Penile Rehabilitation Therapy Following Radical Prostatectomy: A Meta-Analysis

REVIEWS

Penile Rehabilitation Therapy Following Radical Prostatectomy: A Meta-Analysis Chunhui Liu, MD, PhD,1,2 David S. Lopez, PhD,1,3 Ming Chen, MD, PhD,2 and Run Wang, MD, FACS1,4

ABSTRACT

Background: Penile rehabilitation, defined as the use of any drug or device at or after radical prostatectomy to maximize erectile function recovery, is commonly used for post-prostatectomy erectile dysfunction; however, conflicting results based on each study make it difficult to give a recommendation for clinical practice. Aim: To clarify the effect of oral phosphodiesterase type 5 inhibitors (PDE5is), vacuum erection devices, intracorporeal injection therapy, and the combination of these treatments on penile rehabilitation. Methods: A comprehensive publication search was done through the PubMed and Embase databases up to February 8, 2017. The reference lists of the retrieved studies also were investigated. Data were analyzed using STATA 12.0. A fixed- or random-effects model was used to calculate the overall combined odds ratio (OR) or standard mean differences (SMDs). Publication bias was assessed using the Begg and Egger tests. Outcomes: Change in sexual function before and after treatment. Results: After screening, 11 randomized controlled trials and 5 case-control studies were included. The overall meta-analysis showed that penile rehabilitation with PDE5is, vacuum erection devices, and intracorporeal injection significantly increased the number of patients with erectile function improvement (OR ¼ 2.800, 95% CI ¼ 1.932e4.059, P ¼ .000) and International Index of Erectile Function (IIEF) score (SMD ¼ 5.896, 95% CI ¼ 4.032e7.760, P ¼ .000). In subgroup analysis based on study design, randomized controlled trials and case-control studies showed that penile rehabilitation increased the number of patients with erectile function improvement (randomized controlled trials: OR ¼ 2.154, 95% CI ¼ 1.600e2.895, P ¼ .000; case-control studies: OR ¼ 2.800, 95% CI ¼ 1.932e4.059, P ¼ .000). Subgroup analysis for PDE5i treatment also only demonstrated an increased patient response rate (OR ¼ 2.161, 95% CI ¼ 1.675e2.788, P ¼ .000) and IIEF scores (SMD ¼ 0.922, 95% CI ¼ 0.545e1.300, P ¼ .000). However, after PDE5i washout, there was no improvement of spontaneous erectile function (OR ¼ 1.027, 95% CI ¼ 0.713e1.478, P ¼ .610). Clinical Translation: This study provides information about the efficacy of penile rehabilitation that can help clinicians decide treatment strategies. Strengths and Limitations: This meta-analysis has higher statistical power than each study. Preoperative patient characteristics, various treatment methods, and different follow-up times might bring bias to pooled effects. Conclusion: Our meta-analysis confirmed that administration of PDE5is, vacuum erection devices, and intracorporeal injection after radical prostatectomy can increase erection function during treatments. However, current evidence does not support that penile rehabilitation with PDE5is can improve recovery of spontaneous erectile function. Further studies with adequate follow-up and larger samples should be conducted to generate a comprehensive conclusion. Liu C, Lopez DS, Chen M, Wang R. Penile Rehabilitation Therapy Following Radical Prostatectomy: A Meta-Analysis. J Sex Med 2017;14:1496e1503. Copyright
2017, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Key Words: Rehabilitation; Radical Prostatectomy; Erectile Dysfunction; Meta-Analysis

Received June 11, 2017. Accepted September 27, 2017. 1

Division of Urology, Department of Surgery, University of Texas Medical School at Houston, Houston, TX, USA;

2

Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu, China;

3

4

Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Copyright ª 2017, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jsxm.2017.09.020

Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX, USA;

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Penile Rehabilitation for Prostatectomy

