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NY Prostate Cancer Conference - R. Gallina - Session 7: Predicting toxicity after surgery: erectile dysfunction
 

NY Prostate Cancer Conference - R. Gallina - Session 7: Predicting toxicity after surgery: erectile dysfunction

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  • Introduction and Objective: A significant number of patients experience erectile dysfunction (ED) following a nerve-sparing retropubic radical prostatectomy (NSRRP). This results from smooth muscle degeneration secondary to neurapraxia and hypoxia. Early postoperative intervention with intracavernosal alprostadil may improve the return of erections post-NSRRP. Independently, it has been observed that sildenafil improves nocturnal erections. This study examines the effect of nightly sildenafil administration on the return of normal erections following bilateral NSRRP. Methods: This study included 76 men with normal preoperative erectile function, defined as a combined score of ³8 for questions (Q) 3 and 4 from the International Index of Erectile Function (IIEF) and normal nocturnal penile tumescence (NPT) testing (³10 continuous minutes of ³55% base rigidity), scheduled to undergo a bilateral NSRRP performed by an experienced surgeon. Four weeks postsurgery, patients were randomized to either sildenafil (50 mg, n=23; 100 mg, n=28) or placebo (n=25) and entered a 36-week, double-blind treatment period with nightly drug administration (qhs). Erectile function was assessed 8 weeks after discontinuation of drug treatment (week 48) by asking the question "Over the past 4 weeks, have your erections been good enough for satisfactory sexual activity?" and by IIEF and NPT assessments. Responders were defined as those having a combined score of ³8 for IIEF Q3/4 and a positive response to the above question. Results: Forty-eight weeks after bilateral NSRRP, 14 of 51 (27%) patients receiving sildenafil demonstrated return of spontaneous erectile function compared with 1 of 25 (4%) in the placebo group ( P =0.0156). Postoperative NPT assessments were supportive. There were no treatment-related serious adverse events (AEs) reported; 2 patients discontinued due to treatment-related AEs. Conclusions: Nightly administration of sildenafil for 9 months post-NSRRP increased the return of spontaneous erections 7-fold compared with placebo and was well tolerated. Sildenafil may improve oxygenation at the time of nocturnal erections and/or neuronal regeneration. These results support the consideration of this treatment regimen as an adjunct to NSRRP.

NY Prostate Cancer Conference - R. Gallina - Session 7: Predicting toxicity after surgery: erectile dysfunction   NY Prostate Cancer Conference - R. Gallina - Session 7: Predicting toxicity after surgery: erectile dysfunction Presentation Transcript

  • Predicting toxicity after surgery: erectile dysfunction Francesco Montorsi Andrea Gallina Vita-Salute San Raffaele University URI - Urological Research Institure Milan, Italy
  • Mulhall J. J Urol, 181:462-471, 2009 20-90% Fowler FJ Jr, et al. Urology, 42:622, 1993 Kundu SD, et al. J Urol, 172:2227, 2004 Litwin MS, et al. Urology, 54:503, 1999 Rabbani F, et al. J Urol, 164:1929, 2000 Rozet F, et al. J Urol, 174:908, 2005 Stanford JL, et al. JAMA, 283:354, 2000 Walsh PC, et al. Urology, 55:58, 2000
  • Burnett AL, et al. J Urol, 178:597-601, 2007
    • To date, there is still controversy on the ideal definition of post-op EF recovery
        • Ability to have a sexual intercourse
        • IIEF-EF ≥17
        • IIEF-EF ≥22
        • Post-op EF = pre-op EF
        • SEP 2 / SEP 3
        • Others
    WHICH IS THE BEST DEFINITION OF POST-OP ERECTILE FUNCTION RECOVERY
  • Briganti A, et al. J Sex Med, 2011 [Epub ahead of print]
    • AIM : to test the correlation between patient satisfaction and IIEF-EF domain score cut-offs
    • METHODS
    • - # 165 consecutive pts; BNSRRP
