Study_penile_extender_device_treatment_penile_curvature_peyronie's disease.pdf

ORIGINAL RESEARCH—PEYRONIE’S DISEASE
Use of Penile Extender Device in the Treatment of Penile
Curvature as a Result of Peyronie’s Disease. Results of
a Phase II Prospective Study
Paolo Gontero, MD,* Massimiliano Di Marco, MD,† Gianluca Giubilei, MD,‡ Riccardo Bartoletti, MD,§Giovanni Pappagallo, MD,¶ Alessandro Tizzani, MD,* and Nicola Mondaini, MD§ *Urology Department, University of Torino, Torino, Italy; †Urology Department, Silicato Hospital, Rome, Italy; ‡UrologyClinic, University of Florence, Florence, Italy; §Urology Clinic, Hospital S M Annunziata, University of Florence, Florence,Italy; ¶Oncology Unit, Noale Hospital, Noale, Italy A B S T R A C T
Introduction. Pilot experiences have suggested that tension forces exerted by a penile extender may reduce penile
curvature as a result of Peyronie’s disease.
Aim. To test this hypothesis in a Phase II study using a commonly marketed brand of penile extender.
Methods. Peyronie’s disease patients with a curvature not exceeding 50° with mild or no erectile dysfunction (ED)
were eligible. Fifteen patients were required to test the efficacy of the device assuming an effect size of >0.8,
consistent with an “important” reduction in penile curvature. Changes in penile length over baseline and erectile
function (EF) domain scores of the International Index of Erectile Function (IIEF) constituted secondary end points.
Main Outcome Measures. Patients were counselled on the use of the penile extender for at least 5 hours per day for
6 months. Photographic pictures of the erect penis and measurements were carried out at baseline, at 1, 3, 6, and 12
months (end of study). The IIEF-EF domain scores were administered at baseline and at the end of study. Treatment
satisfaction was assessed at end of study using a nonvalidated institutional 5-item questionnaire.
Results. Penile curvature decreased from an average of 31° to 27° at 6 months without reaching the effect size
(P = 0.056). Mean stretched and flaccid penile length increased by 1.3 and 0.83 cm, respectively at 6 months. Results
were maintained at 12 months. Overall treatment results were subjectively scored as acceptable in spite of curvature
improvements, which varied from “no change” to “mild improvement.”
Conclusions. In our study, the use of a penile extender device provided only minimal improvements in penile
curvature but a reasonable level of patient satisfaction, probably attributable to increased penile length. The selection
of patients with a stabilized disease, a penile curvature not exceeding 50°, and no severe ED may have led to outcomes
underestimating the potential efficacy of the treatment. Gontero P, Di Marco M, Giubilei G, Bartoletti R,
Pappagallo G, Tizzani A, and Mondaini N. Use of penile extender device in the treatment of penile
curvature as a result of Peyronie’s disease. Results of a phase II prospective study. J Sex Med 2009;6:558–
566.
Key Words. Peyronie’s Disease; Nonsurgical Treatment; Penile Extender
Introduction
plaints, including penile curvature, painful erec-tions, erectile dysfunction (ED), and penile P eyronie’sdiseasecanbedefinedasanacquired shortening leading to significant detrimental psy- penile deformity of the erect penis, which is chological effects [1–4]. A conservative medical caused by a fibrous plaque. Men with Peyronie’s treatment is usually advocated as the first-line disease may present with a combination of com- therapy, particularly in the early inflammatory 2008 International Society for Sexual Medicine Penile Extenders in the Treatment of Peyronie’s Disease phase, although there is little evidence that this is It is particularly useful for quantifying effects mea- effective [5]. If such management proves unsuc- sured on unfamiliar or arbitrary scales and for cessful, a more invasive surgical approach may be comparing the relative sizes of effects from differ- contemplated once the disease has been stabilized, ent studies. Cohen [12] defined the effect size “d” usually after 1 year from onset [1]. The long-term as the difference between the means, M1–M2, results of surgery are not devoid of complications, divided by standard deviation, s, of either group.
particularly following graft procedures, with ED By convention, the subtraction, M1–M2, is per- and penile shortening being not unusual com- formed so that the difference is positive if it is in plaints [6,7]. It has been claimed that the penile the direction of improvement or in the predicted extender, a nonsurgical device that employs pro- direction, and negative if in the direction of dete- gressive mechanical traction to the penis, produces rioration or opposite to the predicted direction.
a significant improvement in penile length [8,9].