INTRODUCTION Prostate cancer, one of the most common cancers in men, has been responsible for 161,360 new cases and 26,730 deaths in Americans in 2017.1 Prostate-specific antigen testing allows prostate cancer to be diagnosed at a lower disease stage.2 For early localized prostate cancer, radical prostatectomy (RP) is the most commonly used first-line treatment.3 Although many advances have been made in understanding prostate anatomy and the use of minimally invasive technology, erectile dysfunction (ED) after RP remains a common adverse effect negatively affecting patients’ quality of life.4 ED after RP is mainly attributed to neurovascular bundle trauma and this cannot be completely avoided even with the best nerve-spring techniques.5 The neurovascular bundle will be affected by mechanical manipulation, heating, ischemic effects, and local inflammation.6 The reported incidence rates of ED after RP range from 6% to 68%.7 Erectile function can return gradually after surgery, although it can take approximately 2 years or longer.8 Only few patients will return to their baseline erectile function.9 Because of this, penile rehabilitation was proposed to stimulate recovery of erectile function after RP. The concepts of penile rehabilitation can be defined as the use of any drug or device at or after RP to maximize erectile function recovery. Although there are different treatment methods used in penile rehabilitation, the most common approaches of penile rehabilitation after RP are oral phosphodiesterase type 5 inhibitors (PDE5is), vacuum erection devices (VEDs), intracorporeal injection (ICI) therapy, and a combination of these treatments.10 Unfortunately, conflicting results based on each study make it difficult to give a recommendation for clinical practice. Therefore, we conducted a quantitative meta-analysis to clarify the effect of these treatments on penile rehabilitation.

METHODS Search Strategy We performed a comprehensive publication search through the PubMed and Embase databases up to February 8, 2017, with no language limit. The following terms were used: “radical prostatectomy AND erectile function AND rehabilitation OR recovery.” References cited in retrieved articles and reviews also were scanned to identify relevant publications.

Study Selection Studies included in this meta-analysis satisfied the following criteria: (i) a study that included post-RP ED; (ii) a study that included the effect of scheduled PDE5is, ICI, VED, and combinations of these treatments; (iii) a study whose full text and sufficient data could be accessed; and (iv) the language must be English. The main exclusion criteria were (i) reviews, editorial comments, background, animal models, and case reports; (ii) insufficient data; (iii) a duplicated study or study that used a J Sex Med 2017;14:1496e1503

sample more than once; and (iv) studies with PDE5i use as needed.

Data Extraction To ensure objectivity, all articles were independently reviewed by 2 investigators. Discrepancies were resolved by consensus. From each study, the following information was extracted: first author’s name, year of publication, study population, duration of follow-up, treatment methods, assessment tools, and outcomes.

Statistical Analysis Statistical analyses were conducted using STATA 12.0 (StataCorp, College Station, TX, USA). To evaluate the effect of penile rehabilitation, odds ratio (OR) and 95% CI were used for 2-category data and standard mean difference (SMD) and 95% CI were used for continuous data. For heterogeneity among studies, the I2 test was used. If the data did not have significant heterogeneity (I2 < 50%), then the OR and SMD were analyzed by the fixed-effect model. If the data had heterogeneity, then they were analyzed by the random-effect model. Sensitivity analyses were performed by sequentially removing each eligible study. Publication bias was determined by the Begg funnel plot and the Egger test. Subgroup analysis was performed when there were enough data to identify the source of heterogeneity.

RESULTS Study Characteristics The initial search found 623 articles in PubMed and 971 articles in Embase. After applying additional filters, 16 studies involving 2,012 patients were included in this review.11e26 Figure 1 presents the detailed process of selecting and excluding studies. These studies were performed by different medical centers in different countries. Almost all patients received nerve-sparing surgery. The most commonly used treatment was PDE5is.12,16e26 The follow-up time was 12 weeks to 24 months. Of the 16 studies, 11 were randomized controlled trials (RCTs) and the remaining 5 were case-control studies (Table 1). The International Index of Erectile Function (IIEF) was the most commonly used assessment tool for erectile function evaluation. Almost all studies provided the rehabilitation rate or number and some studies provided the IIEF score before and after treatment. Because some studies provided only 1 type of data, the meta-analysis was done twice with different types of data. In the PDE5i group, some studies contained the outcomes after drug washout, so meta-analysis was applied to those data individually. Most data were obtained directly but some data were obtained by calculation.

Penile Rehabilitation and Erectile Function The overall meta-analysis showed that penile rehabilitation with PDE5i, VED, and ICI significantly increased the number of the patients with erectile function improvement (OR ¼ 2.800,

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washout data, no heterogeneity was found in overall comparisons.

1088 articles were identify including: PubMed: 623 articles EMBASE: 971 articles

Publication Bias 1053 articles were excluded after abstract review

35 articles for more detailed evaluation

19 articles were excluded

16 articles included in the meta-analysis

Publication bias was detected by the Begg funnel plot and the Egger test. The shape of the funnel plot was symmetrical in the analysis for the number of patients with erectile function improvement, IIEF scores, and wash out in this meta-analysis (Figure 4AeC). Moreover, no statistical significance was detected by the Egger test (P ¼ .056 for rehabilitation number group; P ¼ .193 for IIEF score group; P ¼ .089 for wash out group).

