- Email: [email protected]
Tadalafil (Cialis) and Erectile Dysfunction After Radiotherapy for Prostate Cancer: An Open-Label Extension of a Blinded Trial
Adult Urology Tadalafil (Cialis) and Erectile Dysfunction After Radiotherapy for Prostate Cancer: An Open-Label Extension of a Blinded Trial Luca Incrocci, A. Koos Slob, and Wim C. J. Hop OBJECTIVES
METHODS
RESULTS
CONCLUSIONS
To determine the efficacy of tadalafil (Cialis) in patients with erectile dysfunction after threedimensional conformal external beam radiotherapy for prostate cancer in an extended open-label phase of the blinded trial. Sixty patients entered a double-blind, placebo-controlled, cross-over study lasting 12 weeks. They received tadalafil 20 mg or placebo for 6 weeks and then crossed over to the alternate medication. Of these 60 patients, 51 (85%) entered a 6-week open-label extension phase. The data were collected using the International Index of Erectile Function (IIEF) questionnaire. Side effects were also recorded. All patients completed the double-blind cross-over study. The 9 patients who did not wish to enter the open-label phase had had significantly worse scores statistically on the erectile function domain of the IIEF with tadalafil in the blinded trial (P ⫽ 0.03). For all IIEF domains, except for sexual desire, tadalafil was equally effective in the double-blind phase as in the open-label phase. For nearly all the IIEF questions, tadalafil caused a significant increase in the mean scores from baseline in the run-in period of the blinded trial. The side effects were mild or moderate and had significantly decreased compared with tadalafil in the blinded trial. Tadalafil is effective in many patients with erectile dysfunction after three-dimensional conformal external beam radiotherapy for prostate cancer. In the open-label extension of the trial, tadalafil showed the same efficacy as in the blinded phase. UROLOGY 70: 1190 –1193, 2007. © 2007 Elsevier Inc.
I
n recent years, the number of patients diagnosed with prostate cancer (PCa) has increased dramatically in the United States1 and Europe,2 because of widespread prostate-specific antigen testing. Although advanced radiation techniques, such as three-dimensional conformal external beam radiotherapy (3D-CRT), were assumed to cause less erectile dysfunction (ED), a review of the published studies showed ED rates reaching 84% in some studies.3 A recent prospective, randomized trial of 68 Gy versus 78 Gy found a 38% postradiotherapy ED rate after 3 years.4 Recently, we published the data of a randomized, double-blind trial to study the efficacy of tadalafil (Cialis; Eli Lilly and Company, Indianapolis, Ind) in 60 patients complaining of ED after 3D-CRT for PCa.5 In the present study, we report on the efficacy of tadalafil in the 51 patients who were included in the This study was supported by an unrestricted grant from Lilly From the Departments of Radiation Oncology and Epidemiology and Biostatistics, Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands Reprint requests: Luca Incrocci, M.D., Ph.D., Department of Radiation Oncology, Erasmus Medical Center-Daniel den Hoed Cancer Center, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands. E-mail: [email protected] Submitted: March 30, 2007, accepted (with revisions): August 10, 2007
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© 2007 Elsevier Inc. All Rights Reserved
open-label extension of the double-blind phase of the earlier study.5
MATERIAL AND METHODS Of the 51 patients, the mean age at 3D-CRT was 65 years (range 50 to 80), and the mean age at trial entry was 69 years (range 53 to 84). Comorbidity (diabetes and/or hypertension) was present in 39% of the men. The mean interval between completion of 3D-CRT and inclusion in the study was 39 months (range 15 to 55). A mean dose of 70 Gy (range 66 to 78) was given by a linear accelerator, with a mean energy of 23 MV (range 18 to 25). The differences in age, comorbidity, tumor characteristics, prostate-specific antigen level, and radiation dose were not statistically significant compared with the whole group of 60 patients who participated in the double-blind trial (P ⬎0.05 for all). A three-field 3D-CRT technique was applied; the clinical target volume was the prostate gland, with or without the seminal vesicles, plus 10 or 15 mm for the planning target volume.
