radical prostatectomy ( rp ) is considered to be a standard curative procedure for patients with organ - confined prostate cancer .
recently , the advent of pioneering nerve - sparing robot - assisted laparoscopic radical prostatectomy ( ns ralp ) has significantly increased the potency rate after rp [ 1 - 3 ] . however , even if ns ralp is performed , a large number of patients still experience erectile dysfunction ( ed ) after surgery . therefore , the need for better penile rehabilitation is anticipated . this increase in need for penile rehabilitation stems from two pillars .
first , the introduction of prostate - specific antigen ( psa ) testing in the 1990s made early detection of prostate cancer possible .
the early screening using psa testing led to a significant drop in patient age , and younger prostate cancer patients have great interest in and need for erectile function ( ef ) after surgery .
second , recent advances in surgical techniques have motivated more prostate cancer patients to consider penile rehabilitation .
ns ralp by an experienced surgeon can minimize nerve injury , and early penile rehabilitation with oral administration of phosphodiesterase type 5 inhibitors ( pde5-is ) can maximize penile recovery in ed patients after rp . after the advent of the orally administered pde5-is in 1998 , there was a huge shift in the ed treatment algorithm .
recent literature shows that pde5-is are safe and effective in treating ed patients after rp .
once daily administration of pde5-is has been experimentally proven to have a protective role in ed , and early administration of pde5-is helps to prevent cavernosal hypoxia , which leads to smooth muscle apoptosis and penile fibrosis [ 8 - 11 ] .
although pde5-is are one of the standard treatments for ed after rp , consensus has not been reached on their use , such as when to start , which drug is best , which dosage to use , how long to use , and when to stop . in the case of tadalafil ,
doses of 10 and 20 mg have been administered on demand to ed patients , and once - a - day dosing of 5 mg has been used since the korea food and drug administration approval in 2008 . moreover , in a study that compared the efficacy , safety , and tolerability of on - demand tadalafil and daily dosed tadalafil for the treatment of ed , 72% of the patients preferred daily dosed tadalafil .
however , clinical studies on the daily administration of low - dose pde5-is and the effect of such treatment on ed patients after rp are sorely lacking .
the present study was therefore conducted to evaluate the efficacy and safety of once daily use of tadalafil 5 mg in the treatment of ed patients after ralp .
we evaluated the records of 116 patients who , between september 2007 and december 2011 , had undergone ralp by an experienced surgeon for localized prostate cancer at our institution .
ralp was first performed in 2004 as a joint effort between our institution and singapore general hospital , which was the site of the initial korean experience .
standard ralp techniques including bladder neck preservation and posterior urethral reconstruction were used because these techniques during ralp can have favorable impacts on the early postoperative recovery of continence .
the 116 patients who developed ed after ns ralp , who had normal preoperative ef , and whose local clinical stage was t2 or lower with a gleason score lower than 8 and a serum psa of less than 20 ng before surgery were included in the study .
the additional exclusion of 24 patients who underwent hormonal or radiation therapy preoperatively or postoperatively , who received any kind of preoperative ed treatment , or to whom pde5-is could not be prescribed resulted in 92 patients .
the 92 patients were retrospectively evaluated in accordance with the ethical standards of the institutional review board at dong - a university hospital . in a study of the 92 patients ,
47 patients were prescribed tadalafil at a dose of 5 mg per day . in the tadalafil group , all patients took 5 mg tadalafil per day 1 hour before bedtime .
for all 47 patients , oral intake of tadalafil 5 mg was initiated early after foley catheter removal , between 2 and 3 weeks after the surgery .
the tadalafil group was then stratified depending on the ns procedure they had undergone : bilateral ns ( n=30 ) and unilateral ns ( n=17 ) .
postoperative ef was assessed through the patients ' responses to the korean version of the five - item international index of erectile function ( iief-5 ) questionnaire , which is also referred to as the sexual health inventory of men .
the iief-5 questionnaire is the abridged version of the iief-15 and consists of 5 questions related to ed diagnosis and ef improvement .