DISCUSSION

Heterogeneity Analysis

Prostate cancer is more commonly diagnosed in younger men than ever before. Cancer treatment with RP provides excellent long-term oncologic outcomes.27 In consequence, there is increased focus on preserving the patient’s quality of life.28 The Fourth International Consultation for Sexual Medicine (ICSM; 2015) provided 9 recommendations for sexual rehabilitation after RP. The committee believed that postoperative erectile function is associated with a patients’ age and preoperative erectile function.29,30 Penile rehabilitation was first introduced by Montorsi et al11 in 1997. Since then, a large number of clinical studies and reviews have focused on this topic. However, the ICSM committee pointed out that there are conflicting data as to whether penile rehabilitation with PDE5is improves recovery of spontaneous erection.29,30 Therefore, there is no agreement as to when, how, and what penile rehabilitation should be used after RP. In this study we conducted a quantitative meta-analysis to clarify the effects of these rehabilitation modalities. To the best of our knowledge, this is the first meta-analysis that included different therapies (ie, PDE5is, VED, and ICI). We also analyzed the treatment effect of PDE5i after washout in RCTs and included case-control studies. The summarized results showed that early ED treatment after RP can improve patient erectile function regardless of whether the data were analyzed from pooled RCTs or from case-control studies. In the subgroup analysis, when using the data before washout, the results showed that PDE5is can increase erectile function in patients with treatment compared with the control group. However, when using the data after washout, the results showed no difference between scheduled PDE5is and no PDE5i usage. Obviously, PDE5is have a therapeutic effect for ED after RP but do not help recovery of spontaneous erectile function based on current publications. Therefore, it is important to provide this information to patients so they can have realistic expectations.

In the meta-analysis using the number of patients with erection function improvement, no significant heterogeneity was found in overall comparisons. However, significant heterogeneity was found in ICI and case-control subgroups. When IIEF data were used, significant heterogeneity was found in overall comparisons, RCTs, and PDE5i subgroups. In the analysis using

Although daily PDE5is did not improve spontaneous erectile function, we cannot ignore the fact that penile rehabilitation with daily PDE5is can preserve the structure of the corporeal cavernosa and penile size.22 In rats with ED, PDE5is can preserve corporal smooth muscle, ameliorate fibrotic degeneration, and improve penile hypoxia.31e33 Preservation of penile

Figure 1. Flow diagram for study selection. 95% CI ¼ 1.932e4.059, P ¼ .000; Figure 2A). Based on the treatment method and study design, a subgroup analysis was performed. Owing to the limited number of studies with VED, ICI, and combination therapies, subgroup analysis was possible only for PDE5is. The analysis for PDE5i treatment only demonstrated an increased patient response rate (OR ¼ 2.161, 95% CI ¼ 1.675e2.788, P ¼ .000). The subgroup analysis based on study design also showed that penile rehabilitation increased the number of patients with erectile function improvement in RCTs and case-control studies (RCTs: OR ¼ 2.237, 95% CI ¼ 1.482e3.377, P ¼ .000; case-control studies: OR ¼ 3.613, 95% CI ¼ 1.876e6.957, P ¼ .000; Figure 2B). The overall meta-analysis using the data of IIEF scores showed similar results (SMD ¼ 1.003 95% CI ¼ 0.663e1.343, P ¼ .000; Figure 2C). In the subgroup analysis for PDE5i therapy, there also were increased IIEF scores (SMD ¼ 0.922, 95% CI ¼ 0.545e1.300, P ¼ .000). However, when the data after PDE5i washout were analyzed, the result showed that PDE5is did not improve spontaneous erectile function (OR ¼ 1.027, 95% CI ¼ 0.713e1.478, P ¼ .610; Figure 2D).

Sensitivity Analysis Sensitivity analysis was conducted to identify the effect of an individual dataset on the final results by sequentially removing each study. The significance of the pooled OR and SMD were not materially altered in the overall comparison (Figure 3AeC).