Study Design The double-blind phase of the study has previously been extensively reported.5 In brief, after a 4-week run-in period without treatment during which baseline data on sexual functioning 0090-4295/07/$32.00 doi:10.1016/j.urology.2007.08.029
Table 1. Comparison of IIEF scores between double-blind and open-label extension phase (n ⫽ 51) Question 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Erection frequency Erection firmness Penetration ability Maintenance frequency Maintenance ability Intercourse frequency Intercourse satisfaction Intercourse enjoyment Ejaculation frequency Orgasm frequency Desire frequency Desire level Overall satisfaction Relationship satisfaction Erection confidence
Baseline Score 2.2 (1.3) 1.4 (0.7) 1.3 (0.7) 1.2 (0.8) 1.3 (0.7) 3.1 (0.9) 1.5 (0.9) 1.6 (1.0) 3.1 (1.7) 4.0 (1.5) 3.9 (0.9) 4.0 (0.9) 2.2 (1.2) 2.3 (1.3) 1.3 (0.7)
Double-Blind Phase Score After Tadalafil* Score After Placebo† 3.6 (1.7) 3.3 (1.8) 3.2 (1.8) 3.1 (1.9) 3.0 (1.7) 3.7 (0.9) 3.2 (1.9) 3.3 (1.6) 3.6 (1.7) 4.3 (1.3) 4.4 (0.7) 4.3 (0.8) 3.6 (1.4) 3.6 (1.3) 3.2 (1.6)
1.9 (1.4) 1.6 (1.2) 1.6 (1.2) 1.4 (1.0) 1.6 (1.2) 3.6 (0.7)† 1.6 (1.2) 1.7 (1.1) 2.5 (1.8) 2.6 (1.8)† 4.2 (0.8) 3.9 (1.1) 2.2 (1.2) 2.3 (1.4) 1.7 (1.3)†
Open Label Score‡ 3.6 (1.5) 3.6 (1.5) 3.5 (1.6) 3.4 (1.7) 3.0 (1.5) 3.7 (0.9) 3.3 (1.6) 3.5 (1.5) 3.9 (1.5) 4.2 (1.4) 4.0 (0.8) 3.9 (0.7) 3.6 (1.1) 3.6 (1.1) 3.4 (1.2)
IIEF ⫽ International Index of Erectile Function. Data presented as mean score, with standard deviation in parentheses. Scale of 1 (almost never or never) to 5 (almost always or always), with 0 indicating no sexual activity. Paired Wilcoxon’s test for all P values. * Between open-label and tadalafil score, P ⬎0.05, except for questions 4 (P ⫽ 0.04), 11 (P ⫽ 0.003), and 12 (P ⫽ 0.002). † Between open-label and placebo scores, P ⬍0.0001, except for questions 6 (P ⫽ 0.64), 11 (P ⫽ 0.21), and 12 (P ⫽ 0.76). ‡ Between open-label and baseline scores, P ⬍0.001, except for questions 10 (P ⫽ 0.38), 11 (P ⫽ 0.86), and 12 (P ⫽ 0.43).
were collected, the patients entered a 12-week, double-blind, placebo-controlled treatment period. Patients received tadalafil 20 mg or placebo for 6 weeks. The study medication (drug or placebo) was taken on demand at the patient’s discretion, with no restrictions regarding the consumption of alcohol or food, at least once a week, and no more than once daily. Patients were informed that the study drug could be effective for up to 36 hours after intake. At week 6, patients crossed over to the alternative treatment. If patients experienced adverse events, the dose could be decreased to 10 mg. At the end of the double-blind phase of the study, patients were allowed to enter a 6-week open-label phase of the trial with 20 mg of tadalafil. Patients were asked to complete the International Index of Erectile Function (IIEF), an international, validated, self-administered, 15-item questionnaire,6 at the end of the open-label period. The responses on the IIEF questionnaire were graded on a scale of 1 (almost never or never) to 5 (almost always or always), with 0 indicating no sexual activity. The mean baseline scores of the 15 IIEF questions were calculated at the end of the run-in period before treatment and compared with mean final scores after 6 and 12 weeks of treatment (tadalafil or placebo) in the double-blind phase and after the 6 weeks of the open-label extension period. The IIEF questions can be grouped into five domains: erectile function (EF), questions 1 to 5 and 15; orgasmic function, questions 9 and 10; sexual desire, questions 11 and 12; intercourse satisfaction, questions 6 to 8; and overall satisfaction, questions 13 and 14. The patients’ IIEF domain scores were calculated at the end of the run-in period and after both treatment periods in the double-blind phase and at the end of the open-label extension. Two global efficacy questions (GEQs) were included, to which patients could respond either positively or negatively: “Has the treatment you have been taking improved your erections?” and “Has the treatment you have been taking led to successful intercourse?” Side effects were categorized as absent, mild, moderate, or severe using a patient-completed standardized form. The hospital medical ethical committee approved the study. UROLOGY 70 (6), 2007
Statistical Analysis The primary efficacy measure was the EF domain of the IIEF, defined as the sum of questions 1 to 5, and 15 of the IIEF questionnaire. The secondary efficacy variables included the other IIEF domains and the two GEQs. The intent-to-treat population was those patients who took at least one dose of study medication. The evaluable population was those patients who attempted sexual activity at least two times in the 6-week open-label extension period. The within-group and betweengroup comparison of the continuous data or scores was done using Wilcoxon’s matched-pairs test and the Mann-Whitney U test, respectively. For the within-group and between-group comparison of percentages, McNemar’s test and Fisher’s exact test was used, respectively. P ⫽ 0.05 (two-sided) was considered the limit of statistical significance.