the iief-5 questionnaire is a self - administered questionnaire that can sensitively detect subtle changes in ef recovery .
each of the 5 questions is scored from 0 to 5 or from 1 to 5 , where 0 , the absence of sexual activity ; 1 , very low / almost never or never / extremely difficult ; 2 , low / a few times / very difficult ; 3 , moderate / sometimes / difficult ; 4 , high / most times / slightly difficult ; and 5 , very high / almost always or always / not difficult . the total iief-5 score is calculated by summing each score from the five questions and varies from 1 to 25 , where a score of 1 to 7 , severe ed ; 8 to 11 , moderate ed ; 12 to 16 , mild - moderate ed ; 17 to 21 , mild ed ; and 22 to 25 , no ed . in the present study , the iief-5 questionnaire was conducted 3 times : before surgery , at 6 months after surgery , and at 1 year after surgery .
all patients were also counseled on ed , tadalafil intake , and its side effects at each visit . in the present study ,
positive responders were defined as those patients whose combined score for q2 , " when you had erections with sexual stimulation , how often were your erections hard enough for penetration ? " and q3 , " during sexual intercourse , how often were you able to maintain your erection after you had penetrated your partner ? " on the iief-5 questionnaire was 8 or more .
outcomes from the tadalafil group and the non - tadalafil group were compared and analyzed according to ns status on the basis of the patients ' iief-5 score .
data were summarized by using descriptive statistics : frequency and percentage for categorical variables and meanstandard deviation and median ( range ) for continuous variables .
differences in the patients ' demographic and clinical characteristics were compared across subgroups with fisher exact test for categorical variables or mann - whitney u - test for continuous variables .
wilcoxon 's rank sum test was performed to test differences in iief-5 domains between time points .
the cumulative incidence of recovery of erection firm enough for sexual intercourse was estimated by the kaplan - meier product limit method .
the log - rank test was also employed to investigate the difference in recovery of erection between groups .
a p - value lower than 0.05 was considered statistically significant . by its nature , this study was explorative and , therefore , no adjustment for multiple testing was applied .
all statistical analyses were carried out by using ibm spss ver . 19.0 ( ibm co. , armonk , ny , usa ) and medcalc 11.6.1.0 ( medcalc , ostend , belgium ) .
demographic and clinical variables at baseline were well balanced between the tadalafil group and the non - tadalafil group ( table 1 ) .
the 92 patients who were screened for eligibility according to the inclusion and exclusion criteria were retrospectively assessed in the present study .
the patients in the tadalafil group ( n=47 ) and those in the non - tadalafil group ( n=45 ) were also stratified according to ns status . in the tadalafil group , 63.8% of the patients ( n=30 ) underwent a bilateral ns procedure and 36.2% of the patients ( n=17 ) underwent a unilateral ns procedure . in the non - tadalafil group , bilateral ns
was performed for 60% of the patients ( n=27 ) and unilateral ns was performed for 40% of the patients ( n=18 ) .
compared with the non - tadalafil group , the tadalafil group regardless of ns procedure reported a statistically significant improvement in ef ( p=0.0049 , log - rank test ) . at 6 months after the surgery
, 11% of the patients in the tadalafil group ( n=5 ) responded positively to tadalafil , whereas there were no positive responders in the non - tadalafil group . at 12 months after the surgery ,
32% of the patients in the tadalafil group ( n=15 ) were able to perform intercourse , and 9% of the patients in the non - tadalafil group ( n=4 ) had erection sufficient for sexual intercourse .
once - daily use of tadalafil 5 mg resulted in ef improvement during the course of 1 year after ns ralp ( fig .
the mean iief-5 score at 1 year also differed between the tadalafil group and the non - tadalafil group as shown in table 2 ( p<0.05 , wilcoxon 's rank sum test ) and in fig .