    • All pts had preop normal EF ( IIEF-EF≥26 )
    • All pts reached post IIEF-EF≥17
    • - Data included preop abd postop IIEF-IS
    • IIEF-OS
    • Pts were segregrated according to the highest IIEF-EF reached postop
    • Group 1 IIEF-EF 17-21
    • Group 2 IIEF-EF 22-25
    • Group 3 IIEF-EF ≥26
  • Briganti A, et al. J Sex Med, 2011 [Epub ahead of print] Postop intercoruse and overall sexual satisfaction
    • In preop fully potent men treated with BNSRRP a lower satisfaction is expected when an IIEF-EF cut-off 17 is used
    • Conversely, no difference was found using a cut-off of 22 or 26
  • FACTORS PREDICTING RECOVERY OF ERECTIONS AFTER RADICAL PROSTATECTOMY: 1. PRE-OPERATIVE FACTORS 3. POST-OPERATIVE FACTORS 2. INTRA-OPERATIVE FACTORS a. Extent of NVBV preservation b. Surgical experience c. Surgical technique a. Adequate on demand or rehabilitative treatment a. Pre-operative erectile function b. Patient age c. Age difference between patient and partners d. Comorbidity profile
  • Rabbani et al J Urol ,164:1929-34,2000 >65 vs <60 yrs p=0.0007 PRE-OPERATIVE FACTORS PREDICTING RECOVERY OF ERECTIONS AFTER RADICAL PROSTATECTOMY Age at surgery
  • ERECTILE FUNCTION OUTCOME OF UNTREATED PATIENTS AFTER BILATERAL NERVE SPARING RADICAL PROSTATECTOMY p<0.001 Gallina A, et al. 2011 submitted EF recovery according to age at surgery <55 60.0-64.9 55.0-55.9 65.0-69.9 >70
  • Rabbani et al J Urol ,164:1929-34,2000 PRE-OPERATIVE FACTORS PREDICTING RECOVERY OF ERECTIONS AFTER RADICAL PROSTATECTOMY Partial vs Full p=0.038 Pre-operative erectile function
  • ERECTILE FUNCTION OUTCOME OF UNTREATED PATIENTS AFTER BILATERAL NERVE SPARING RADICAL PROSTATECTOMY >26 22-25 18-21 11-17 1-10 p<0.001 Gallina A, et al. 2011 submitted EF recovery according to pre-operatory IIEF-EF
  • Charlson Comorbity Index p=0.03 ERECTILE FUNCTION OUTCOME OF UNTREATED PATIENTS AFTER BILATERAL NERVE SPARING RADICAL PROSTATECTOMY Gallina A, et al. 2011 submitted 0 2+ 1
  • AGE DIFFERENCE BETWEEN PATIENT AND PARTNER IS A PREDICTIVE FACTOR OF POTENCY RATE FOLLOWING RADICAL PROSTATECTOMY Descazeaud et al, J Urol 2006;176:2594-8 Age difference was an independent predictive factor of overall potency status following RP (p=0.008) 200 consecutive patients treated with RP with a minimum 1-year follow-up ^ Potency was defined as erection sufficient for sexual intercourse with vaginal penetration
  • Novara G et al. J Sex Med 2010; 7:839–845
    • Age 65 years, absence of associated comorbidities, and good preoperative erectile function are the most important preoperative factors to select those patients for whom bilateral nerve-sparing RALP can achieve the best results.
  • FACTORS PREDICTING RECOVERY OF ERECTIONS AFTER RADICAL PROSTATECTOMY: 1. PRE-OPERATIVE FACTORS 3. POST-OPERATIVE FACTORS 2. INTRA-OPERATIVE FACTORS a. Extent of NVBV preservation b. Surgical experience c. Surgical technique a. Adequate on demand or rehabilitative treatment a. Pre-operative erectile function b. Patient age c. Age difference between patien and partners d. Comorbidity profile
  • Changes in IIEF-5 score after nerve sparing radical prostatectomy showing significant decrease in IIEF-5 score depending on extent of nerve sparing PREDICTION OF POSTOPERATIVE SEXUAL FUNCTION AFTER NERVE SPARING RADICAL RETROPUBIC PROSTATECTOMY Michl et al. J Urol 2005,176,227-31 INTRA-OP FACTORS PREDICTING RECOVERY OF ERECTIONS AFTER RADICAL PROSTATECTOMY
  • Ayyathurai et al, BJU Int. 2008;101:833-6. FACTORS AFFECTING ERECTILE FUNCTION AFTER RADICAL RETROPUBIC PROSTATECTOMY: RESULTS FROM 1620 CONSECUTIVE PATIENTS UNI AND MULTIVARIABLE ANALYSES PREDICTING EF RECOVERY AFTER SURGERY The proportion of men with a return of EF (erectile function sufficient for intercourse) was directly proportional to the number of previous RRPs performed by the surgeon: 60% of men reported a returned of potency from the first 265 RRPs, compared to 75% from the most recent 265 ( p =0.001).
