Efficacy and safety of udenafil for the treatment of erectile dysfunction after total mesorectal excision of rectal cancer: A randomized, double-blind, placebo-controlled trial Soo Yeun Park, MD, Gyu-Seog Choi, MD, PhD, Jun Seok Park, MD, PhD, Hye Jin Kim, MD, Ju-A Park, MD, and Jong Ik Choi, MD, Daegu, Korea
Background. Nerve-preserving surgery has been provided for patients with rectal cancer; however, sexual dysfunction remains a common complication of rectal cancer surgery. This study explored the efficacy of udenafil to treat erectile dysfunction in male patients who underwent total mesorectal excision (TME) for rectal cancer. Methods. We conducted a randomized, double-blind, placebo-controlled clinical trial involving 80 male patients who had decreased International Index of Erectile Function-5 (IIEF-5) scores after TME for rectal cancer. Patients received placebo (50 mg) or udenafil (50 mg) for 12 weeks. The primary outcome variable was the change in IIEF-5 scores. The secondary outcome variables were Sexual Encounter Profile (SEP) questions 2 (Q2) and 3 (Q3), and the Global Assessment Question (GAQ). Results. Baseline IIEF-5 scores, SEP Q2 and Q3 responses, and spontaneous erection rates were consistent in both groups. At the end of treatment, the change in IIEF-5 scores from the baseline was significantly higher in the udenafil group than it was in the placebo group (mean IIEF-5 score, 4.8 ± 4.0 vs 2.0 ± 1.7; P < .05). Responses to SEP Q2, SEP Q3, and GAQ were significantly higher in the udenafil group than they were in the placebo group (SEP Q2, P = .025; SEP Q3, P = .044; GAQ, P < .001). Treatment-related adverse events (n = 4) were all mild in severity. Conclusion. Oral udenafil was deemed safe and effective for the treatment of erectile dysfunction in patients who underwent TME for rectal cancer. (Surgery 2015;157:64-71.) From the Colorectal Cancer Center, Kyungpook National University Medical Center, School of Medicine, Kyungpook National University, Daegu, Korea
RECTAL CANCER has a significant effect on patient’s survival and quality of life. Over the last 2 decades, total mesorectal excision (TME) clearly improved local disease control and long-term oncologic outcomes of rectal cancer.1,2 In addition, the Disclosure: The authors declare no conflicts of interest. This study was registered with ClinicalTrials.gov, number NCT01421940. Dong-A Pharmaceutical Company provided matched udenafil and placebo capsules but had no influence on the study design and conduction. This study received no financial support from the industry. Accepted for publication July 16, 2014. Reprint requests: Gyu-Seog Choi, MD, PhD, Professor, Colorectal Cancer Center, Kyungpook National University Medical Center, 807 Hogukro, Buk-gu, Daegu 702-210, Korea. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2014.07.007
64 SURGERY
development of TME has helped surgeons to enhance nerve-sparing rectal cancer surgery.3 Given the complex nerve pathways located near the surgical plane of rectal cancer surgery, there is a substantial effect of rectal cancer surgery on sexual function. Although this sexual dysfunction is caused by various factors, the main reason is injury to the pelvic autonomic nerves during surgical resection.4 Functional changes after rectal cancer surgery have resulted in sexual dysfunction in 40–65% of patients.5,6 Fortunately, the rates of sexual dysfunction after rectal cancer surgery were reduced after TME was implemented. Nevertheless, sexual dysfunction is still reported at wideranging rates (10–50%) and it worsens patient quality of life.5,7-10 Although sexual dysfunction is a well-known complication after rectal cancer surgery, few studies have addressed the treatment of this complication.