most of the patients who had undergone ns ralp experienced ed after the surgery . at 6 months , the total iief-5 scores of the tadalafil group and the non - tadalafil group were 10.03.4 and 7.04.0 , respectively ( p<0.0001 , mann - whitney u test ) . at 1 year after the surgery , the total iief-5 score in the tadalafil group was significantly greater than that in the non - tadalafil group ( 13.25.6 vs 7.74.8 , p<0.0001 ; mann - whitney u test ) .
moreover , there was a significant increase in all 5 domains of the iief-5 in the tadalafil group , whereas in the non - tadalafil group no significant increases were observed in any of the domains at 1 year ( q4 , p<0.0001 ; q1 , p<0.0001 ; q3 , p<0.0001 ; q2 , p=0.006 ; q5 , p<0.0001 ) . in the tadalafil group ,
the iief-5 score of the bilateral ns group was greater on all 5 domains of the iief-5 questionnaire than the score in the unilateral ns group at 1 year after surgery ( table 3 ) .
1 , the patients ' ns status largely influenced the response rate to tadalafil ( p=0.0098 , log - rank test ) . among the patients who were prescribed
tadalafil 5 mg per day , four patients ( 13% ) in the bilateral ns group and one patient ( 6% ) in the unilateral ns group positively responded to tadalafil at 6 months after the surgery . at 1 year , 12 patients ( 40% ) in the bilateral ns group and 3 patients ( 18% ) in the unilateral ns group responded positively to tadalafil and were able to perform intercourse . in the non - tadalafil group ,
only three patients ( 11% ) for whom bilateral ns was performed and one patient ( 6% ) for whom unilateral ns was performed had erections sufficient for vaginal intercourse . in the tadalafil group , two patients did not attempt sexual intercourse even though they had sufficient erections after the surgery . according to the results of the study , the once - daily dosage of tadalafil 5 mg was most effective when bilateral ns was performed .
daily use of tadalafil was well tolerated in the present study . at 6 months , flushing and dizziness
were the most commonly reported adverse events . in the tadalafil group , four patients ( 8.5% ) experienced flushing and one patient ( 2.1% ) experienced dizziness at 6 months . at 1 year , two patients ( 4.3% ) had headache , one patient ( 2.1% ) experienced dizziness , and three patients ( 6.4% ) were reported to experience flushing after taking the drug .
in our retrospective review , we learned that the dropout rate was 8% ( 4 of 51 ) over a period of 1 year ; two of the four patients had discontinued treatment owing to the high cost of the medication and the other two patients owing to a lack of efficacy .
the results of the current study of daily administration of tadalafil 5 mg for 1 year demonstrate the efficacy and safety of once - a - day dosing of tadalafil 5 mg in ed patients after ralp .
after the surgery , patients in the tadalafil group showed greater improvement in ef than did those in the non - tadalafil group .
the potency rate in the tadalafil groups who underwent either unilateral or bilateral ns continued to increase after the surgery , whereas the magnitude of improvement in the bilateral ns group was far greater than in the unilateral ns group . according to the iief-5 scores at 6 months and 1 year in the tadalafil group , the scores of the bilateral ns group ( 10.73.3 and 15.05.3 , respectively ) were significantly higher than the scores in the unilateral ns group ( 8.73.2 and 10.14.7 , respectively ) .
erection sufficient enough for sexual intercourse with the administration of tadalafil was observed in 40% of the patients in the bilateral ns group and 18% of the patients in the unilateral ns group .
the efficacy of daily administration of tadalafil was highly dependent on the degree of neurovascular bundle preservation .
reported that the efficacy of sildenafil citrate for ed patients who underwent bilateral , unilateral , and non - ns retropubic rp was 71.7% , 50% , and 15.4% , respectively . in another study that evaluated 91 ed patients after rp
, 52% of the patients ( n=48 ) responded positively to sildenafil citrate and were able to have successful vaginal intercourse 1 year after the surgery . in a randomized , double - blind , placebo - controlled , parallel study , montorsi et al .   reported that tadalafil once - a - day significantly improved ef compared with the placebo group .