  • INTRAFASCIAL NERVE SPARING RADICAL PROSTATECTOMY Eichelberg C et al . Eur Urol. 2007;51:105-10 Montorsi F et al Eur Urol 2005;48:938–45 Masterson TA, et al. BJU Int. 2008; 101 : 1217-22 . Nielsen ME, et al J Urol. 2008 180:2557-64 MSKCC series: 6-month EF recovery rates 67% vs 45%, respectively (p=0.01)
  • RALP VS OPEN RADICAL PROSTATECTOMY: RETROSPECTIVE COMPARISON OF A SINGLE CENTER Log rank p<0.001 RALP (n=289) 533 patients treated with bilateral intra-fascial nerve sparing radical prostatectomy RRP (n=244) Buffi N et al, Eur Urol Suppl 2010;58, abstract#81
  • Low risk of ED (age ≤ 65 years, IIEF-EF ≥ 26, CCI ≤ 1) p < 0.001 RALP VS OPEN RADICAL PROSTATECTOMY: RETROSPECTIVE COMPARISON OF A SINGLE CENTER Intermediate risk of ED (age 66-69 years or IIEF-EF 11-25,CCI ≤1) RALP RRP p < 0.001 High risk of ED (age ≥70 years or IIEF-EF ≤10 or CCI ≥2) RALP RRP p = 0.3 RALP RRP
  • COMPARISON OF OPEN AND ROBOTIC-ASSISTED LAPAROSCOPIC RADICAL PROSTATECOMY WITH A BILATERAL INTRAFASCIAL NERVE-SPARING APPROACH: RESULTS OF A HIGH VOLUME SINGLE SURGEON SERIES. Gallina et al. 2011, submitted KM curves predicting EF recovery according to surgical approach 6 months 12 months 24 months Open IBNS 28% 42% 51% RALP-IBNS 61% 69% 69%
  • COMPARISON OF OPEN AND ROBOTIC-ASSISTED LAPAROSCOPIC RADICAL PROSTATECOMY WITH A BILATERAL INTRAFASCIAL NERVE-SPARING APPROACH: RESULTS OF A HIGH VOLUME SINGLE SURGEON SERIES. Gallina et al. 2011, submitted Only preop fully potent patients (IIEF-EF ≥ 26) , aged <65 years 6 months 12 months 24 months Open IBNS 38% 57% 68% RALP-IBNS 71% 81% 81%
  • FACTORS PREDICTING RECOVERY OF ERECTIONS AFTER RADICAL PROSTATECTOMY: 1. PRE-OPERATIVE FACTORS 3. POST-OPERATIVE FACTORS 2. INTRA-OPERATIVE FACTORS a. Extent of NVBV preservation b. Surgical experience c. Surgical technique a. Adequate on demand or rehabilitative treatment a. Pre-operative erectile function b. Patient age c. Age difference between patient and partner d. Comorbidity profile
  • RECOVERY OF SPONTANEOUS ERECTILE FUNCTION AFTER NSRRP WITH AND WITHOUT EARLY INTRACAVERNOUS INJECTIONS OF ALPROSTADIL: RESULTS OF A PROSPECTIVE, RANDOMIZED TRIAL.
    • 30 potent patients with clinically localized prostate cancer underwent NSRRP and was subsequently randomized to:
    • Group 1 : alprostadil injections 3 times per week for 12 weeks (n= 15 patients)
    • Group 2 : observation without any erectogenic treatment (n=15 patients).