RESULTS Of the 60 patients, 51 (85%) entered the open-label phase, and all completed it. These patients had had higher scores with tadalafil in the double-blind phase for the EF domain (P ⫽ 0.03). The 9 patients who did not enter the open-label phase had had a low response to the study medication during the double-blind phase. The side effects did not play a role in the decision, and the differences were not statistically significant between the two groups (P ⫽ 0.9). The IIEF scores between the double-blind phase and open-label extension phase were compared (Table 1), as were the five domains of the IIEF (Table 2). An improvement in erections was reported by 84% of the patients and successful intercourse by 69%. In the double-blind phase, the corresponding values were 72% and 55%. No statistically significant difference was found between the percentage of patients answering positively 1191
Table 2. Comparison of five domain scores of IIEF between double-blind and open-label extension phase (n ⫽ 51) IIEF Domain
Baseline Score
Erectile function* Orgasmic function† Sexual desire‡ Intercourse satisfaction§ Overall satisfaction储
8.8 (3.2) 7.1 (2.8) 8.0 (1.8) 6.1 (2.1) 4.5 (2.5)
Double-Blind Phase Score After Tadalafil Score After Placebo 19.5 (9.5) 7.9 (2.8) 8.8 (1.5) 10.2 (3.8) 7.2 (2.7)
10.0 (6.3) 5.1 (3.5) 8.1 (1.8) 7.0 (2.3) 4.5 (2.6)
Open Label Score 20.7 (8.5) 8.1 (2.7) 7.9 (1.4) 10.6 (3.3) 7.3 (2.3)
IIEF ⫽ International Index of Erectile Function. Data presented as mean score, with standard deviation in parentheses. Erectile function domain, questions 1–5 and 15; orgasmic domain, questions 9 and 10; sexual desire domain, questions 11 and 12; intercourse satisfaction domain, questions 6 – 8; overall satisfaction domain, questions 13 and 14. Paired Wilcoxon’s test for all P values. * Between baseline and open label, P ⬍0.0001, between open label and tadalafil, P ⫽ 0.06, and between open label and placebo, P ⬍0.0001. † Between baseline and open label, P ⫽ 0.01, between open label and tadalafil, P ⫽ 0.64, and between open label and placebo, P ⬍0.0001. ‡ Between baseline and open label, P ⫽ 0.65, between open label and tadalafil, P ⫽ 0.001, and between open label and placebo, P ⫽ 0.53. § Between baseline and open label, P ⬍0.0001, between open label and tadalafil, P ⫽ 0.30, and between open label and placebo, P ⬍0.0001. 储 Between baseline and open label, P ⬍0.0001, between open label and tadalafil, P ⫽ 0.59, and between open label and placebo, P ⬍0.0001.
Table 3. Side effects after tadalafil or placebo (double-blind phase) and tadalafil (open-label phase) (n ⫽ 51)
Side Effect Headache Flushing Myalgia Nasal congestion Dyspepsia Back pain Dizziness
Double-Blind Phase Tadalafil Placebo 27 (14) 16 (8) 12 (6) 6 (3) 24 (12) 4 (2) 2 (1)
Open-Label Phase Tadalafil
Between Tadalafil Open Label and Double Blind
8 (4) 10 (5) 6 (3) 4 (2) 10 (5) 2 (1) 2 (1)
0.002 0.25 0.25 1.00 0.01 1.00 1.00
2 (1) 2 (1) 4 (2) 4 (2) 2 (1) 4 (2) 2 (1)
P Value Between Tadalafil Open Label and Placebo Double Blind 0.25 0.21 1.00 1.00 0.12 1.00 1.00
Data presented as percentage, with n in parentheses.