Thus, effect size quantifies the size of the differ- Two preliminary pilot experiences have sug- ence between groups, and may therefore be said to gested that the tension forces exerted by a penile be a true measure of the significance of the differ- extender could also reduce penile curvature as a ence. Effect sizes were defined as “small, d = 0.2,” result of Peyronie’s disease [10,11]. The combina- “medium, d = 0.5,” and “large, d = 0.8”. Effect tion of these effects may provide an intriguing sizes can also be interpreted in terms of the treatment option in selected Peyronie’s disease percent of non-overlap of the experimental patients. We tested this hypothesis in a Phase II group’s values with those of the control group: a d study designed to assess whether a penile extender of 0.8 indicates a non-overlap of 47.4% in the produces significant improvement in penile curva- two distributions; a d of 0.5 indicates a 33% ture as a result of Peyronie’s disease.
non-overlap; and a d of 0.2 a 14.7% non-overlap.
It was assumed that with 15 evaluable patients, the finding of a “relevant” reduction in penile cur- Materials and Methods
vature, defined by an effect size Ն0.8, would havea statistical power of 80% and a probability of a false negative result of less than 5% (2-sided).
Patients with a penile curvature as a result of Pey- Changes in flaccid and stretched penile length, ronie’s disease were considered eligible for the plaque size, treatment tolerability, patient comp- study if they met the following inclusion criteria: liance and satisfaction, as well as changes in the (i) a penile curvature not exceeding 50°, sustained IIEF-EF domain scores at last follow-up com- by fibrous plaques detectable through genital pared with the baseline measurements constituted palpation or ultrasound (US); (ii) a history of the disease lasting at least 12 months; and (iii) nopenile pain in the flaccid state. Previous medical treatment did not contraindicate study participa- Baseline patients’ assessment included full medical tion. The exclusion criteria were a history of major and sexual history, and physical examination. The psychiatric disorder, reduced manual dexterity that EF domain scores of the IIEF were administered might prevent the correct use of the device, pre- at baseline and at the end of the study (6 months vious penile surgery, or severe ED based on the after treatment discontinuation). Patients scoring erectile function (EF) domain scores of the Inter- severe abnormal values (IIEF-EF Յ 10) were national Index of Erectile Function (IIEF).
excluded [13]. A penile US was required for studyentry in order to record the size of plaques (deter- End Points and Sample Size Statistics mined as the product of length and width in Changes in penile curvature during erection com- mm[2]) and the location and sonographic app- pared with the baseline after 6 months of treat- earance (calcified, hypoechoic, hyperechoic) of ment and durability of the response 6 months after the plaques. Fibrous nodules undetectable sono- treatment discontinuation were considered the graphically were measured manually using a primary study end points. Given the objective caliper. The same measurement method was used difficulty of estimating the standard deviation of in each patient for the posttreatment determina- baseline penile curvature, calculation of the sample size was based on the “effect size” [12].
The degree of curvature was documented using Effect-size is a standardized, scale-free measure photographic pictures taken by the clinician from of the relative size of the effect of an intervention.
three angles (frontal, lateral, and dorsal) during an in-office intracavernous injection test with 20 mcg In cases of concomitant untreated ED, patients alprostadil or, for patients refusing the injection, were advised to postpone the use of erectile aids by self-photographs during an at-home full erec- until the end of study. Sexual activity was not inter- tion. The former was strictly required for patients dicted at any time during the study. It was sug- scoring abnormal IIEF-EF domain scores.
gested that patients wear the device for up to 9 The magnitude of curvature on photographs hours/day and it was explained that, based on the was determined by placing a goniometer in the available evidence [10,16,17], the magnitude of angle formed by the intersection of two drawn both the straightening and the elongating effect segments running parallel to each of the two would be proportional to the traction time. The bended portions of the shafts. Following pharma- minimum daily use for testing treatment efficacy cological erection, the center of the goniometer was assumed to be 5 hours and this was the was placed over the point of maximum curvature minimum requirement for entry into the study.