    • Patients were assessed at the 6-month followup by sexual history, physical examination, color Doppler sonography of the cavernous arteries and polisomnographic recording of nocturnal erections
    Montorsi F et al. J Urol.158:1408-10,1997
  • RECOVERY OF SPONTANEOUS ERECTILE FUNCTION AFTER NSRRP WITH AND WITHOUT EARLY INTRACAVERNOUS INJECTIONS OF ALPROSTADIL: RESULTS OF A PROSPECTIVE, RANDOMIZED TRIAL. Complications in patients treated with alprostadil injections: 3 cases (19%) Montorsi F et al. J Urol.158:1408-10,1997 Group 2 Group 1 p value Recovery of spontaneous erection sufficient for satisfactory sexual intercourse 8 (67%) 3 (20%) <0.001
  • MAY DRUGS ALTER THE PATHOPHYSIOLOGY OF POST PROSTATECTOMY ED?
    • Biopsy of corpus cavernosum with a 19 gauge Tru-Cut needle
    • First biopsy in the operating room with the patient under
    • general anesthesia prior to incision
    • Postoperative management for 6 months:
    • Group 1: sildenafil 50 mg at bedtime every other night
    • Group 2: sildenafil 100 mg at bedtime every other night
    • Second biopsy under local anesthesia in the office and with
    • ultrasound guidance
    Schwartz et al, J Urol 171:771, 2004
    • 21 patients (11 in Group 1 and 10 in Group 2) met all inclusion criteria and completed the study
    MAY DRUGS ALTER THE PATHOPHYSIOLOGY OF POST PROSTATECTOMY ED? Schwartz et al, J Urol 171:771, 2004 Pre-op Post-op p Content of SM (%) Group 1 Sildenafil 50 mg 51.5 52.7 ns Content of SM (%) Group 2 Sildenafil 100 mg 42.8 56.9 <0.05
  • Effects of nightly sildenafil treatment on recovery of spontaneous erections: results *Responders: patients with combined IIEF Q3/4 score of ≥ 8 and positive response to question: “ Over the past 4 weeks, have your erections been good enough for satisfactory sexual activity? ” at 8 weeks after discontinuation of drug Nightly sildenafil (50 – 100 mg) vs placebo after 36 weeks of treatment in 123 patients with normal preoperative EF, wishing to return to sexual activity Placebo n=25 Sildenafil n=51 † p=0.0156 Responders %* † Padma-Nathan et al. Int J Impot Res;20:479-86,2008
  • REINVENT: IIEF-EF domain score ≥22 after 2 months of open-label on-demand vardenafil treatment n=138 n=142 n=146 Patients previously on: Patients with IIEF-EF score ≥22 (%) Montorsi et al. Eur Urol. 2008;54:924-31 Placebo Vardenafil nightly Vardenafil on-demand
  • KAPLAN-MEIER CURVES PREDICTING EF RECOVERY ACCORDING TO THE TYPE OF TREATMENT IN THE OVERALL POPULATION TREATED WITH BNSRP (N=435) CHRONIC PDE5-I (n=95) ON-DEMAND PDE5-I (n=147) p=0.1 NO TREATMENT (n=193) p<0.001 Briganti A et al, AUA, 2009 % 1 yr % 2 yrs Chronic PDE5-I 62.4 78.5 On demand PDE5-I 48.0 66.9 No treatment 28.1 35.8
  • KAPLAN-MEIER CURVES: EF RECOVERY ACCORDING TO THE TYPE OF TREATMENT IN PTS AT LOW RISK OF ED (age ≤ 65 yrs, IIEF-EF ≥ 26, CCI ≤1 ; N=184) p=0.04 p=0.5 CHRONIC PDE5-I ON-DEMAND PDE5-I NO TREATMENT NO TREATMENT p=0.02 p=0.8 ON-DEMAND PDE5-I CHRONIC PDE5-I KAPLAN-MEIER CURVES : EF RECOVERY ACCORDING TO THE TYPE OF TREATMENT IN PTS AT HIGH RISK OF ED (age ≥ 70 yrs or IIEF-EF ≤ 10 or CCI ≥ 2; N=136) Briganti A et al, AUA, 2009 % 1 yr % 2 yrs Chronic PDE5-I 77.1 87.1 On demand PDE5-I 74.5 89.8 No treatment 67.2 69.5 % 1 yr % 2 yrs CHRONIC PDE5-I 37.4 67.8 ON DEMAND PDE5-I 30.9 63.7 NO TREATMENT 20.2 23.5