regarding an improvement in erections (P ⫽ 0.10) in the open-label phase and double-blind phase; however, the difference regarding successful intercourse was statistically significant (P ⫽ 0.04). Seventeen patients (33%) reported that their spontaneous erections (ie, without any concomitant sexual activity) improved with tadalafil; this was 49% in the double-blind phase (P ⫽ 0.11). Side effects The side effects (Table 3) were mild or moderate and transient and did not result in drug discontinuation. Open-label tadalafil resulted in a statistically significant lower incidence of headache (P ⫽ 0.002) and dyspepsia (P ⫽ 0.01) compared with the incidence in the doubleblind phase. No statistically significant difference was found between the side effects experienced with tadalafil in the open-label phase and placebo in the blinded phase. Comment Despite the decrease in overall cancer mortality rates in developed countries, cancer remains a major public health problem. In The Netherlands, 8,000 patients annually are diagnosed with PCa. Of the patients treated by 1192
3D-CRT, about 40% complain of ED 1 to 3 years after treatment.4,7 Sildenafil (Viagra) has been reported to be effective in 57% of patients complaining of ED after 3D-CRT for PCa in the only randomized trial performed to date.8 Tadalafil has been introduced more recently and has demonstrated its superiority over placebo in the treatment of ED of different etiologies in many clinical trials.9 –11 In these studies, 81% of the patients reported improved erections with tadalafil 20 mg compared with 35% with placebo. Also, tadalafil is effective up to 36 hours after intake,12 and its efficacy is not affected by food or alcohol intake.13 Both tadalafil and sildenafil are selective inhibitors of cyclic guanosine monophosphatespecific phosphodiesterase type 5, and hence inhibit the degradation of cyclic guanosine monophosphate in the cavernosal smooth muscle cells,14 restoring erectile response to sexual stimulation in patients with ED.9 –11,15 To our knowledge, no randomized, placebo-controlled, double-blind trials have been performed to assess the efficacy of tadalafil to treat ED after radiotherapy (RT) for PCa except ours.5 In that trial, we showed that tadalafil significantly increases erectile functioning after UROLOGY 70 (6), 2007
3D-CRT as determined by the increase in scores of the IIEF and GEQs compared with placebo.5 The only randomized, double-blind trial published to date on the efficacy of sildenafil to treat post-RT ED reported similar results.8 Patients who entered the open-label phase of our study had had a higher score on the IIEF EF domain in the double-blind phase of the earlier study.5 It is understandable that only those patients who responded to the drug in the double-blind phase were motivated to proceed with the unblinded drug. The side effects did not play a role in the decision and were not significant different statistically between the two groups. Nevertheless, in the open-label phase, the score of the IIEF EF domain was not significantly different compared with that in the blinded phase. Regarding the improvement in erections as reported by the GEQ, the difference between the open-label and double-blind phase was not statistically significant. In contrast, the difference in percentage of successful intercourse attempts was statistically significant. No patients discontinued the study. The side effects were graded as mild or moderate and were transient. Tadalafil 20 mg open-label caused significantly less headache and dyspepsia than in the double-blind phase, indicating that patients using the drug for a longer period had a decrease in side effects. This should be mentioned to patients willing to use tadalafil but reporting side effects at the very beginning of treatment. On the basis of a previous titration trial with sildenafil after 3D-CRT in which most patients (90%) used sildenafil 100 mg,8 we decided to use tadalafil 20 mg in the present trial. A possible criticism of this approach is that we do not know whether tadalafil 10 mg would also be effective in treating RT-induced ED.
CONCLUSIONS The results of our study have shown that tadalafil is an effective oral drug to treat men with ED after RT for PCa. The 20-mg dose was well tolerated, and the side effects were mild or moderate, decreased over time, and never led to drug discontinuation. Because of the simplicity of delivery (effective for up to 36 hours and not affected by food or alcohol intake) and the acceptable side effects, tadalafil might be the first treatment option for patients with post-RT ED, but not using nitrates. Nevertheless, the development and testing of new drugs (and combi-
UROLOGY 70 (6), 2007
nation therapies) are needed to improve the outcome in this difficult-to-treat population. Acknowledgment. To Cleo Slagter, M.D. for helping to collect the data.