Surgery Volume 157, Number 1
Currently, phosphodiesterase type 5 (PDE-5) inhibitors are used widely as the first- line oral treatment for erectile dysfunction of varying causes. Radical prostatectomy for the treatment of prostate cancer is frequently associated with erectile dysfunction, and this type of erectile dysfunction is attributed mainly to intraoperative damage to the neurovascular system. The efficacy of PDE-5 inhibitors in the treatment of erectile dysfunction after radical prostatectomy has been demonstrated.11-13 However, the administration of the PDE-5 inhibitor to patients with rectal cancer has been reported rarely. Udenafil (Zydena, Dong-A, Seoul, Korea) is an oral selective PDE-5 inhibitor that was developed recently. It is rapidly absorbed, reaches maximal concentration within 1–1.5 hours after administration, and has a relatively long half-life (11–13 h).14 In previous clinical trials, udenafil was demonstrated to be safe and effective as a once-daily prescription for patients with erectile dysfunction of various causes.14,15 The aim of this randomized, double-blind, placebo-controlled trial was to explore the efficacy of udenafil in the treatment of erectile dysfunction, as well as its safety in male patients who underwent TME for rectal cancer. METHODS Study design and patients. This clinical study was a double-blind, placebo-controlled, randomized trial. Patients were enrolled at a single center (Kyungpook National University Medical Center, Daegu, Korea). An institutional review board approved the study protocol before patient enrollment and study commencement. All patients read and signed the informed consent form before undergoing any trial procedures or interventions. This study was registered on www.clinicaltrials.gov (NCT01421940). Male patient aged 20–65 years and scheduled for TME for rectal cancer within 15 cm from the anal verge were screened for this study. The International Index of Erectile Function-5 (IIEF-5) questionnaire was assessed both preoperatively and 12 weeks after the operation. Eligible patients had to have decreased IIEF-5 scores by $5 at 12 weeks postoperatively compared with those recorded preoperatively. Exclusion criteria included preoperative erectile dysfunction (IIEF5 score < 14); intact erectile function after surgery; non–nerve-sparing surgery; cardiovascular diseases, with the exception of controlled hypertension, or poorly controlled blood pressure; history of stroke or spinal cord injury; history of prostate
Park et al 65
cancer; treatment with nitrate or antiandrogens; uncontrolled diabetes (hemoglobin A1C > 12%); or a history of major hematologic, renal, or hepatic disease. Randomization and interventions. Patients were enrolled at separate investigation and monitoring units. Eligible patients were randomly assigned at a 1:1 ratio to either udenafil or placebo tablet by block randomization. Block allocation sequences were created at random using numbers generated by a computer program. All participants and investigators were blinded to treatment assignment. The film-coated placebo and udenafil tablets were same in color, shape, size, texture, and taste. Eligible patients were prescribed udenafil or placebo drugs every 4 weeks when they visited the hospital. Treatment compliance was checked at the first week after prescription by telephone. Subsequently, monitoring units followed patients every 2 weeks by telephone or at each hospital visit. Outcomes. The primary outcome was the change in IIEF-5 score from the baseline (before starting medication) to the end of the treatment. The IIEF-5, which is a 5-item version of the IIEF questionnaire (composed of 4 questions about erectile function and 1 question about intercourse satisfaction) was used to evaluate erectile function.16 The IIEF-5 score ranges from 1 to 25, and a lower score indicates a greater severity of the erectile dysfunction. Patients were assessed with IIEF-5 at the end of treatment and at next 12 weeks after then. The secondary outcomes were the response rates of the Sexual Encounter Profile (SEP) questions 2 (SEP Q2: Were you able to insert your penis into your partner’s vagina?) and 3 (SEP Q3: Did your erection last long enough for you to complete intercourse with ejaculation?), as well as the Global Assessment Questionnaire (GAQ: Has the treatment you have been taking during the study improved your erection?), and the presence of spontaneous erection (SE) without medication. IIEF-5 scores and responses to SEP Q2 and SEP Q3 were collected: (i) before surgery, (ii) at 12 weeks after surgery (baseline), (iii) at the end of treatment, and (iv) at 12 weeks after treatment completion (follow-up). Patients were asked the GAQ at the end of treatment, and information on SE was collected preoperatively, at baseline, and at follow-up. Safety variables. Patients were monitored closely for any signs of adverse events. Safety assessment included the presence of all reported adverse events regardless of relationship to the study drug, monitoring of vital signs, abnormality
66 Park et al
Surgery January 2015
Fig 1. CONSORT diagram for this study.