and the limbs were positioned along the shaft,proximal to and distal to this point. Posttreatment curvature was determined in each patient using the Follow-up visits were scheduled at 1 (t1), 3 (t3), 6 same method they had chosen at baseline. Penile (t6), and 12 months (t12) (end of study, after a wash- measurements (t0) were obtained employing the out period of 6 months) to record side effects, standard technique validated by Wessells et al.
treatment compliance, calculations of curvature [14]. Using a taper ruler to the nearest 0.5 cm, the using fresh photographs, and to carry out genital penis was initially measured in the flaccid state and examinations and take penile measurements. At then while applying tension to maximally stretch the end of the study, the EF domain scores of the it, from the pubopenile skin junction to the IIEF and a satisfaction questionnaire were admin- meatus. The circumference was measured at istered. The latter consists of a set of five questions midshaft. Inter-operator agreement was assessed designed by the investigators that ask patients by performing a set of measurements on a small to assess subjective improvements in penile curva- sample of young volunteers (N = 8) with individual ture (Q1) on a 0–4 scale (0 = worsening, 1 = variability always falling below 0.5 cm.
unchanged, 2 = mild improvement, 3 = significantimprovement, 4 = complete resolution), as well asto assess flaccid penile length (Q2), erect penile Device Description and Treatment Schedule length (Q3), and overall results (Q4) on a 0–3 After signing the informed consent form, patients result). Lastly, Q5 addresses overall results on a penile extender, the Andropenis® (Andromedical, 0–4 scale (0 = no result, 1 = very mild, 2 = accept- Madrid, Spain), a device designed to exert a able, 3 = good, 4 = optimal results). Plaque size continuous and gradually increasing traction force was also calculated at the end of study using on the penis. The device consists of a plastic ring, a caliper or a penile US. The study protocol was where the penis is introduced, and from where two granted Ethical Committee approval in February dynamic metallic rods originate the traction.
In the upper part there is a plastic support where a silicone band holds the glans in place.
Detailed instructions on how to increase the trac-tion force from 600 g during the first month, 900 g Out of a set of 40 patients referring with a com- during the second month, up to 1200 g during plaint of penile curvature between February 2005 the fifth and sixth months were provided following and May 2006, 19 met the inclusion criteria and the manufacturer’s leaflet. Briefly, the traction is entered the study. Reasons for exclusion were con- rendered a dynamic process by means of the rigid genital curvature (N = 2), concomitant penile pain rods combined with the action of “compression (N = 6), disease history lasting less than 12 months springs” (springs that react by exerting a traction (N = 6), a curvature exceeding 50° (N = 4), and when compressed). As the tissues are stretching refusal to undergo the proposed treatment (N = throughout months of treatment, more and more 3). Baseline characteristics of the sample for age, elongations of the two metal rods of Andropenis® disease features, EF domain scores of the IIEF, combined with the action of the “compression and penile measurements are listed in Table 1.
springs” are needed to achieve the needed traction None of the eligible patients was taking ED Penile Extenders in the Treatment of Peyronie’s Disease Baseline patient characteristics (N = 19) One patient discontinued treatment with the penile stretcher after a few days because of discom- fort caused by the device and three patients did not attend the scheduled follow-up visits and were lost to follow-up. Data on the 6-month treatment period and follow-up were available for all 15 remaining patients. Median time of daily use of the device was 5.5 hours (minimum–maximum: 3–6 hours) at 1 month, 5 hours (minimum–maximum: 3–6 hours) at 3 months, and 5 hours (minimum– determination: US N = 13or calliper N = 6) maximum: 2–8 hours) at 6 months, respectively (P = 0.191; Greenhouse–Gasser corrected, repea- Penile curvature decreased from a mean base- line value of 31° (SD 1.55) to 27° (SD 2.79) after 6 months of treatment (P = 0.059) (Figure 1).