  • KAPLAN-MEIER CURVES PREDICTING EF RECOVERY ACCORDING TO THE TYPE OF TREATMENT IN PATIENTS AT INTERMEDIATE RISK OF ED (age 66-69 yrs or IIEF-EF 11-25, CCI≤1 ; N=115) p=0.04 p=0.02 NO TREATMENT CHRONIC PDE5-I ON-DEMAND PDE5-I Briganti A et al, AUA, 2009 % 1 yr % 2 yrs CHRONIC PDE5-I 33.2 74.5 ON DEMAND PDE5-I 28.1 52.9 NO TREATMENT 33.3 39.4
  • Mulhall et al. BJU Int 2010; 105:37-41
    • Clinically organ-confined prostate cancer
    • Fully functional erections corroborated by his partner
    • Bilateral nerve-sparing RP
    • Committed to pharmacological penile rehabilitation
  • Initial challenge with sildenafil citrate (4 attempts with 100 mg) Sildenafil 100 mg 3 times/week Erection sufficiently hard for penetration Trimix (papaverine 30 mg/mL, phentolamine 1 mg/mL and PGE1 10 μg/mL) 3 times/week Mulhall et al. BJU Int 2010; 105:37-41
  • Mulhall et al. BJU Int 2010; 105:37-41 Delaying the start of rehabilitation of EF was associated with poorer outcomes for EF
  • EF RECOVERY ACCORDING TO TIME FROM RP TO THERAPY INITIATION ≤ 2 months >2 months Log rank p=0.002
    • 154 patients treated with BNSRP . All patients received therapy for ED either as on-demand (n=96; 62.43%) or as rehabilitation treatment (n=58; 37.7%).
    CONCLUSIONS. if a post-operative treatment is planned this should be initiated soon after surgery Gallina A et al, Eur Urol Suppl 2010:58, abstract#82 1-yr 2-yr ≤ 2 months 81% 81% > 2 months 50% 71%
  • AT LEAST ONE PDE5 INHIBITOR DOSE PER WEEK SHOULD BE TAKEN IN ORDER TO IMPROVE ERECTILE FUNCTION RECOVERY AFTER BILATERAL NERVE SPARING RADICAL PROSTATECTOMY
    •   238 consecutive patients treated with BNSRP between 2005 and 2010 at a single tertiary referral center used PDE5-I on demand after surgery
    • Post-operative erectile function (EF) recovery was defined as an EF domain score of the IIEF (IIEF-EF) ≥22
    • Kaplan-Meier curves assessed the time to EF recovery according to the number of pills dichotomized according to the most-informative cut-off (more than 1 pill per week vs. <1 pill per week)
    • The association between the number of pills and EF recovery was assessed in univariable and multivariable Cox regression analyses after accounting for age at surgery and pre-EF
    Gallina A et al. AUA meeting 2011
  • AT LEAST ONE PDE5 INHIBITOR DOSE PER WEEK SHOULD BE TAKEN IN ORDER TO IMPROVE ERECTILE FUNCTION RECOVERY AFTER BILATERAL NERVE SPARING RADICAL PROSTATECTOMY Gallina A et al. AUA meeting 2011 <1 pill per week ≥ 1 pill per week Log rank p<0.001 KM curves predicting EF recovery according to the number pills taken
  • AT LEAST ONE PDE5 INHIBITOR DOSE PER WEEK SHOULD BE TAKEN IN ORDER TO IMPROVE ERECTILE FUNCTION RECOVERY AFTER BILATERAL NERVE SPARING RADICAL PROSTATECTOMY
    • We demonstrated that the number of pills taken (a proxy of sexual activity) is a major determinant of EF recovery in patients treated with BNSRP.
    • The association between number of pills per week was confirmed at multivariable analyses after adjusting for age and pre-operative EF (p<0.001; HR 4.0)
    • At least 1 pill of PDE5-I inhibitors on demand per week should be taken in order to improve EF recovery after surgery both in pre-operative potent patients as well as in those with EF impairment before surgery.
