Peyronie s Disease Pharmacotherapy and Traction Therapy

Transcription

1 Peyronie s Disease Pharmacotherapy and Traction Therapy Ronny Ban Wei Tan MBBS, MRCSEd, M Med (Surgery), FAMS (Urology) Consultant Department of Urology Tan Tock Seng Hospital, Singapore

2 Presenting Symptoms and Duration 1-4 Curvature 80-91% Nodule 15% Pain 3-22% ED 15-28% Penile shortening 14% 4-6 mo 1-3 mo 7-12 mo Chronic >12 mo mo >24 mo <1 mo 1 Kadioglu A, et al: 2002 J Urol. 2 Rhoden EL, et al: 2010 JSM. 3 Kadioglu A, et al: 2004 IJIR. 4 Chung E, et al: 2012 BJUI.

3 Acute Phase Natural History Baseline Follow-up ,2 11,4 19,2 18,4 % of Patients Curvature Penile Length (cm) EFD Score 0 Length Loss Difficult Penetration No Penetration 1 Mulhall JP, et al: 2006 J Urol.

4 Natural History Early vs Late Presentation 2 years 4 years 60 Pain and curvature may continue 50 to improve 40 None Better Same Worse *Not statistically significant 1 Gelbard MK, et al: 1990 J Urol.

5 An Aside Important to discuss MR Safarinejad 5 important RCTs on PD therapies from MR Safarinejad 42 RCTs since 2001; 22 single author Publications withdrawn due to questionable validity Cochrane review noted significant discrepancies in his data compared to similar cohorts Data to be reported at face value

6 Pharmacologic and Traction Therapies Reviewed Oral Vitamin E Potassium Paraaminobenzoate (Potaba) Tamoxifen Colchicine Carnitine PDE5 Inhibitors Pentoxifylline Omega-3 fatty acids Coenzyme Q10 ***Only reviewing RCT data (penile traction / VED exempt)*** Topical Verapamil Trifluoperazine Magnesium Sulfate Liposomal Superoxide Dismutase Topical + Iontophoresis Verapamil Dexamethasone Lidocaine Penile traction and vacuum erection devices

7 Oral Therapies

8 Vitamin E (Tocopherol) Mechanism: Antioxidant / free radical scavenger Reducing penile fibrosis Adverse events High doses (>400 IU/day) increases serious events (stroke, MI,?prostate ca) GI symptoms Benefits Inexpensive Readily available ROS TGF-β Penile Fibrosis and Plaque Formation

9 Vitamin E vs Carnitine vs Placebo Safarinejad, et al. 1 RCT, PC N=236 PD mo 6 mo treatment Vit E 300mg bid Carnitine 1g bid Vit E + Carnitine Placebo Results* (C=Curve, P=Pain, Plq=Plaque) C 18.9% P 60.4% Plq 11.3% C 20.4% P 63% Plq 12.9% C 22.6% P 62.3% Plq 13.2% C 18.4% P 59.2% Plq 11.1% *P=0.09 (curve), 0.1 (pain), 0.1 (plaque) 1 Safarinejad MR, et al: 2007 J Urol.

10 Vitamin E vs Intralesional Interferon Inal, et al. 1 RCT PD x 10.8 months ILI IFN x 12 wks N=30 Vit E 400IU bid x 6 mo ILI IFN + Vit E Results* (C=Curve, P=Pain, Plq=Plaque) C -1.5 P 71% Plq C +1.5 P 50% Plq C -1.5 P 83.3% Plq *P>0.05 for all parameters 1 Inal T, et al: 2006 Urology.

11 Vitamin E + Colchicine vs Ibuprofen Prieto Castro, et al. 1 RCT PD < 6 mo Deformity < 30 Treatment x 6 mo Ibuprofen 400mg qday N=45 Vit E 600mg qday + Colchicine 1g q12h Curve Imp 18%* Pain Imp 68% Plaque +0.13* Curve Imp 48%* Pain Imp 91% Plaque -0.26* *P=0.01 and 0.001, respectively 1 Prieto Castro, RM, et al: 2003 BJU Int.