in laboratory results, and complete physical examination. A serious adverse event was defined as an adverse event that was life-threatening, required admission to the hospital, or required intervention to prevent a serious outcome. Statistical analysis. Assuming a standard deviation of 5.4 for the 12-week IIEF-5 score, a sample size of 40 patients in each arm was needed to provide a 95% power to detect an IIEF-5 score difference of 4 between the 2 groups, with a 2sided test at a = 0.01 and a 10% missing value. An efficacy analysis was performed using the data from the modified intention-to-treat sample, including patients who had received $1 dose of the study drug and completed follow-up assessment. Safety assessment was performed for patients who received $1 dose of the study drug. IIEF-5 scores were analyzed via analysis of covariance using the baseline value as a covariate. The response rates of SEP Q2, SEP Q3, GAQ, and SE were assessed using the Chi-square test. Regarding patient characteristics and safety assessment, Student’s t test was used for comparison of continuous variables and the Chi-square test was used for categorical data. Data were analyzed using the SPSS
software package Chicago, IL).
for
Windows
(SPSS
15.0,
RESULTS Patients. Between October 2009 and January 2012, 176 patients were assessed for study eligibility, 80 of whom were assigned randomly to either the udenafil group (n = 40) or the placebo group (n = 40; Fig 1). Two patients (1 in the placebo group and 1 in the udenafil group) withdrew from the study after randomization because of the burden of participation; therefore, they did not take the prescribed medication. In the udenafil group, 1 patient discontinued the treatment because of facial flushing, and another patient chose to stop medication in noncompliance. One patient in the placebo group stopped medication because of dyspepsia. One patient in each group did not visit the hospital for the follow-up. In total, 73 patients completed all questionnaires and were included in the modified intention-to-treat analysis. No differences were observed between the patients included in the placebo and udenafil groups regarding demographics such as age, body mass index, tumor height, type of operation, type of
Park et al 67
Surgery Volume 157, Number 1
Table I. Patient demographic and baseline characteristics Variable Age (y) BMI (kg/m2) Hypertension Diabetes mellitus Tumor height (from anal verge), cm Type of operation Open Laparoscopic Robot Anastomosis Colorectum Coloanal Protective stoma Stage I II III Neoadjuvant radiotherapy Adjuvant chemotherapy
Placebo (n = 37) 55.9 24.1 8 2 7.8
(5.6) (2.9) (21.6%) (5.4%) (3.9)
Udenafil (n = 36) 53.6 24.4 7 3 7.1
(7.5) (2.6) (19.4%) (8.3%) (3.4)
3 (8.1%) 25 (67.6%) 9 (24.3%)
2 (5.6%) 21 (58.3%) 13 (36.1%)
30 (81.1%) 7 (18.9%) 2 (5.4%)
26 (72.2%) 10 (27.8%) 3 (8.3%)
13 11 13 13 15
15 15 6 14 13
P value .182 .622 .818 .620 .437 .532
.371
(35.1%) (29.7%) (35.1%) (35.1%) (40.5%)
(41.7%) (41.7%) (16.7%) (38.9%) (36.1%)
.620 .190
.740 .697
Values are mean ± SD or n (%) unless otherwise indicated. ASA, American Society of Anesthesiologists; BMI, body mass index.