References 1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2006. CA Cancer J Clin 56: 106 –130, 2006. 2. Jensen OM, Esteve J, Moller H, et al: Cancer in the European community and its members states. Eur J Cancer 26: 1167–1256, 1990. 3. Incrocci L, Slob AK, and Levendag P: Sexual dysfunction after radiotherapy for prostate cancer: a review. Int J Radiat Oncol Biol Phys 52: 681– 693, 2002. 4. van der Wielen GJ, van Putten WLJ, and Incrocci L: Sexual function after three dimensional conformal radiotherapy for prostate cancer: results from a dose-escalation trial. Int J Radiat Oncol Biol Phys 68: 479 – 484, 2007. 5. Incrocci L, Slagter C, Slob AK, et al: A randomized, double-blind, placebo-controlled, cross-over study to assess the efficacy of tadalafil (Cialis®) in the treatment of erectile dysfunction following three-dimensional conformal external-beam radiotherapy for prostatic carcinoma. Int J Radiat Oncol Biol Phys 66: 439 – 444, 2006. 6. Rosen RC, Riley A, Wagner G, et al: The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 49: 822– 830, 1997. 7. Turner SL, Adams K, Bull CA, et al: Sexual dysfunction after radical radiation therapy for prostate cancer: a prospective evaluation. Urology 54: 124 –129, 1999. 8. Incrocci L, Koper PCM, Hop WCJ, et al: Sildenafil citrate (Viagra) and erectile dysfunction following external-beam radiotherapy for prostate cancer: a randomized, double-blind, placebo-controlled, cross-over study. Int J Radiat Oncol Biol Phys 51: 1190 –1195, 2001. 9. Padma-Nathan H, McMurray JG, Pullman WE, et al: On-demand IC351 (Cialis) enhances erectile function in patients with erectile dysfunction. Int J Impotence Res 13: 2–9, 2001. 10. Brock GB: Tadalafil: a new agent for erectile dysfunction. Can J Urol 10: 17–22, 2003. 11. Eardley I, Cartledge J: Tadalafil (Cialis) for men with erectile dysfunction. Int J Clin Pract 56: 300 –304, 2002. 12. Porst H, Padma-Nathan H, Giuliano F, et al: Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology 62: 121–126, 2003. 13. Forgue ST, Patterson BE, Bedding AW, et al: Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol 61: 280 –288, 2006. 14. Ballard SA, Gingell CJ, Tang K, et al: Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activity of cyclic nucleotide phosphodiesterase isoenzymes. J Urol 159: 2164 –2171, 1998. 15. Goldstein I, Lue TF, Padma-Nathan H, et al: Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 338: 1397–1404, 1998.
1193
METHODS
RESULTS
CONCLUSIONS
To determine the efficacy of tadalafil (Cialis) in patients with erectile dysfunction after threedimensional conformal external beam radiotherapy for prostate cancer in an extended open-label phase of the blinded trial. Sixty patients entered a double-blind, placebo-controlled, cross-over study lasting 12 weeks. They received tadalafil 20 mg or placebo for 6 weeks and then crossed over to the alternate medication. Of these 60 patients, 51 (85%) entered a 6-week open-label extension phase. The data were collected using the International Index of Erectile Function (IIEF) questionnaire. Side effects were also recorded. All patients completed the double-blind cross-over study. The 9 patients who did not wish to enter the open-label phase had had significantly worse scores statistically on the erectile function domain of the IIEF with tadalafil in the blinded trial (P ⫽ 0.03). For all IIEF domains, except for sexual desire, tadalafil was equally effective in the double-blind phase as in the open-label phase. For nearly all the IIEF questions, tadalafil caused a significant increase in the mean scores from baseline in the run-in period of the blinded trial. The side effects were mild or moderate and had significantly decreased compared with tadalafil in the blinded trial. Tadalafil is effective in many patients with erectile dysfunction after three-dimensional conformal external beam radiotherapy for prostate cancer. In the open-label extension of the trial, tadalafil showed the same efficacy as in the blinded phase. UROLOGY 70: 1190 –1193, 2007. © 2007 Elsevier Inc.