12 Vitamin E vs Sildenafil Ozturk, et al. 1 RCT N=39 Take Home 12 wks treatment No evidence Vit for E 400 benefit IU qday in chronic Sildenafil phase50 mg qday Limited data suggesting benefit when combined with colchicine in acute phase Inferior to sildenafil on improving pain Pain 42.8%* Plaque -33.3% Pain 66.6%* Plaque -33.3% *P= Ozturk U, et al: 2014 Ir J Med Sci.

13 Potassium Para-aminobenzoate (Potaba) Mechanism: Anti-inflammatory Stabilization of serotoninmonoamine oxidase activity (antifibrotic) Adverse events GI upset Skin photosensitization Other Expensive - $375/month

14 Potassium Para-aminobenzoate (Potaba) Multicenter, RCT, PC 1 N=75, PD < 12 mo Plaque Volume % Change in 300 Curvature Potaba 3g/qid x 12 mo p= % 250 Response: 90% 80% Decrease plaque 200 Take Home 70% 60% Decrease curve Early 30% in disease 150 course, Potaba may 50% Dropout: prevent further worsening of disease40% % Potaba (14%) No improvement of established curvature 20% Placebo (8%) 50 10% 0% Pain improvement similar 0 Placebo Placebo Potaba Decrease Pts with no baseline Baseline 12 Months Increase curvature developed less curve with Potaba P=0.07 Potaba No Change 1 Weidner W, et al: 2005 Eur Urol.

15 Tamoxifen Mechanism: Estrogen receptor antagonist Modulates the release of TGF-β1 1 Blocks TGF-β receptors Confirmed antifibrotic activity in retroperitoneal fibrosis 2 Adverse events: Nausea, muscle cramps, sensory paresthesias, changes in libido Other Inexpensive 1 Miculeck AA, et al: 2001 Arch Facial Plast Surg. 2 Dedeoglu F, et al: 2001 J Rheumatol.

16 Tamoxifen RCT, PC 1 N=25, mean 20 mo duration Consecutive patients All with plaque, no hourglass Tamoxifen 20mg bid x 3 mo Similar rate of AE (8%) Gastritis Improvements Placebo Tamoxifen P>0.05 Pain Curve Plaque 1 Teloken C, et al: 1999 J Urol.

17 Tamoxifen vs Acetyl-L-carnitine RCT 1 Curve (º) Baseline Treatment Plaque mm 3 Baseline Treatment N=48, acute=15 Tamoxifen 20mg bid vs Carnitine 1g bid Treatment - 3 mo Evaluated up to 6 mo Curve improved in carnitine Plaque size improved in both P < Tamoxifen Carnitine P < Tamoxifen Carnitine 1 Biagiotti G, et al: 2001 BJU Int.

18 ILI Verapamil + Carnitine vs ILI Verapamil + Tamoxifen RCT 1 N=60, chronic disease Take Home (mean 13 mo) Verapamil Among 10mg men with 60 chronic PD: 25 weekly x 10 Tamoxifen wk does 50 not improve curvature Propionyl-L-carnitine Likely does not impact plaque volume g/day x 3 mo Inadequate data in acute phase 10 Inferior to carnitine 20 Tamoxifen 40mg/day x mo 90 0 Curve (º) Baseline Tamoxifen + ILI Ver Treatment P < 0.01 Carnitine + ILI Ver 40 0 Plaque mm 3 Baseline Tamoxifen + ILI Ver Treatment P < Carnitine + ILI Ver 1 Cavallini G, et al: 2002 BJU Int.

19 Colchicine Mechanism: Down-regulates TGF-B expression Inhibits tubulin movement Reduces leukocyte action / diminishes wound contracture Adverse events: GI, neutropenia, anemia, bone marrow suppression Other Most common choice by American urologists ~$500 / month Colchicine

20 Vitamin E + Colchicine vs Ibuprofen Prieto Castro, et al. 1 RCT PD < 6 mo Deformity < 30 Treatment x 6 mo Ibuprofen 400mg qday N=45 Vit E 600mg qday + Colchicine 1g q12h Curve Imp 18%* Pain Imp 68% Plaque +0.13* Curve Imp 48%* Pain Imp 91% Plaque -0.26* *P=0.01 and 0.001, respectively 1 Prieto Castro, RM, et al: 2003 BJU Int.