anastomosis, rate of fecal diversion, and tumor stage (Table I). The rates of patients treated with neoadjuvant radiotherapy and adjuvant chemotherapy were also similar between the 2 groups. Outcomes. No differences were observed in the mean preoperative and baseline IIEF-5 scores between the two treatment groups (Fig 2). Analyses of the intervisit differences in each group revealed that both groups showed a significant decrease in baseline compared with preoperative IIEF-5 scores. After 12 weeks of treatment, the mean IIEF-5 scores in the udenafil group were greater than those of the placebo group by 3.4 (95% CI, 1.3–5.5; P < .001; Fig 2), and the mean change in the IIEF-5 scores from the baseline was 4.8 ± 4.0 for the udenafil group, which was significantly greater than observed for the placebo group (2.0 ± 1.7; P < .001). At the follow-up evaluation, the mean change in IIEF-5 scores from the baseline was higher in the udenafil group (5.9 ± 5.0) than it was in the placebo group (4.4 ± 4.1); however, the difference was not significant (P = .093). Table II shows changes of IIEF-5 score at the end of 12 weeks of treatment in the udenafil group compared with the patients’ variables. The change of IIEF-5 varied according to the type of anastomosis: It was significantly higher in colorectal anastomosis than in coloanal anastomosis. Receiving preoperative radiotherapy, old age, and open operations were related to a
Fig 2. International Index of Erectile Function-5 (IIEF5) score at each visit including preoperative, 12 weeks after surgery (baseline), at the end of 12 weeks of treatment (treatment: * p54 Neoadjuvant radiotherapy Yes No Type of operation Open Laparoscopy Robot Anastomosis Colorectum Coloanal
n (%)
Change of IIEF-5 score (SD)
17 (47.2) 19 (52.8)
5.1 (3.8) 4.4 (4.3)
P value .755
.186 14 (38.9) 22 (61.1)
3.7 (3.7) 5.5 (4.1)
2 (5.6) 21 (58.3) 13 (36.1)
2.0 (2.8) 4.3 (4.2) 6.0 (3.6)
26 (72.2) 10 (27.8)
5.7 (4.1) 2.6 (2.4)
.234*
.011
*Kruskal-Wallis H test. IIEF-5, International Index of Erectile Function-5.
was significantly higher than that recorded in the placebo group (97.2% vs 81.1%, P = .027); however, the response rate to SEP Q3 was not different between the 2 groups (61.1% in the udenafil group vs 54.1% in the placebo group; P = .542). Table III summarizes the other secondary outcome variables. Changes in the percentage of positive responses from the baseline to the end of treatment were significantly higher in the udenafil group. Assessment of GAQ at the end of treatment showed a significantly higher response rate in the udenafil group than in the placebo group (83.0% vs 16.2%; P < .001). Regarding SE, the response rates before surgery were 100% in both groups, and they were 40.5% and 50.0% in the placebo and udenafil groups, respectively, at baseline, without intergroup differences (P = .417). The response rate to SE at follow-up was higher in the udenafil group, with marginal significance (97.2% in the udenafil group vs 93.8% in the placebo group; P = .051). Safety. Table IV provides a summary of the adverse events observed in both groups. In total, 4 (10.5%) adverse events were reported in the udenafil group and 1 (2.6%) adverse event was reported in the placebo group. The treatmentrelated adverse events included face flushing (n = 2), headache (n = 1), and urticaria (n = 1), which were all mild in severity. One patient in each group discontinued treatment because of adverse events. In the other patients, the adverse events resolved without any further treatment.
Fig 3. (A) Changes in Sexual Encounter Profile question 2 (SEP Q2) and (B) changes in Sexual Encounter Profile question 3 (SEP Q3) from baseline to 12 weeks of treatment (treatment) and to 12 weeks after treatment completion (follow-up; *P < .05).
DISCUSSION In this study, the efficacy and safety of the administration of 50 mg udenafil was assessed in male patients who had decreased erectile function at 12 weeks after TME for rectal cancer. Udenafil has been shown to be efficacious and well tolerated in several previous trials. To our knowledge, this is the first study to examine the efficacy of udenafil in the treatment of erectile dysfunction in patients with operatively resected rectal cancer. Udenafil significantly improved erectile dysfunction during the treatment period, as assessed based on the improvement of IIEF-5 scores and response rates to SEP Q2, SEP Q3, and GAQ. In addition, no serious adverse events were observed during the study. Although the response rates to SEP Q2 and SE were higher after udenafil medication at followup, the long-term efficacy at 12 weeks after the completion of treatment was not consistent. Operative resection is the most important treatment for patients with rectal cancer. Although TME technique has improved nerve preservation, as well as cancer control, various degrees of sexual