The degree of curvature worsened (+10°) in one patient, remained unchanged in eight, and decreased in six (-20° in 2/6, –10° in 2/6, and –5° in 2/6). Curvature values remained unchanged in each patient after the 6 months wash-out period.
Figures 2 and 3 report the box plots related to the changes in the flaccid and stretched penile length, respectively at 6 months. After 6 months of treat- ment with the penile extender, a significant IIEF-EF domain score N (%) Normal (26–30) (Wilcoxon Z = –2.852, P = 0.004 and Wilcoxon Z = –3.068, P = 0.002) and overall mean gain of 1.3 and of 0.83 cm for the flaccid and stretched penile length, respectively was observed. Table 2 US = ultrasound; IIEF-EF domain = erectile function domain of the Interna-tional Index of Erectile Function; ED = erectile dysfunction.
reports the changes which occurred across all timeintervals in penile curvature and length. The gainin length was maximal in the t0–t1 time interval Figure 1 Plots
changes over baseline in the penilecurvature after 6-month treatmentwith the penile extender and at 12months (after 6 months of treatmentdiscontinuation).
Figure 2 Box plot showing changes
over baseline in the flaccid penile
length after 6-month treatment with
the penile extender and at 12 months
(after 6 months of treatment discon-
tinuation).
and showed progressive declines in t1–t3 and t3–t6 showed only marginal improvements, from a mean intervals. Curvature degrees and penile length baseline value of 23.8 (SD 4.07) to 24.7 (SD 4.11) remained stable at 12 months (t6–t12). Changes in at 12 months (P = 0.23). Specifically, 6 months penile girth were negligible and not significant after treatment, the IIEF-EF domain score nor- (mean value of 9.86 cm at baseline and of 9.96 cm malized in three out of six patients with mild ED at baseline, while two patients with normal pretreat- Plaque size did not show significant changes ment EF scored IIEF-EF values consistent with during the study period (1.35 cm vs. 1.30 cm, P = 0.4). No patient requested treatment for ED Mean patient satisfaction scores for the 5-item during the study period. IIEF-EF domain scores questionnaire are reported in Table 3. The treat- Figure 3 Box plot showing changes
over baseline in the stretched penile
length
with the penile extender and at 12months (after 6 months of treatmentdiscontinuation).
Penile Extenders in the Treatment of Peyronie’s Disease treatment will produce a beneficial effect [20].
stretched and flaccid penile length at different time At this stage, surgery may be contemplated as the intervals and corresponding 95% confidence intervals last remaining option to restore successful sexual intercourse [7]. All the currently available surgical techniques are essentially unable to provide a cura- tive effect of the disease; rather, they aim to palliate its side effects by restoring a straight shape to the curved penis. Strict selection criteria (i.e., highly motivated patients with severe curvature impair- ing sexual intercourse) are mandatory as tunical lengthening surgical procedures carry a significant risk of complications leading to a high patient dissatisfaction rate. On the other side, tunical shortening procedures such us the Nesbit cor- poroplasty, in spite of the low morbidity, may result in a significant loss of penile length [21]. We selected a study population of patients with clini- cally stable Peyronie’s disease and a mild to mod- erate degree of curvature (not exceeding 50°) and no severe ED as defined by the EF domain scores t0 = baseline; t1 = 1 month of treatment; t3 = 3 months of treatment; t6 = 6months of treatment; t12 = 12 months from treatment onset corresponding to 6 of the IIEF [11]. No specific treatment is currently months of follow-up after stopping the treatment; NA = not applicable.
available for this disease subgroup as surgery mayprobably turn out to be an overtreatment whilenonsurgical options are unlikely to be effective ment was generally well tolerated, with only three once the disease is stabilized [22]. Notably, the patients reporting bruising (N = 2) or itching majority of our patients had previously failed Based on the preliminary evidence reported by Discussion
Scroppo et al. [10] of a 50% reduction in the cur- Several treatment options, including oral com- vature of the shaft after the application of progres- pounds, intralesional and topical agents, have been sive mechanical traction forces on the penis over proposed for the treatment of Peyronie’s disease a 6-month period, these patients may be ideal but the evidence that any of these may be effective candidates for a trial with a penile extender device.