21 Colchicine vs Placebo RCT, PC, n=78 1 Mean disease 15 mo Colchicine mg qday x 4 mo Take Home In acute phase May Pain improve curvature Curvature / pain Change when in combined Resolutionwith Improvement Vitamin E Plaque Vol Colchicine In chronic 60% phase -1º >0.05 No evidence for benefit Placebo 64% +3º >0.05 P= 1 Safarinejad MR: 2004 IJIR.

22 Mechanism: Antiproliferative effect on endothelial cells Sources Red meat / dairy Adverse events GI, Seizures, fishy odor Other Inexpensive Carnitine

23 Vitamin E vs Carnitine vs Placebo Safarinejad, et al. 1 RCT, PC N=236 PD mo 6 mo treatment Vit E 300mg bid Carnitine 1g bid Vit E + Carnitine Placebo Results* (C=Curve, P=Pain, Plq=Plaque) C 18.9% P 60.4% Plq 11.3% C 20.4% P 63% Plq 12.9% C 22.6% P 62.3% Plq 13.2% C 18.4% P 59.2% Plq 11.1% *P=0.09 (curve), 0.1 (pain), 0.1 (plaque) 1 Safarinejad MR, et al: 2007 J Urol.

24 ILI Verapamil + Carnitine vs ILI Verapamil + Tamoxifen Curve (º) Plaque mm 3 RCT 1 N=60, chronic phase (mean 13 mo) Verapamil 10mg weekly x 10 wk Propionyl-L-carnitine 2g/day x 3 mo Tamoxifen 40mg/day x 3 mo Baseline Tamoxifen + ILI Ver Treatment P < Carnitine + ILI Ver Baseline Tamoxifen + ILI Ver Treatment P < Carnitine + ILI Ver 1 Cavallini G, et al: 2002 BJU Int.

25 RCT 1 Tamoxifen vs Acetyl-L-carnitine N=48, acute= Take Home P < Tamoxifen 20mg bid vs 120 Two types of carnitine evaluated Carnitine 1g bid 70 Propionyl-L-carnitine Treatment - 3 mo Acetyl-L-carnitine Evaluated up Mixed to 6 mo data on benefits of propionyl Curve improved Limited in data showing benefit of acetyl 30 carnitine over tamoxifen on curvature and plaque Plaque size improved size in both 0 Curve (º) Baseline Treatment Tamoxifen Carnitine 0 Plaque mm 3 Baseline Treatment P < Tamoxifen Carnitine 1 Biagiotti G, et al: 2001 BJU Int.

26 PDE5 Inhibitors Mechanism: Antifibrotic (cgmp and NO) Secondarily inhibits TGF-β1 Adverse events: Flushing, congestion, Headache Other Cost Secondary benefits on erectile function

27 ESWT vs ESWT + Tadalafil RCT, ED+PD 1 Inclusion: PD 12 mo Curve <30 Painful erections 4wks ESWT + tadalafil 5mg qday N=100 ESWT alone 12 and 24 wks* Curve -1º Pain 74% Plaque to 0.09cm 2 Curve -1º Pain 80% Plaque -0.05cm 2 * P>0.05; Pain = painful erections 1 Palmieri A, et al: 2012 Int J Androl.

28 Vitamin E vs Sildenafil Ozturk, et al. 1 RCT N=39 12 wks treatment Vit Take E 400 Home IU qday Sildenafil 50 mg qday No evidence for benefit of PDE5s on curvature / plaque Possible improvement in penile pain Pain 42.8%* Plaque -33.3% Pain 66.6%* Plaque -33.3% *P= Ozturk U, et al: 2014 Ir J Med Sci.