Park et al 69
Surgery Volume 157, Number 1
Table III. Changes in the secondary efficacy outcome variables
Time
Placebo (n = 37), n (%)
SEP Q2 (change from baseline)* Treatment 10 (27.0) Follow-up 13 (35.1) SEP Q3 (change from baseline)* Treatment 1 (2.7) Follow-up 6 (16.2) SE Preoperative 37 (100) Postoperative 15 (40.5) Follow-up 31 (93.8) GAQ Treatment 6 (16.2)
Table IV. Adverse events Variables
Udenafil (n = 36), n (%)
P value
18 (50.0) 19 (52.8)
.044 .129
8 (22.2) 8 (22.2)
.011 .515
36 (100) 18 (50.0) 35 (97.2)
.999 .417 .051
30 (83.3)
Background. Nerve-preserving surgery has been provided for patients with rectal cancer; however, sexual dysfunction remains a common complication of rectal cancer surgery. This study explored the efficacy of udenafil to treat erectile dysfunction in male patients who underwent total mesorectal excision (TME) for rectal cancer. Methods. We conducted a randomized, double-blind, placebo-controlled clinical trial involving 80 male patients who had decreased International Index of Erectile Function-5 (IIEF-5) scores after TME for rectal cancer. Patients received placebo (50 mg) or udenafil (50 mg) for 12 weeks. The primary outcome variable was the change in IIEF-5 scores. The secondary outcome variables were Sexual Encounter Profile (SEP) questions 2 (Q2) and 3 (Q3), and the Global Assessment Question (GAQ). Results. Baseline IIEF-5 scores, SEP Q2 and Q3 responses, and spontaneous erection rates were consistent in both groups. At the end of treatment, the change in IIEF-5 scores from the baseline was significantly higher in the udenafil group than it was in the placebo group (mean IIEF-5 score, 4.8 ± 4.0 vs 2.0 ± 1.7; P < .05). Responses to SEP Q2, SEP Q3, and GAQ were significantly higher in the udenafil group than they were in the placebo group (SEP Q2, P = .025; SEP Q3, P = .044; GAQ, P < .001). Treatment-related adverse events (n = 4) were all mild in severity. Conclusion. Oral udenafil was deemed safe and effective for the treatment of erectile dysfunction in patients who underwent TME for rectal cancer. (Surgery 2015;157:64-71.) From the Colorectal Cancer Center, Kyungpook National University Medical Center, School of Medicine, Kyungpook National University, Daegu, Korea
RECTAL CANCER has a significant effect on patient’s survival and quality of life. Over the last 2 decades, total mesorectal excision (TME) clearly improved local disease control and long-term oncologic outcomes of rectal cancer.1,2 In addition, the Disclosure: The authors declare no conflicts of interest. This study was registered with ClinicalTrials.gov, number NCT01421940. Dong-A Pharmaceutical Company provided matched udenafil and placebo capsules but had no influence on the study design and conduction. This study received no financial support from the industry. Accepted for publication July 16, 2014. Reprint requests: Gyu-Seog Choi, MD, PhD, Professor, Colorectal Cancer Center, Kyungpook National University Medical Center, 807 Hogukro, Buk-gu, Daegu 702-210, Korea. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2014.07.007
64 SURGERY
development of TME has helped surgeons to enhance nerve-sparing rectal cancer surgery.3 Given the complex nerve pathways located near the surgical plane of rectal cancer surgery, there is a substantial effect of rectal cancer surgery on sexual function. Although this sexual dysfunction is caused by various factors, the main reason is injury to the pelvic autonomic nerves during surgical resection.4 Functional changes after rectal cancer surgery have resulted in sexual dysfunction in 40–65% of patients.5,6 Fortunately, the rates of sexual dysfunction after rectal cancer surgery were reduced after TME was implemented. Nevertheless, sexual dysfunction is still reported at wideranging rates (10–50%) and it worsens patient quality of life.5,7-10 Although sexual dysfunction is a well-known complication after rectal cancer surgery, few studies have addressed the treatment of this complication.