I
n recent years, the number of patients diagnosed with prostate cancer (PCa) has increased dramatically in the United States1 and Europe,2 because of widespread prostate-specific antigen testing. Although advanced radiation techniques, such as three-dimensional conformal external beam radiotherapy (3D-CRT), were assumed to cause less erectile dysfunction (ED), a review of the published studies showed ED rates reaching 84% in some studies.3 A recent prospective, randomized trial of 68 Gy versus 78 Gy found a 38% postradiotherapy ED rate after 3 years.4 Recently, we published the data of a randomized, double-blind trial to study the efficacy of tadalafil (Cialis; Eli Lilly and Company, Indianapolis, Ind) in 60 patients complaining of ED after 3D-CRT for PCa.5 In the present study, we report on the efficacy of tadalafil in the 51 patients who were included in the This study was supported by an unrestricted grant from Lilly From the Departments of Radiation Oncology and Epidemiology and Biostatistics, Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands Reprint requests: Luca Incrocci, M.D., Ph.D., Department of Radiation Oncology, Erasmus Medical Center-Daniel den Hoed Cancer Center, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands. E-mail: [email protected] Submitted: March 30, 2007, accepted (with revisions): August 10, 2007
1190
© 2007 Elsevier Inc. All Rights Reserved
open-label extension of the double-blind phase of the earlier study.5
MATERIAL AND METHODS Of the 51 patients, the mean age at 3D-CRT was 65 years (range 50 to 80), and the mean age at trial entry was 69 years (range 53 to 84). Comorbidity (diabetes and/or hypertension) was present in 39% of the men. The mean interval between completion of 3D-CRT and inclusion in the study was 39 months (range 15 to 55). A mean dose of 70 Gy (range 66 to 78) was given by a linear accelerator, with a mean energy of 23 MV (range 18 to 25). The differences in age, comorbidity, tumor characteristics, prostate-specific antigen level, and radiation dose were not statistically significant compared with the whole group of 60 patients who participated in the double-blind trial (P ⬎0.05 for all). A three-field 3D-CRT technique was applied; the clinical target volume was the prostate gland, with or without the seminal vesicles, plus 10 or 15 mm for the planning target volume.
Study Design The double-blind phase of the study has previously been extensively reported.5 In brief, after a 4-week run-in period without treatment during which baseline data on sexual functioning 0090-4295/07/$32.00 doi:10.1016/j.urology.2007.08.029
Table 1. Comparison of IIEF scores between double-blind and open-label extension phase (n ⫽ 51) Question 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Erection frequency Erection firmness Penetration ability Maintenance frequency Maintenance ability Intercourse frequency Intercourse satisfaction Intercourse enjoyment Ejaculation frequency Orgasm frequency Desire frequency Desire level Overall satisfaction Relationship satisfaction Erection confidence
Baseline Score 2.2 (1.3) 1.4 (0.7) 1.3 (0.7) 1.2 (0.8) 1.3 (0.7) 3.1 (0.9) 1.5 (0.9) 1.6 (1.0) 3.1 (1.7) 4.0 (1.5) 3.9 (0.9) 4.0 (0.9) 2.2 (1.2) 2.3 (1.3) 1.3 (0.7)
Double-Blind Phase Score After Tadalafil* Score After Placebo† 3.6 (1.7) 3.3 (1.8) 3.2 (1.8) 3.1 (1.9) 3.0 (1.7) 3.7 (0.9) 3.2 (1.9) 3.3 (1.6) 3.6 (1.7) 4.3 (1.3) 4.4 (0.7) 4.3 (0.8) 3.6 (1.4) 3.6 (1.3) 3.2 (1.6)
1.9 (1.4) 1.6 (1.2) 1.6 (1.2) 1.4 (1.0) 1.6 (1.2) 3.6 (0.7)† 1.6 (1.2) 1.7 (1.1) 2.5 (1.8) 2.6 (1.8)† 4.2 (0.8) 3.9 (1.1) 2.2 (1.2) 2.3 (1.4) 1.7 (1.3)†
Open Label Score‡ 3.6 (1.5) 3.6 (1.5) 3.5 (1.6) 3.4 (1.7) 3.0 (1.5) 3.7 (0.9) 3.3 (1.6) 3.5 (1.5) 3.9 (1.5) 4.2 (1.4) 4.0 (0.8) 3.9 (0.7) 3.6 (1.1) 3.6 (1.1) 3.4 (1.2)
IIEF ⫽ International Index of Erectile Function. Data presented as mean score, with standard deviation in parentheses. Scale of 1 (almost never or never) to 5 (almost always or always), with 0 indicating no sexual activity. Paired Wilcoxon’s test for all P values. * Between open-label and tadalafil score, P ⬎0.05, except for questions 4 (P ⫽ 0.04), 11 (P ⫽ 0.003), and 12 (P ⫽ 0.002). † Between open-label and placebo scores, P ⬍0.0001, except for questions 6 (P ⫽ 0.64), 11 (P ⫽ 0.21), and 12 (P ⫽ 0.76). ‡ Between open-label and baseline scores, P ⬍0.001, except for questions 10 (P ⫽ 0.38), 11 (P ⫽ 0.86), and 12 (P ⫽ 0.43).
