actually 28 different types of collagen; these are further subdivided into five to seven groups based on similarities in either structure or function. The collagen types that comprise the primary structural components of Peyronie’s disease are types I and III; these are classified as fibrillar collagens and are almost completely composed of triple helical collagen. To be classified as collagen, a protein must contain somewhere within the molecule a triple helical portion composed of three polypeptide chains. This structure can only be maintained if it is composed primarily of a triple amino acid repeat consisting of glycine followed by two amino acids that are usually either proline or hydroxyproline; in fact, collagen is unique in that it is the only protein that contains hydroyproline in abundance. The triple helical structure of the collagen molecule protects the protein from degradation; thus, once formed, mature triple helical collagen molecules are extremely stable and resistant to degradation. Conversely, because it is so stable, the triple helix is not the preferred conformation of the newly synthesized collagen molecules and in order for it to form properly, the nascent proteins require a significant amount of post-translational modification of their amino acids – for example, the hydroxyproline in collagen is formed by hydroxylation of proline molecules present in the propeptide chain. In addition, the propeptides must be “chaperoned” to prevent them from “tangling” or folding improperly during the slow “winding” process of the triple helix. In short, collagen is an abundant, stable and highly complex molecule that is “hard to make, and hard to break”.



Pathophysiology

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

Presenter

Presentation Notes

Vitamin E Potassium Para-aminobenzoate (Potaba) Tamoxifen Colchicine Carnitine PDE5 Inhibitors Pentoxifylline Omega-3 fatty acids Coenzyme Q10

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




Pathophysiology

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.


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

Presenter

Presentation Notes

Initial studies evaluated time and dose responses: Surgical specimens of excised plaque & normal tunica were weighed and incubated in buffer containing 400U of collagenase (time response) Samples collected hourly for 12 h and also at 24 and 48 h Extent of digestion evaluated by amino acid release to buffer (ninhydrin) and weight loss in remaining tissue Time response experiments: Normal pericardium (autopsy specimen) injected with varying doses (10-400U) and incubated for 24h Extent of digestion in pericardium determined by comparing the radius of the affected tissue to the size of the initial “bleb” resulting from injection

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


Presenter

Presentation Notes

Extent of digestion evaluated by amino acid release to buffer (ninhydrin) and weight loss in remaining tissue

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


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

Presenter

Presentation Notes

Palpation of a plaque is often the criteria used in these studies to diagnose PD, however, this is very subjective. Williams and Thomas paper 1970. Not talking about 1700’s historical; Picture of 1970 / 1980’s

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)


CCH Improved PDQ BotherDomain Score over 52 Weeks

PD

Q B

othe

r Sca

le

P=0.0451 P=0.0496


2.4(32.4%)

1.6(20.7%

)

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


Most Common Adverse Events > 5%

ITT analysis/Preferred term listed



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%




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




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).

Presenter

Presentation Notes

Whilst these results are promising, the question is whether a mean curvature of reduction of 17° is functionally signiﬁcant for the patient. It is generally accepted that a curvature of >30–45° will inhibit penetrative intercourse and is an indication for surgical interv ention. It could therefore be argued that at this degree of curvature, the collagenase injection could conv ert a curvature that prevents penetrative intercourse to one where intercourse is possible, assuming a mean curvature reduction of 17°. Furthermore, it may have a role in those men with more mild curvatures, that are not severe enough to justify surgery, but which do cause cosmetic or psychological concerns for the patient. The degree of improvement in relation to initial curvature is shown in Fig. 1

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.

Health & Medicine

Intralesional treatment in Peyronie's Disease