Surgery Volume 157, Number 1
Currently, phosphodiesterase type 5 (PDE-5) inhibitors are used widely as the first- line oral treatment for erectile dysfunction of varying causes. Radical prostatectomy for the treatment of prostate cancer is frequently associated with erectile dysfunction, and this type of erectile dysfunction is attributed mainly to intraoperative damage to the neurovascular system. The efficacy of PDE-5 inhibitors in the treatment of erectile dysfunction after radical prostatectomy has been demonstrated.11-13 However, the administration of the PDE-5 inhibitor to patients with rectal cancer has been reported rarely. Udenafil (Zydena, Dong-A, Seoul, Korea) is an oral selective PDE-5 inhibitor that was developed recently. It is rapidly absorbed, reaches maximal concentration within 1–1.5 hours after administration, and has a relatively long half-life (11–13 h).14 In previous clinical trials, udenafil was demonstrated to be safe and effective as a once-daily prescription for patients with erectile dysfunction of various causes.14,15 The aim of this randomized, double-blind, placebo-controlled trial was to explore the efficacy of udenafil in the treatment of erectile dysfunction, as well as its safety in male patients who underwent TME for rectal cancer. METHODS Study design and patients. This clinical study was a double-blind, placebo-controlled, randomized trial. Patients were enrolled at a single center (Kyungpook National University Medical Center, Daegu, Korea). An institutional review board approved the study protocol before patient enrollment and study commencement. All patients read and signed the informed consent form before undergoing any trial procedures or interventions. This study was registered on www.clinicaltrials.gov (NCT01421940). Male patient aged 20–65 years and scheduled for TME for rectal cancer within 15 cm from the anal verge were screened for this study. The International Index of Erectile Function-5 (IIEF-5) questionnaire was assessed both preoperatively and 12 weeks after the operation. Eligible patients had to have decreased IIEF-5 scores by $5 at 12 weeks postoperatively compared with those recorded preoperatively. Exclusion criteria included preoperative erectile dysfunction (IIEF5 score < 14); intact erectile function after surgery; non–nerve-sparing surgery; cardiovascular diseases, with the exception of controlled hypertension, or poorly controlled blood pressure; history of stroke or spinal cord injury; history of prostate
Park et al 65
cancer; treatment with nitrate or antiandrogens; uncontrolled diabetes (hemoglobin A1C > 12%); or a history of major hematologic, renal, or hepatic disease. Randomization and interventions. Patients were enrolled at separate investigation and monitoring units. Eligible patients were randomly assigned at a 1:1 ratio to either udenafil or placebo tablet by block randomization. Block allocation sequences were created at random using numbers generated by a computer program. All participants and investigators were blinded to treatment assignment. The film-coated placebo and udenafil tablets were same in color, shape, size, texture, and taste. Eligible patients were prescribed udenafil or placebo drugs every 4 weeks when they visited the hospital. Treatment compliance was checked at the first week after prescription by telephone. Subsequently, monitoring units followed patients every 2 weeks by telephone or at each hospital visit. Outcomes. The primary outcome was the change in IIEF-5 score from the baseline (before starting medication) to the end of the treatment. The IIEF-5, which is a 5-item version of the IIEF questionnaire (composed of 4 questions about erectile function and 1 question about intercourse satisfaction) was used to evaluate erectile function.16 The IIEF-5 score ranges from 1 to 25, and a lower score indicates a greater severity of the erectile dysfunction. Patients were assessed with IIEF-5 at the end of treatment and at next 12 weeks after then. The secondary outcomes were the response rates of the Sexual Encounter Profile (SEP) questions 2 (SEP Q2: Were you able to insert your penis into your partner’s vagina?) and 3 (SEP Q3: Did your erection last long enough for you to complete intercourse with ejaculation?), as well as the Global Assessment Questionnaire (GAQ: Has the treatment you have been taking during the study improved your erection?), and the presence of spontaneous erection (SE) without medication. IIEF-5 scores and responses to SEP Q2 and SEP Q3 were collected: (i) before surgery, (ii) at 12 weeks after surgery (baseline), (iii) at the end of treatment, and (iv) at 12 weeks after treatment completion (follow-up). Patients were asked the GAQ at the end of treatment, and information on SE was collected preoperatively, at baseline, and at follow-up. Safety variables. Patients were monitored closely for any signs of adverse events. Safety assessment included the presence of all reported adverse events regardless of relationship to the study drug, monitoring of vital signs, abnormality
66 Park et al
Surgery January 2015
Fig 1. CONSORT diagram for this study.