were collected, the patients entered a 12-week, double-blind, placebo-controlled treatment period. Patients received tadalafil 20 mg or placebo for 6 weeks. The study medication (drug or placebo) was taken on demand at the patient’s discretion, with no restrictions regarding the consumption of alcohol or food, at least once a week, and no more than once daily. Patients were informed that the study drug could be effective for up to 36 hours after intake. At week 6, patients crossed over to the alternative treatment. If patients experienced adverse events, the dose could be decreased to 10 mg. At the end of the double-blind phase of the study, patients were allowed to enter a 6-week open-label phase of the trial with 20 mg of tadalafil. Patients were asked to complete the International Index of Erectile Function (IIEF), an international, validated, self-administered, 15-item questionnaire,6 at the end of the open-label period. The responses on the IIEF questionnaire were graded on a scale of 1 (almost never or never) to 5 (almost always or always), with 0 indicating no sexual activity. The mean baseline scores of the 15 IIEF questions were calculated at the end of the run-in period before treatment and compared with mean final scores after 6 and 12 weeks of treatment (tadalafil or placebo) in the double-blind phase and after the 6 weeks of the open-label extension period. The IIEF questions can be grouped into five domains: erectile function (EF), questions 1 to 5 and 15; orgasmic function, questions 9 and 10; sexual desire, questions 11 and 12; intercourse satisfaction, questions 6 to 8; and overall satisfaction, questions 13 and 14. The patients’ IIEF domain scores were calculated at the end of the run-in period and after both treatment periods in the double-blind phase and at the end of the open-label extension. Two global efficacy questions (GEQs) were included, to which patients could respond either positively or negatively: “Has the treatment you have been taking improved your erections?” and “Has the treatment you have been taking led to successful intercourse?” Side effects were categorized as absent, mild, moderate, or severe using a patient-completed standardized form. The hospital medical ethical committee approved the study. UROLOGY 70 (6), 2007
Statistical Analysis The primary efficacy measure was the EF domain of the IIEF, defined as the sum of questions 1 to 5, and 15 of the IIEF questionnaire. The secondary efficacy variables included the other IIEF domains and the two GEQs. The intent-to-treat population was those patients who took at least one dose of study medication. The evaluable population was those patients who attempted sexual activity at least two times in the 6-week open-label extension period. The within-group and betweengroup comparison of the continuous data or scores was done using Wilcoxon’s matched-pairs test and the Mann-Whitney U test, respectively. For the within-group and between-group comparison of percentages, McNemar’s test and Fisher’s exact test was used, respectively. P ⫽ 0.05 (two-sided) was considered the limit of statistical significance.
RESULTS Of the 60 patients, 51 (85%) entered the open-label phase, and all completed it. These patients had had higher scores with tadalafil in the double-blind phase for the EF domain (P ⫽ 0.03). The 9 patients who did not enter the open-label phase had had a low response to the study medication during the double-blind phase. The side effects did not play a role in the decision, and the differences were not statistically significant between the two groups (P ⫽ 0.9). The IIEF scores between the double-blind phase and open-label extension phase were compared (Table 1), as were the five domains of the IIEF (Table 2). An improvement in erections was reported by 84% of the patients and successful intercourse by 69%. In the double-blind phase, the corresponding values were 72% and 55%. No statistically significant difference was found between the percentage of patients answering positively 1191
Table 2. Comparison of five domain scores of IIEF between double-blind and open-label extension phase (n ⫽ 51) IIEF Domain
Baseline Score
Erectile function* Orgasmic function† Sexual desire‡ Intercourse satisfaction§ Overall satisfaction储
8.8 (3.2) 7.1 (2.8) 8.0 (1.8) 6.1 (2.1) 4.5 (2.5)
Double-Blind Phase Score After Tadalafil Score After Placebo 19.5 (9.5) 7.9 (2.8) 8.8 (1.5) 10.2 (3.8) 7.2 (2.7)
10.0 (6.3) 5.1 (3.5) 8.1 (1.8) 7.0 (2.3) 4.5 (2.6)
Open Label Score 20.7 (8.5) 8.1 (2.7) 7.9 (1.4) 10.6 (3.3) 7.3 (2.3)
IIEF ⫽ International Index of Erectile Function. Data presented as mean score, with standard deviation in parentheses. Erectile function domain, questions 1–5 and 15; orgasmic domain, questions 9 and 10; sexual desire domain, questions 11 and 12; intercourse satisfaction domain, questions 6 – 8; overall satisfaction domain, questions 13 and 14. Paired Wilcoxon’s test for all P values. * Between baseline and open label, P ⬍0.0001, between open label and tadalafil, P ⫽ 0.06, and between open label and placebo, P ⬍0.0001. † Between baseline and open label, P ⫽ 0.01, between open label and tadalafil, P ⫽ 0.64, and between open label and placebo, P ⬍0.0001. ‡ Between baseline and open label, P ⫽ 0.65, between open label and tadalafil, P ⫽ 0.001, and between open label and placebo, P ⫽ 0.53. § Between baseline and open label, P ⬍0.0001, between open label and tadalafil, P ⫽ 0.30, and between open label and placebo, P ⬍0.0001. 储 Between baseline and open label, P ⬍0.0001, between open label and tadalafil, P ⫽ 0.59, and between open label and placebo, P ⬍0.0001.