J Sex Med 2017;14:1496e1503

Study

Year 11

Country

Patients, n

Montorsi et al

1997

Italy

27

Mulhall et al12 Raina et al13 Köhler et al14 Raina et al15

2005 2006 2007 2007

USA USA USA USA

132 95 28 91

Montorsi et al16

2008

423

Bannowsky et al17 Padma-Nathan et al18

2008 2008

Pace et al19 Aydogdu et al20 Bannowsky et al21 Montorsi et al22 Nakano et al23 Seo et al24 Natali et al25

2010 2011 2012 2014 2014 2014 2015

Europe, USA, Canada, South Africa Germany North America, France, Belgium, Australia Italy Turkey Germany European country, Canada Japan Korea, Singapore Italy

Canat et al26

2015

Turkey

41 125 40 65 36 423 103 92 196

95

Treatment methods

Follow-up

Evaluation tools for ED

Study design

Alprostadil injections 3 times/wk or penile injection therapy Sildenafil 100 mg and penile injection VED daily VED daily Intraurethral alprostadil 125 mg or 250 mg 3 times/wk for 9 mo Vardenafil 10 or 5 mg nightly for 9 mo; vardenafil 5, 10, or 20 mg on demand for 9 mo Sildenafil 25 mg/d at night Sildenafil 50 or 100 mg/d once daily at nighttime

6 mo

VAS and IIEF

RCT

18 mo 9 mo 6 mo 9 mo

IIEF IIEF-5, SHIM IIEF SHIM

Case-control RCT RCT Case-control

13.5 mo

IIEF-EF

RCT

52 wk 48 wk

IIEF-5 IIEF

RCT RCT

24 wk 12 mo 12 mo 13.5 mo 12 mo 12 mo 24 mo

IIEF IIEF-EF IIEF-5 IIEF-EF IIEF-5 IIEF-5 IIEF-5

RCT RCT RCT RCT Case-control Case-control Case-control

12 mo

IIEF-6

RCT

Sildenafil 50 or 100 mg/d for 8 wk Tadalafil 20 mg/d 3 d/wk Vardenafil 5 or 10 mg/d Tadalafil 5 mg once daily, tadalafil 20 mg on demand Vardenafil 10 or 20 mg at least once weekly Tadalafil 5 mg/d Sildenafil 100 mg, tadalafil 20 mg and then 20 mg as required; sildenafil 100 mg or vardenafil 20 mg 3 times/wk, or tadalafil 20 mg 2 times/wk Tadalafil 20 mg 3 times/wk or on demand

Penile Rehabilitation for Prostatectomy

J Sex Med 2017;14:1496e1503

Table 1. Information of included studies in this meta-analysis

ED ¼ erectile dysfunction; IIEF ¼ International Index of Erectile Function; RCT ¼ randomized controlled trial; SHIM ¼ Sexual Health Inventory for Men; VAS ¼ visual analog scale; VED ¼ vacuum erection device.

1499

1500

Liu et al

A

B Study ID

OR (95% CI)

Mix Montorsi et al (1997) Mulhall et al (2005) Subtotal (I−squared = 0.0%, p = 0.569)

8.00 (1.40, 45.76) 3.44 4.59 (2.11, 9.99) 8.79 5.03 (2.48, 10.24) 12.23

% Weight

%

Study OR (95% CI)

Weight

Montorsi et al (1997)

8.00 (1.40, 45.76)

3.44

Bannowsky et al (2008)

2.38 (0.64, 8.89)

5.11

Nathan et al (2008)

7.95 (0.97, 64.77)

2.57

Montorsi et al (2008)

1.42 (0.86, 2.36)

11.28

Pace et al (2010)

2.15 (0.52, 9.00)

4.58

Aydogdu et al (2011)

1.41 (0.52, 3.84)

6.99

Bannowsky et al (2012)

2.54 (0.55, 11.77)

4.15

Mulhall et al (2012)

4.58 (2.14, 9.78)

8.94

.

Montorsi et al (2014)

1.52 (0.76, 3.03)

9.56

PDE5i Bannowsky et al (2008) Nathan et al (2008) Montorsi et al (2008) Pace et al (2010) Aydogdu et al (2011) Bannowsky et al (2012) Mulhall et al (2012) Natali et al (2015) Montorsi et al (2014) Nakano et al (2014) Seo et al (2014) Subtotal (I−squared = 13.6%, p = 0.315)

Subtotal (I−squared = 31.9%, p = 0.163)

2.24 (1.48, 3.38)

56.62

Mulhall et al (2005)

4.59 (2.11, 9.99)

8.79

Raina et al (2006)

1.55 (0.45, 5.37)

5.49

Raina et al (2007)

21.70 (6.11, 77.05) 77.05

5.36

Natali et al (2014)

1.87 (0.95, 3.68)

9.69

Nakano et al (2014)

2.42 (1.05, 5.58)

8.30

Seo et al (2014)

4.80 (1.45, 15.89)

5.75

Subtotal (I−squared = 64.9%, p = 0.014)

3.61 (1.88, 6.96)

43.38

2.80 (1.93, 4.06)

100.00

ID RCT

.