in laboratory results, and complete physical examination. A serious adverse event was defined as an adverse event that was life-threatening, required admission to the hospital, or required intervention to prevent a serious outcome. Statistical analysis. Assuming a standard deviation of 5.4 for the 12-week IIEF-5 score, a sample size of 40 patients in each arm was needed to provide a 95% power to detect an IIEF-5 score difference of 4 between the 2 groups, with a 2sided test at a = 0.01 and a 10% missing value. An efficacy analysis was performed using the data from the modified intention-to-treat sample, including patients who had received $1 dose of the study drug and completed follow-up assessment. Safety assessment was performed for patients who received $1 dose of the study drug. IIEF-5 scores were analyzed via analysis of covariance using the baseline value as a covariate. The response rates of SEP Q2, SEP Q3, GAQ, and SE were assessed using the Chi-square test. Regarding patient characteristics and safety assessment, Student’s t test was used for comparison of continuous variables and the Chi-square test was used for categorical data. Data were analyzed using the SPSS
software package Chicago, IL).
for
Windows
(SPSS
15.0,
RESULTS Patients. Between October 2009 and January 2012, 176 patients were assessed for study eligibility, 80 of whom were assigned randomly to either the udenafil group (n = 40) or the placebo group (n = 40; Fig 1). Two patients (1 in the placebo group and 1 in the udenafil group) withdrew from the study after randomization because of the burden of participation; therefore, they did not take the prescribed medication. In the udenafil group, 1 patient discontinued the treatment because of facial flushing, and another patient chose to stop medication in noncompliance. One patient in the placebo group stopped medication because of dyspepsia. One patient in each group did not visit the hospital for the follow-up. In total, 73 patients completed all questionnaires and were included in the modified intention-to-treat analysis. No differences were observed between the patients included in the placebo and udenafil groups regarding demographics such as age, body mass index, tumor height, type of operation, type of
Park et al 67
Surgery Volume 157, Number 1
Table I. Patient demographic and baseline characteristics Variable Age (y) BMI (kg/m2) Hypertension Diabetes mellitus Tumor height (from anal verge), cm Type of operation Open Laparoscopic Robot Anastomosis Colorectum Coloanal Protective stoma Stage I II III Neoadjuvant radiotherapy Adjuvant chemotherapy
Placebo (n = 37) 55.9 24.1 8 2 7.8
(5.6) (2.9) (21.6%) (5.4%) (3.9)
Udenafil (n = 36) 53.6 24.4 7 3 7.1
(7.5) (2.6) (19.4%) (8.3%) (3.4)
3 (8.1%) 25 (67.6%) 9 (24.3%)
2 (5.6%) 21 (58.3%) 13 (36.1%)
30 (81.1%) 7 (18.9%) 2 (5.4%)
26 (72.2%) 10 (27.8%) 3 (8.3%)
13 11 13 13 15
15 15 6 14 13
P value .182 .622 .818 .620 .437 .532
.371
(35.1%) (29.7%) (35.1%) (35.1%) (40.5%)
(41.7%) (41.7%) (16.7%) (38.9%) (36.1%)
.620 .190
.740 .697
Values are mean ± SD or n (%) unless otherwise indicated. ASA, American Society of Anesthesiologists; BMI, body mass index.
anastomosis, rate of fecal diversion, and tumor stage (Table I). The rates of patients treated with neoadjuvant radiotherapy and adjuvant chemotherapy were also similar between the 2 groups. Outcomes. No differences were observed in the mean preoperative and baseline IIEF-5 scores between the two treatment groups (Fig 2). Analyses of the intervisit differences in each group revealed that both groups showed a significant decrease in baseline compared with preoperative IIEF-5 scores. After 12 weeks of treatment, the mean IIEF-5 scores in the udenafil group were greater than those of the placebo group by 3.4 (95% CI, 1.3–5.5; P < .001; Fig 2), and the mean change in the IIEF-5 scores from the baseline was 4.8 ± 4.0 for the udenafil group, which was significantly greater than observed for the placebo group (2.0 ± 1.7; P < .001). At the follow-up evaluation, the mean change in IIEF-5 scores from the baseline was higher in the udenafil group (5.9 ± 5.0) than it was in the placebo group (4.4 ± 4.1); however, the difference was not significant (P = .093). Table II shows changes of IIEF-5 score at the end of 12 weeks of treatment in the udenafil group compared with the patients’ variables. The change of IIEF-5 varied according to the type of anastomosis: It was significantly higher in colorectal anastomosis than in coloanal anastomosis. Receiving preoperative radiotherapy, old age, and open operations were related to a
Fig 2. International Index of Erectile Function-5 (IIEF5) score at each visit including preoperative, 12 weeks after surgery (baseline), at the end of 12 weeks of treatment (treatment: * p54 Neoadjuvant radiotherapy Yes No Type of operation Open Laparoscopy Robot Anastomosis Colorectum Coloanal
n (%)
Change of IIEF-5 score (SD)
17 (47.2) 19 (52.8)
5.1 (3.8) 4.4 (4.3)
P value .755
.186 14 (38.9) 22 (61.1)
3.7 (3.7) 5.5 (4.1)
2 (5.6) 21 (58.3) 13 (36.1)
2.0 (2.8) 4.3 (4.2) 6.0 (3.6)
26 (72.2) 10 (27.8)
5.7 (4.1) 2.6 (2.4)
.234*
.011
*Kruskal-Wallis H test. IIEF-5, International Index of Erectile Function-5.