remains weak, such that observation alone is In our series, the mean curvature of the shaft considered a viable option [7,18,19]. The lack of decreased by 4° (13% of the baseline value) fol- precise data on the pathogenesis of Peyronie’s lowing a 6-month treatment period using the same disease is probably one key element that prevents brand of penile extender. Albeit of borderline the development of appropriate treatment strate- significance, the magnitude of improvement did gies for this disease. Some data suggest that the not meet the expected “effect size” necessary to currently available nonsurgical options may have a state that the treatment was effective. Interestingly window of opportunity in the acute phase of the enough, these results were comparable with the disease. Once the disease has stabilized, typically average absolute improvement in penile curvature after 12–18 months, it is unlikely that any medical (13.5%) reported in a recent meta-analysis on Mean scores of the 12-month satisfaction questionnaire (N = 15) Q1: How would you rate your penile curvature?* Q2: How would you rate your flaccid penile length?† Q3: How would you rate your erect penile length?† Q4: How would you rate your sexual life?† Q5: How would you rate the overall result achieved?‡ *Q1 scores: 0 = worsening; 1 = unchanged; 2 = acceptable improvement; 3 = significant improvement; 4 = complete resolution.
†Q2, Q3, Q4 scores: 0 = reduced; 1 = unchanged; 2 = acceptable improvement; 3 = significant improvement.
‡Q5 scores: 0 = no result; 1 = very mild; 2 = acceptable; 3 = good; 4 = optimal.
intralesional injection therapy, one of the most risk of study dropout from patients with a severe popular treatment modalities for Peyronie’s curvature that could have been less compliant to disease [5]. Measurable reductions in curvature ranging from 5° up to 20° were recorded in 6 out Variations in plaque size constituted a second- of 15 (40%) evaluable patients, the remaining ary study end point. The lack of significant post- patients having stable (8/15) or progressive (1/15) treatment changes in the current study is likely disease. Although spontaneous improvement in to be clinically irrelevant and it does not affect the the degree of bending has been reported [2,23], potential efficacy of the device as no correlation this is less likely to occur when the disease is between the extent of the plaque and the severity stabilized, as in our series. Of note, no changes in of curvature has been demonstrated so far. Besides, penile curvature were detected after 6 months it is possible that the two different methods of treatment wash out. If it seems reasonable to employed in the current study to obtain plaque state that the treatment proved effective in some size (US or caliper) may not be equally accurate.
patients, the small sample size did not allow us to Whether the application of the device in the identify predictors of response. In a subgroup of acute disease phase may reduce the plaque size our patients refusing an in-office intracavernous remains to be proven. The application of a penile injection, the curvature was calculated based on extender in the current study caused only minimal at-home photographs, a methodology that has and self-resolving side effects, leading to discon- been recently found to underestimate the degree tinuation of treatment in only one case. Mean of penile bending as compared with trimix intrac- baseline IIEF-EF domain scores were consistent avernous injection[24]. This may have led to inac- with mild ED as we deliberately excluded patients curate measurements, given the inability of the with severe ED that may be less amenable for investigator to assess the rigidity of the erection.
conservative treatment of Peyronie’s disease.
It may be speculated that the shorter daily use of Sexual dysfunction is a common complication in the device in our study in comparison with the the presence of fibrous penile plaques with both study of Scroppo et al. [10] might account for the psychological and organic factors contributing lower degree of curvature reduction.
to its pathogenesis [22]. Currently, there is no The mean time of daily use of the device in evidence that any medical treatment may have our study tended to be close to the minimum beneficial effects on the sexual function of Pey- required for study entry. It is likely that a more ronie’s disease patients [5]. An average 5-point strict protocol requiring a minimum of 8 or 9 improvement of the IIEF-EF domain scores has hours of daily use would greatly reduce patients’ been recently reported in a pilot experience on compliance [10,17]. Our results were overall a penile traction device [11]. Posttreatment lower than that reported in a recent pilot study IIEF-EF domain scores in our study showed where an average 33% curvature reduction was marginal, nonsignificant changes compared with baseline scores. It is possible that the lower degree Differences in selection criteria, device proper- of baseline sexual dysfunction in our series as ties, and treatment schedule may account for these opposed to the one of the Levine et al. study [11] discrepancies in outcomes and represent limita- (mean IIEF-EF domain score of 23.8 vs. 18.3) may tions of the current study. For instance, the require- account for the lower degree of improvement.
ment of a “clinically” stable disease for study entry Notably, our finding corroborates the safety may have led to select a subgroup of patients with a profile of the penile traction device as opposed disease less amenable to plastic changes following to the detrimental effect on sexual function some- the application of traction forces as opposed to a times reported following graft surgery [6].