29 Pentoxifylline Mechanism: Nonselective PDE inhibitor Anti-inflammatory Inhibits fibroblast proliferation Downregulates TGF-B Increases fibrinolytic activity Adverse events: GI, dizziness, headache, flushing Other: Inexpensive

30 Pentoxifylline vs Placebo RCT, PC, 6 mo, n=228 1 Inclusion: > 12 mo, pain during erection, able to penetrate, plaque < 2cm (non-painful, non-calcified plaque), PD+ED, progression on other oral therapies Pain w/ Take Home Curvature Δ Plaque Area Erection (% change) (mm 2 ) Single trial demonstrates efficacy of Pentoxifylline -89% Dorsal -22% -29% pentoxifylline in all parameters in chronic 400 mg bid Lateral -20% PD refractory to other oral agents Ventral -40% Placebo -83% Dorsal +31% Lateral +22% Ventral +27% +43% P = to to Safarinejad MR: 2004 IJIR.

31 This image cannot currently be displayed. Omega-3 Fatty Acids Mechanism: Stimulates production of collagenase Dietary Sources (EPA / DHA): Fish / marine sources, select dairy products Adverse events: GI, Fishy odor Other: Inexpensive

32 RCT, DB, PC 1 Omega-3 vs Placebo Mean PD duration? mo N=224 Mean curve ~30º Eicosapentaenoic + docosahexaenoic acids 1.84g/day Inclusion: Take Home 6 mo Omega-3 Pain during Omega-3 erection fatty acids (EPA+ DHA) are Able to not penetrate effective in chronic phase PD patients Non-painful refractory scar, to other oral PD therapies Plaque <2cm 2, non-painful Failed prior oral therapy Curve +10.6º Plq +69% Pain -17% Placebo Curve +9.8º Plq +68% Pain -15% *P > 0.05 for all variables 1 Safarinejad MR: 2009 JSM.

33 Mechanism: Antioxidant Dietary Sources: Beef, chicken, pork, fish Adverse events: Increased risk of bleeding, pruritus, rash, GI Other: Inexpensive Coenzyme Q10

34 RCT, DB, PC 1 Coenzyme Q10 vs Placebo Mean PD duration 20 mo N=186 Mean curve ~30-35º CoQ10 300mg qday Inclusion: Take Home ED+PD 6 mo Limited data suggests CoQ10 CoQ10improves Pain during curve erection and plaque size in chronic phase Able to penetrate PD refractory to other oral agents Non-painful scar, *Crv -37 to 50% Plaque <2cm 2, non-painful *Plq -40% Pain -86% Failed 2 prior oral therapies Placebo *Crv +24 to 37% *Plq +36% Pain -84% *P < for curve, plaque, > 0.05 for pain 1 Safarinejad MR: 2010 IJIR.

35 Topical Therapies

36 Liposomal Superoxide Dismutase vs Placebo SOD Free radical scavenger RCT, PC, DB 1 Crossover, 8 wk N=39 Assessments: Baseline, 4, 8, 12 wks Patients: 23% with prior PD therapies 79% with curvature Pain improvement primary endpoint P=0.017 P= Riedl CR, et al: 2005 Eur Urol.

37 Verapamil vs Trifluoperazine vs MgSO4 vs Placebo N=27 N=30 Ver TriF Plc Ver MgSO4 Plc RCT, PC, DB 1 3 mo tx, then open label verapamil x 6 mo Mean duration 3.4 yr, curve 45º Objective measures: Pt estimate of curvature Pain = yes/no Plaque by calipers 1 Fitch WP, et al: 2007 JSM.

38 Topical Ver vs TriF vs MgSO4 vs Placebo 100% 90% 88% 100% Ver TriF Mg Plc Early 100% * Termination 80% 70% 67% 78% * 71% 71% 60% 60% 50% 40% 30% 38% 43% 30% 29% 44% * 33% 20% 10% 0% 19% 10% 14% 11% 0% Pain Resolution Reduction Curvature Amt Imp Curv Reduction Plaque AE's 0% *P = <0.05; Ver vs Plc 1 Fitch WP, et al: 2007 JSM.