after 12 weeks of drug administration , iief - ef domain scores 26 were obtained for 67 patients ( 45.9% ) in the tadalafil group and 21 patients ( 31.3% ) in the placebo group . however , in a randomized , double - blind , placebo - controlled study on the effects of nightly sildenafil citrate for the prevention of ed after bilateral ns rp , erection good enough for satisfactory sexual activity occurred only in 27% of the sildenafil group ( n=14 of 51 ) and in 4% of the placebo group ( n=1 of 25 ) . moreover , montorsi et al .   conducted a prospective , randomized , double - blind , double - dummy , multinational , multicenter , parallel group study and evaluated 628 patients after bilateral ns rp .
they compared the efficacy of on - demand versus nightly dosages of vardenafil and reported that iief scores 22 were obtained in 24.8% , 32.0% , and 48.2% of the placebo , vardenafil nightly , and vardenafil on - demand groups , respectively .
response rates to sildenafil after ns rp varied from 10% to 76% , whereas the response rates for the non - ns group varied from 0% to 15% .
the potency rate of 32% in the tadalafil group in the current study is slightly lower than the rates in previously published studies . the slightly lower response rate ( 32% ) in the tadalafil group may stem from the rather stringent criteria applied in this study . for instance , several other studies did not provide a clear definition or criteria for a positive response , and in those studies a positive response did not necessarily mean the ability to achieve sexual intercourse . in the current study , a summed score of 8 or more on q2 ( " when you had erections with sexual stimulation , how often were your erections hard enough for penetration ? " ) and q3 ( " during sexual intercourse , how often were you able to maintain your erection after you had penetrated your partner ? " ) of the iief-5 questionnaire was required for patients to be classified as positive responders .
the relatively older age of the patients in the present study ( 67.96.8 years ) might have had a negative impact on the potency rate .
furthermore , 2 patients in the tadalafil group did not attempt sexual intercourse even though they had sufficient erections after the surgery .
lastly , the biopsy gleason score , which is known to be related to psa failure , was slightly higher in the tadalafil group than in the non - tadalafil group even though a high gleason score of 8 or more was observed in only three of the patients ( one in the non - tadalafil group and two in the tadalafil group ) .
diverse factors including preoperative ef , frequency of sexual intercourse before surgery , type of ns procedure , degree of postoperative potency , and the interval between surgery and the administration of pde5-is might have affected the potency results .
the discrepancy among published results suggests that further confirmatory studies are needed on the effects of pde5-is and the optimal regimen .
the mechanism of action of pde5-is is related to the etiology of ed after rp .
even though the ns technique with the advent of ralp significantly improved the potency rate , neurapraxia and nerve injury still persist even 1 year after surgery .
the patients ' iief-5 score at 1 year was significantly lower than the patients ' iief-5 score at preoperative baseline , and most patients ( n=116 ) experienced ed after the surgery even though ns ralp was performed .
when neurologic injury occurs , penile hypoxia and fibrosis lead to the absence of spontaneous nocturnal erections , which decreases the release of nitric oxide .
this decrease in nitric oxide production leads to a drop in the amount of available cyclic guanosine monophosphate ( cgmp ) .
pde5-is inhibit pde5 , which metabolizes cgmp , and this results in an increase in cgmp levels .
this increase in the amount of cgmp coupled with nitric oxide induces corporal smooth muscle relaxation , and this leads to subsequent erection by allowing blood flow to the penis [ 21 - 24 ] .
the whole process requires nerve preservation , because if there is no cgmp , there is no substrate for pde5 to metabolize .
this mechanism of action explains why the effect of tadalafil was much greater in the bilateral ns group than in the unilateral ns group in the current study .
persistent use of pde5-is inhibits hypoxia - associated fibrosis by amplifying the depressed nitric oxide signaling pathway , and this leads to erectile recovery after rp . in a recent study that compared the effects of different pde5-is ,
tadalafil was the most effective agent , followed by vardenafil , although there was no significant difference in the safety profile of the drugs . in long - term studies
, once daily administration of tadalafil 5 mg was effective and safe and thus became a viable alternative to the widely used on - demand administration of tadalafil for ed patients .