    Gallina A et al. AUA meeting 2011
    • Aim: To define the predictors of successful outcome with pharmacological penile rehabilitation following RP in a retrospective databes of 92 patients.
    • Inclusion criteria:
    • Presence of functional erections permitting sexual intercourse pre-RP
    • Commencement of rehabilitation within 12 months of RP.
    • Patients were instructed to obtain a penetration-rigidity erection on at least three occasions per week and to continue this regimen until at least 18 months after RP using either sildenafil or intracavernosal injection therapy (if oral therapy failed)
    Müller A et al. J Sex Med 2009; 6:2806–12
  • Müller A et al. J Sex Med 2009; 6:2806–12
  • Stepwise logistic regression analysis predicting failure to recover natural erections sufficient for intercourse Müller A et al. J Sex Med 2009; 6:2806–12
    • 49% of the patients freely decided not to start any ED therapy (group 1).
    • Of the remaining patients, 36 (36%) opted for an as-needed PDE5-I (group 2),whereas 15 (15%) decided to use a daily PDE5-I (group 3).
    • At the 18-mo follow-up, the overall discontinuation rate from both treatment modalities was 72.6% (eg, 72.2% vs. 73.3% in group 2 vs. group 3; p = 0.79).
    Salonia A et al Eur Urol 53:564-70,2008
  • AVAILABLE TOOLS FOR PREDICTING ERECTILE FUNCTION RECOVERY AFTER RADICAL PROSTATECOTMY
    • 435 patients treated with retropubic BNSRP between 2004 and 2008
    • Cox regression models tested the association between preoperative predictors (age at surgery, preoperative IIEF-EF domain score, CCI, BMI) and EF recovery (IIEF-EF≥22).
    • Independent predictors of EF recovery were then used to stratify patients into three groups according to the risk of erectile dysfunction (ED) after surgery:
        • low (≤65 yrs, IIEF-EF≥26, CCI≤1; n=184)
        • intermediate (66–69 yrs or IIEF-EF 11-25,CCI≤1; n=115)
        • high (≥70 years or IIEF-EF≤10 or CCI≥2; n=136)
    Briganti et al. J Sex Med 2010;7:2521–25
  • Briganti et al. J Sex Med 2010;7:2521–25 Erectile function recovery in the overall population
  • Briganti et al. J Sex Med 2010;7:2521–25 Erectile function recovery according to the novel risk stratification
  • Briganti et al. J Sex Med 2010;7:2521–25 Novel risk stratification according to post-operative treatment No therapy Pro-erectile therapy
  • Briganti et al. J Sex Med 2010;7:2521–25 Multivariable cox regression analyses predicting EF recovery
  • Briganti et al. J Sex Med 2010;7:2521–25 RISK STRATIFICATION AUC: 69.1%
    • LOW RISK (≤65 yrs, IIEF-EF≥26, CCI≤1)
    • INTERMEDIATE RISK (66–69 yrs or IIEF-EF 11-25,CCI≤1)
    • HIGH RISK (≥70 years or IIEF-EF≤10 or CCI≥2)
  • Eastham JA et al J Urol. 179:2207-10, 2008
    • A total of 1,577 men were included in the study.
    • Freedom from biochemical recurrence was defined as post-radical prostatectomy prostate specific antigen less than 0.2 ng/ml.
    • Continence was defined as not having to wear any protective pads.
    • Potency was defined as erection adequate for intercourse upon most attempts with or without phosphodiesterase-5 inhibitor
  • Eastham JA et al J Urol. 179:2207-10, 2008 Probability of attaining and maintaining trifecta in patient after RP
  • AUC:77.3% Eastham JA et al J Urol. 179:2207-10, 2008
  • CONCLUSIONS
    • Several predictors of post-operative erectile funciton have been identified
          • Pre-operative factors
          • Intra-operative factors
          • Post-operative factors
    • To date, only 2 models are available for post operative EF prediction, but the results are far from the ideal prediction.
    • The lack of a uniform evaluation of pre-operative erectile function, as well as of a clear definition of post-operative potency rend the prediction of erectile function recovery very difficult
  •