was significantly higher than that recorded in the placebo group (97.2% vs 81.1%, P = .027); however, the response rate to SEP Q3 was not different between the 2 groups (61.1% in the udenafil group vs 54.1% in the placebo group; P = .542). Table III summarizes the other secondary outcome variables. Changes in the percentage of positive responses from the baseline to the end of treatment were significantly higher in the udenafil group. Assessment of GAQ at the end of treatment showed a significantly higher response rate in the udenafil group than in the placebo group (83.0% vs 16.2%; P < .001). Regarding SE, the response rates before surgery were 100% in both groups, and they were 40.5% and 50.0% in the placebo and udenafil groups, respectively, at baseline, without intergroup differences (P = .417). The response rate to SE at follow-up was higher in the udenafil group, with marginal significance (97.2% in the udenafil group vs 93.8% in the placebo group; P = .051). Safety. Table IV provides a summary of the adverse events observed in both groups. In total, 4 (10.5%) adverse events were reported in the udenafil group and 1 (2.6%) adverse event was reported in the placebo group. The treatmentrelated adverse events included face flushing (n = 2), headache (n = 1), and urticaria (n = 1), which were all mild in severity. One patient in each group discontinued treatment because of adverse events. In the other patients, the adverse events resolved without any further treatment.
Fig 3. (A) Changes in Sexual Encounter Profile question 2 (SEP Q2) and (B) changes in Sexual Encounter Profile question 3 (SEP Q3) from baseline to 12 weeks of treatment (treatment) and to 12 weeks after treatment completion (follow-up; *P < .05).
DISCUSSION In this study, the efficacy and safety of the administration of 50 mg udenafil was assessed in male patients who had decreased erectile function at 12 weeks after TME for rectal cancer. Udenafil has been shown to be efficacious and well tolerated in several previous trials. To our knowledge, this is the first study to examine the efficacy of udenafil in the treatment of erectile dysfunction in patients with operatively resected rectal cancer. Udenafil significantly improved erectile dysfunction during the treatment period, as assessed based on the improvement of IIEF-5 scores and response rates to SEP Q2, SEP Q3, and GAQ. In addition, no serious adverse events were observed during the study. Although the response rates to SEP Q2 and SE were higher after udenafil medication at followup, the long-term efficacy at 12 weeks after the completion of treatment was not consistent. Operative resection is the most important treatment for patients with rectal cancer. Although TME technique has improved nerve preservation, as well as cancer control, various degrees of sexual
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Table III. Changes in the secondary efficacy outcome variables
Time
Placebo (n = 37), n (%)
SEP Q2 (change from baseline)* Treatment 10 (27.0) Follow-up 13 (35.1) SEP Q3 (change from baseline)* Treatment 1 (2.7) Follow-up 6 (16.2) SE Preoperative 37 (100) Postoperative 15 (40.5) Follow-up 31 (93.8) GAQ Treatment 6 (16.2)
Table IV. Adverse events Variables
Udenafil (n = 36), n (%)
P value
18 (50.0) 19 (52.8)
.044 .129
8 (22.2) 8 (22.2)
.011 .515
36 (100) 18 (50.0) 35 (97.2)
.999 .417 .051
30 (83.3)