VED Raina et al (2006) Subtotal (I−squared = .%, p = .)

1.55 (0.45, 5.37) 1.55 (0.45, 5.37)

5.49 5.49

.

Intraurethral Raina et al (2007) Subtotal (I−squared = .%, p = .)

21.70 (6.11, 77.05 ) 5.36 21.70 (6.11, 77.05 ) 5.36

2.38 (0.64, 8.89) 7.95 (0.97, 64.77) 1.42 (0.86, 2.36) 2.15 (0.52, 9.00) 1.41 (0.52, 3.84) 2.54 (0.55, 11.77) 4.58 (2.14, 9.78) 1.87 (0.95, 3.68) 1.52 (0.76, 3.03) 2.42 (1.05, 5.58) 4.80 (1.45, 15.89) 2.13 (1.59, 2.85)

5.11 2.57 11.28 4.58 6.99 4.15 8.94 9.69 9.56 8.30 5.75 76.92

2.80 (1.93, 4.06)

100.00

. Case control

.

.

Overall (I−squared = 52.4%, p = 0.009)

Overall (I−squared = 52.4%, p = 0.009)

NOTE: Weights are from random effects analysis

NOTE: Weights are from random effects analysis

.013

1

.013

77

C

1

77

D %

Study SMD (95% CI)

ID

Weight

Study

%

ID

Mix Mulhall et al (2005)

1.25 (0.87, 1.62)

11.75

Subtotal (I−squared = .%, p = .)

1.25 (0.87, 1.62)

11.75

K?hler et al (2007)

1.49 (0.65, 2.34)

7.42

Subtotal (I−squared = .%, p = .)

1.49 (0.65, 2.34)

7.42

OR (95% CI)

Weight

Nathan et al (2008)

9.08 (1.12, 73.62)

1.71

Montorsi et al (2008)

0.77 (0.46, 1.30)

56.80

Aydogdu et al (2011)

1.41 (0.52, 3.84)

11.27

Montorsi et al (2014)

0.91 (0.46, 1.80)

30.22

Subtotal (I−squared = 48.4%, p = 0.121)

1.03 (0.71, 1.48)

100.00

1.03 (0.71, 1.48)

100.00

.

PDE5i

VED

.

PDE5i Bannowsky et al (2008)

1.79 (1.06, 2.53)

8.36

Nathan et al (2008)

0.49 (−0.02, 0.99)

10.51

Pace et al (2010)

1.05 (0.38, 1.71)

9.01

Bannowsky et al (2012)

1.88 (1.05, 2.70)

7.59

Nakano et al (2014)

0.24 (−0.17, 0.65)

11.44

Seo et al (2014)

1.05 (0.62, 1.49)

11.18

Montorsi et al (2014)

0.40 (0.13, 0.67 )

12.63

Canat (2015)

1.11 (0.56, 1.66)

10.09

Subtotal (I−squared = 78.3%, p = 0.000)

0.92 (0.54, 1.30)

80.83

1.00 (0.66, 1.34)

100.00

.

Overall (I−squared = 48.4%, p = 0.121)

.

Overall (I−squared = 78.4%, p = 0.000) NOTE: Weights are from random effects analysis

−2.7

0

2.7

.0136

1

73.6

Figure 2. Forest plot for estimate of the effect of penile rehabilitation of erectile dysfunction after radical prostatectomy. Panel A shows the number of patients with improvement in erection function. Panel B shows study design subgroup. Panel C shows International Index of Erectile Function score group. Panel D shows phosphodiesterase type 5 inhibitor after washout. OR ¼ odds ratio; SMD ¼ standard mean difference. Figure 2 is available in color at www.jsm.jsexmed.org.