moreover , the mean half - life of tadalafil ( 17.5 hours ) is longer than that of sildenafil and vardenafil ( about 4 hours ) .
the longer duration of the drug may allow patients with ed to enjoy sexual activity free from the burden of planning drug intake before intercourse , which can improve the patients ' sexual quality of life [ 27 - 29 ] .
previously published studies maintain that pde5-is can be administered as early as at the time of removal of the foley catheter or within 1 month after rp .
early administration of pde5-is helps to prevent cavernosal hypoxia , which leads to smooth muscle apoptosis and penile fibrosis . in our study , all patients in the tadalafil group initiated oral intake of tadalafil 5 mg right after foley catheter removal , between 2 to 3 weeks after the surgery , and tadalafil was administered for a period of 1 year .
the potency rate of the bilateral ns group who took tadalafil ( 40% ) was significantly higher than that of the non - tadalafil group ( 11% ) at 1 year after the surgery .
the results of our study suggest that ed after ralp can be well treated with once daily dosage of tadalafil 5 mg if ns ralp is performed .
therefore , tadalafil should be considered as a first - line treatment for a well - selected subgroup of ed patients after rp .
the current study was neither randomized nor placebo - controlled because it was carried out in a retrospective manner .
although the results of the study should be applied with caution , the findings suggest that once daily dosage of tadalafil 5 mg was effective and well - tolerated by ed patients after ralp at 1 year after the surgery .
a second limitation of the current study is related to the relatively small number of patients .
however , the current study can be a pilot for further studies that have larger randomized samples of patients . despite these limitations , this study is the first long - term study that evaluated the efficacy and safety of tadalafil 5 mg once daily use in ed patients after ns ralp .
more confirmatory studies that are prospective , crossover , randomized , placebo - controlled , and double - blind are clearly required to determine the effects and the optimal regimen of tadalafil in ed patients after ralp .
this study is the first long - term study that evaluated the efficacy and safety of tadalafil 5 mg once daily use in ed patients after ns ralp .
the results of the study indicate that once - a - day dosing of tadalafil 5 mg is effective and safe in properly selected ed patients after ns ralp . at 1 year after the surgery
, a recovery rate of 40% was attained in the bilateral ns group who took tadalafil 5 mg once per day before bedtime .
once daily administration of tadalafil 5 mg was effective and safe for ed patients who had undergone ns ralp , and the patients showed gradual improvement in their ef over a period of 1 year .
 purposeto evaluate the efficacy and safety of tadalafil 5 mg once daily use in the treatment of erectile dysfunction ( ed ) after robot - assisted laparoscopic radical prostatectomy ( ralp).materials and methodsthe study retrospectively evaluated 92 patients who underwent ralp at dong - a university hospital . 
 the patients were surveyed by use of the abridged five - item version of the international index of erectile function ( iief-5 ) questionnaire , which was self - administered before surgery and at 6 months and 1 year after surgery . 
 the 92 patients were classified into the tadalafil group ( n=47 ) and the non - tadalafil group ( n=45 ) . 
 each group was then classified depending on the nerve - sparing ( ns ) procedure used : bilateral ns or unilateral ns.resultsat 6 months , the total iief-5 scores of the tadalafil group and the non - tadalafil group were 10.03.4 and 7.04.0 , respectively . 
 at 1 year , the total iief-5 score in the tadalafil group was significantly greater than that in the non - tadalafil group ( 13.25.6 vs. 7.74.8 , p<0.0001 ) . 
 statistically significant improvements ( p<0.05 ) were observed in the tadalafil group for all 5 domains of the iief-5 score , whereas in the non - tadalafil group there was no significant improvement in any of the domains at 1 year . 
 the reported side effects were flushing ( 8.5% , n=4 ) , headache ( 4.3% , n=2 ) , and dizziness ( 2.1% , n=1).conclusionsin ed patients after ns ralp , a once - daily dose of tadalafil 5 mg was well tolerated and significantly improved ef compared with that in the non - tadalafil group . 