39 How Much Verapamil is Actually Absorbed in the Penile Plaque? Martin, et al 1 : N=8, ED undergoing IPP 1 week prior to surgery, verapamil administered periurethrally at penoscrotal junction x 1 hour Applied 10 PM night before and 5 AM morning of surgery Strip of corpora taken Chromatography Verapamil noted in urine but not in tunical samples 1 Martin DJ, et al: 2002 J Urol.

40 Topical Therapies Adverse Effects: Topical verapamil 11% contact dermatitis 1 Systemic absorption Take Home Trifluoperazine Limited data suggests a benefit for 71% topical (anxiety, verapamil agitation, blurred Findings vision, are insomnia, questionable due to a lack depression) of evidence 1 demonstrating tunical Dexamethasone absorption Skin thinning / discoloration Other Cost

41 Topical + Iontophoresis Therapies

42 Topical Therapies Iontophoresis Author (Year) Mehrsai (2013) Greenfield (2007) Di Stasi (2004) Montorsi (2000) Montorsi (2000) N= Type Rx Δ Pain Δ Curve Δ Plaque 60 RCT Ver + Dex (TEA vs ILI) 42 RCT, DB, PC *TEA -4.1/10 ILI -1.8/10 <30º at end TEA 87% ILI 67% Ver vs Saline Rx 65% (-9º) Sal 58% (-8º) TEA -151mm 3 ILI -64mm 3 73 RCT Ver + Dex No Pain: *Rx -22º *Rx -496mm placebo 3 (Rx) vs Lido *Rx 76% Con 0º Con -5mm 3 Data are (Con) limited Con 11% 25 No Ver + Dex Rx -100% Rx -88% Rx -90% control 40 RCT, DB, PC Orgotein + Dex + Lido Take Home Iontophoresis with verapamil and dexamethasone likely improves pain, curvature, and plaque volume over *Rx -100% PC -12% *Rx 62% Imp PC 5% Imp *Rx -79% PC -5% * = Significance

43 Traction and Vacuum Therapies

44 Traction and Vacuum Therapy in PD Author (Year) N = Type Rx Δ IIEF EFD Δ Pain Δ Curve Length (cm) Martinez- Salamanca (2014) Rybak (2012) Gontero (2009) Levine (2008) Raheem (2010) Lue (1999) 96 Retro; 1º Tx 111 Retro; Surg 15 Pro; 1º Tx PTT x 6 mo (6-8 hr/day) vs no Rx PTT >2 hrs / day x 3 mo at 4 wks 10 Pro PTT 2-8 hrs / day x 6 mo 31 Pro; 1º Tx 4 Retro; Surg * = Significance VED 10 min bid x 3 mo VED daily x 6 mo (up to 18 mo) *PTT +6 Con -6 Take Home *PTT -3 Con +2.4 *PTT -20º Con +22º PTT as primary and/or adjunctive therapy PTT >5 may hrs / improve length, curvature, day x 6 mo pain, and erectile function VED with inadequate data in PD *PTT +1.5 Con -2.4 *PTT +0.9 to 1.5 Con -0.5 to 0.2 PTT -4º PTT +1.3 PTT +5.3 PTT -17º PTT +0.5 to 2.5 NS % with -5 to -20º 35% with +0.5 to to +10 (combined surgical lengthening)

45 Summary 1. No consistent, strong evidence to definitively suggest efficacy and/or superiority of any one oral therapy in PD 2. Oral therapies with limited evidence suggesting a benefit on curve / plaque Colchicine + Vit E Acute phase Potaba Acute phase Acetyl carnitine Pentoxifylline Chronic phase CoQ10 Chronic phase 3. Oral therapies with no proven benefits on curve / plaque Tamoxifen PDE5 Inhibitors Omega-3 fatty acids

46 Summary 4. Topical therapies Superoxide dismutase may improve pain Verapamil may improve curve / plaque mechanism unclear Iontophoresis with verapamil + dexamethasone likely improves curvature, pain, and plaque volume 5. Penile traction therapy improves length, and may improve curvature, pain, and erectile function 6. Insufficient data on vacuum therapies in PD

47 Thank you