Peyronie’s plaque in the acute phase. The reason The Andropenis® produced an effective and for these strict inclusion criteria was to minimize durable (over the 6-month off treatment period) the possibility of self-improvement of the curvature lengthening of the penis both in the flaccid and the that could more likely occur during the acute stretched state. The elongating effect was of a disease phase. Also, by restricting the limit of penile lower magnitude than that observed in our previ- bending to 50°, we may have reduced the chances to ous study where dysmorphophobic and postsur- obtain an effect of significant magnitude. Baseline gery short penises underwent the same treatment mean curvature in our study was 31° as compared protocol [9]. A reduction in penile elasticity as a with 51° in the study by Levine et al. [11]. With consequence of the reduced content in elastin these inclusion criteria, we aimed to minimize the within the fibrous plaques could explain why Penile Extenders in the Treatment of Peyronie’s Disease Peyronie’s disease patients are less susceptible to caused negligible side effects. Overall results were the elongating effects of the penile extender [25].
self-reported as “acceptable,” making this mini- Even though baseline penile size in our patients mally invasive treatment modality a potential new falls within the normal range based on the criteria treatment option in selected Peyronie’s disease outlined by Wessells et al. [14], penile lengthening was probably the most notable clinical findingof the current study. Penile shortening, a bother- Corresponding Author: Paolo Gontero, MD, Senior
some symptom of Peyronie’s disease, cannot be Lecturer in Urology, C.so Dogliotti, 14, 10126 addressed as an end point by any medical treatment.
+3900116334202; E-mail: [email protected] Restoration of penile lengthening would involve acomplete reversal of the fibrotic process, a finding Conflict of Interest: None declared.
that has never been proved to occur with anyspecific treatment modality in Peyronie’s disease.
Statement of Authorship
Besides, it is usually significantly worsened bysurgery, no matter which procedure is employed, leading to a high dissatisfaction rate [7]. From this (a) Conception and Design
perspective, the penile extender could play an essential role as part of a multimodal treatment (b) Acquisition of Data
strategy. In the absence of validated instruments to Paolo Gontero; Massimiliano Di Marco; Gianluca assess the patients’ perception of the efficacy of the Giubilei; Riccardo Bartoletti; Nicola Mondaini (c) Analysis and Interpretation of Data
device, we designed a specific posttreatment 5-item Paolo Gontero; Giovanni Pappagallo; Alessandro questionnaire. Average scores for the two questions about the flaccid and stretched penile length wereconsistent with “acceptable results,” meaning that patient self-judgment of the gain in both the flaccid (a) Drafting the Article
and the erect penile length somehow substantiated Paolo Gontero; Giovanni Pappagallo; Alessandro the objective changes we recorded through mea- surements. While improvement in sexual function (b) Revising It for Intellectual Content
and penile curvature were rated as intermediate Paolo Gontero; Riccardo Bartoletti; Giovanni Pap- between “no changes” and “acceptable,” the overall pagallo; Alessandro Tizzani; Nicola Mondaini results were surprisingly assessed by the patients as“acceptable.” Our satisfaction assessment is limited by the absence of a comparative pre- and posttreat- (a) Final Approval of the Completed Article
ment analysis, and lack of validation. Notwith- Paolo Gontero; Massimiliano Di Marco; Gianluca standing these limitations, it hints at favorable Giubilei; Riccardo Bartoletti; Giovanni Pappagallo; acceptance of the device that warrants further study to explore the clinical utility of this noninvasivetreatment modality in Peyronie’s disease.
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