structure also can be done with the use of a VED because the VED has been shown to have antihypoxic, antiapoptotic, and antifibrotic effects in rat models.34 Therefore, we still recommend penile rehabilitation for patients to preserve penile integrity during the erectile function recovery period. When penile rehabilitation with PDE5is is used, it is important to discuss the economic impact and potential adverse effects, such as headache, flushing, hypotension, nasal congestion, dyspepsia, and hearing or vision loss on rare occasions.35 The controversial oncologic risk with melanoma and prostate cancer recurrence with longterm PDE5i use is beyond the scope of this meta-analysis and

physicians should discuss these issues with patients on an individual basis.36,37 The limitations of this meta-analysis should be acknowledged. First, preoperative patient characteristics differed. Preoperative patient characteristics, such as age and preoperative erectile function, play important roles in the probability of recovering erectile function after surgery. The different preoperative patient characteristics can cause bias to meta-analysis. Second, in this study, various methods were included, such as PDE5is, VED, and ICI, and different PDE5is were used. This also can cause bias to our pooled effects. Because of the limited sample, further J Sex Med 2017;14:1496e1503

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Penile Rehabilitation for Prostatectomy

A

A

Meta−analysis estimates, given named study is omitted Lower CI Limit Estimate Upper CI Limit

Begg funnel plot with pseudo 95% confidence limits 3

Montorsi et al (1997) Mulhall et al (2005) Raina et al (2006)

2

Raina et al (2007) Bannowsky et al (2008)

logES

Nathan et al (2008) Montorsi et al (2008)

1

Pace et al (2010) Aydogdu et al (2011)

0

Bannowsky et al (2012) Mulhall et al (2012) Natali et al (2015) Montorsi et al (2014)

−1

Nakano et al (2014)

0

Seo et al (2014) 1.781.93

B

2.80

4.06

4.46

Meta−analysis estimates, given named study is omitted Lower CI Limit Estimate Upper CI Limit

B

.5 s.e. of: logES

1

Begg funnel plot with pseudo 95% confidence limits 2

Mulhall et al (2005) K?hler et al (2007)

1.5

SMD

Bannowsky et al (2008) Nathan et al (2008)

1

Pace et al (2010) Bannowsky et al (2012)

.5

Nakano et al (2014) Seo et al (2014)

0

Montorsi et al (2014)

0

Canat (2015) 0.59 0.66

C

1.00

1.34

1.45

C

.2 s.e. of: SMD

.4

Begg funnel plot with pseudo 95% confidence limits 2

Meta−analysis estimates, given named study is omitted Lower CI Limit Estimate Upper CI Limit

Nathan et al (2008)

logES

1

Montorsi et al (2008)

0

−1

Aydogdu et al (2011)

−2 0

1

Figure 4. Begg funnel plot for different groups. Panel A shows

Montorsi et al (2014) 0.61 0.71

.5 s.e. of: logES

1.03

1.48

2.29

Figure 3. Sensitivity analysis for the effect of penile rehabilitation

the number of patients with improvement in erection function. Panel B shows International Index of Erectile Function score group. Panel C shows phosphodiesterase type 5 inhibitor after washout.

of erectile dysfunction after radical prostatectomy. Panel A shows the number of patients with improvement in erection function. Panel B shows International Index of Erectile Function score group. Panel C shows phosphodiesterase type 5 inhibitor after washout.

CONCLUSION

subgroup analysis for VED and ICI could not be performed. Third, the follow-up time in the studies was inconsistent. Erectile function after RP is time dependent. Differences in follow-up time can cause bias. Fourth, we included only Englishlanguage articles in this meta-analysis; this can lead to selection bias and influence the pooled results.

Our meta-analysis confirmed that administration of PDE5is, VED, and ICI after RP can increase erection function during treatments. However, current evidence does not support that penile rehabilitation with PDE5is can improve recovery of spontaneous erectile function. Further studies with adequate follow-up and larger samples should be conducted to generate a comprehensive conclusion.

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Corresponding Author: Run Wang, MD, FACS, Division of Urology, Department of Surgery, University of Texas McGovern Medical School, 6431 Fannin Street, MSB 6.018, Houston, TX 77030, USA. Tel: þ1-713-500-7337; Fax: þ1-713-500-7319; E-mail: [email protected] Conflicts of Interest: The authors report no conflicts of interest. Funding: None.

STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Chunhui Liu; Run Wang (b) Acquisition of Data Chunhui Liu; Ming Chen (c) Analysis and Interpretation of Data Chunhui Liu; Ming Chen Category 2 (a) Drafting the Article Chunhui Liu (b) Revising It for Intellectual Content David S. Lopez; Run Wang Category 3 (a) Final Approval of the Completed Article Chunhui Liu; Run Wang

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