Table 3. Side effects after tadalafil or placebo (double-blind phase) and tadalafil (open-label phase) (n ⫽ 51)
Side Effect Headache Flushing Myalgia Nasal congestion Dyspepsia Back pain Dizziness
Double-Blind Phase Tadalafil Placebo 27 (14) 16 (8) 12 (6) 6 (3) 24 (12) 4 (2) 2 (1)
Open-Label Phase Tadalafil
Between Tadalafil Open Label and Double Blind
8 (4) 10 (5) 6 (3) 4 (2) 10 (5) 2 (1) 2 (1)
0.002 0.25 0.25 1.00 0.01 1.00 1.00
2 (1) 2 (1) 4 (2) 4 (2) 2 (1) 4 (2) 2 (1)
P Value Between Tadalafil Open Label and Placebo Double Blind 0.25 0.21 1.00 1.00 0.12 1.00 1.00
Data presented as percentage, with n in parentheses.
regarding an improvement in erections (P ⫽ 0.10) in the open-label phase and double-blind phase; however, the difference regarding successful intercourse was statistically significant (P ⫽ 0.04). Seventeen patients (33%) reported that their spontaneous erections (ie, without any concomitant sexual activity) improved with tadalafil; this was 49% in the double-blind phase (P ⫽ 0.11). Side effects The side effects (Table 3) were mild or moderate and transient and did not result in drug discontinuation. Open-label tadalafil resulted in a statistically significant lower incidence of headache (P ⫽ 0.002) and dyspepsia (P ⫽ 0.01) compared with the incidence in the doubleblind phase. No statistically significant difference was found between the side effects experienced with tadalafil in the open-label phase and placebo in the blinded phase. Comment Despite the decrease in overall cancer mortality rates in developed countries, cancer remains a major public health problem. In The Netherlands, 8,000 patients annually are diagnosed with PCa. Of the patients treated by 1192
3D-CRT, about 40% complain of ED 1 to 3 years after treatment.4,7 Sildenafil (Viagra) has been reported to be effective in 57% of patients complaining of ED after 3D-CRT for PCa in the only randomized trial performed to date.8 Tadalafil has been introduced more recently and has demonstrated its superiority over placebo in the treatment of ED of different etiologies in many clinical trials.9 –11 In these studies, 81% of the patients reported improved erections with tadalafil 20 mg compared with 35% with placebo. Also, tadalafil is effective up to 36 hours after intake,12 and its efficacy is not affected by food or alcohol intake.13 Both tadalafil and sildenafil are selective inhibitors of cyclic guanosine monophosphatespecific phosphodiesterase type 5, and hence inhibit the degradation of cyclic guanosine monophosphate in the cavernosal smooth muscle cells,14 restoring erectile response to sexual stimulation in patients with ED.9 –11,15 To our knowledge, no randomized, placebo-controlled, double-blind trials have been performed to assess the efficacy of tadalafil to treat ED after radiotherapy (RT) for PCa except ours.5 In that trial, we showed that tadalafil significantly increases erectile functioning after UROLOGY 70 (6), 2007
3D-CRT as determined by the increase in scores of the IIEF and GEQs compared with placebo.5 The only randomized, double-blind trial published to date on the efficacy of sildenafil to treat post-RT ED reported similar results.8 Patients who entered the open-label phase of our study had had a higher score on the IIEF EF domain in the double-blind phase of the earlier study.5 It is understandable that only those patients who responded to the drug in the double-blind phase were motivated to proceed with the unblinded drug. The side effects did not play a role in the decision and were not significant different statistically between the two groups. Nevertheless, in the open-label phase, the score of the IIEF EF domain was not significantly different compared with that in the blinded phase. Regarding the improvement in erections as reported by the GEQ, the difference between the open-label and double-blind phase was not statistically significant. In contrast, the difference in percentage of successful intercourse attempts was statistically significant. No patients discontinued the study. The side effects were graded as mild or moderate and were transient. Tadalafil 20 mg open-label caused significantly less headache and dyspepsia than in the double-blind phase, indicating that patients using the drug for a longer period had a decrease in side effects. This should be mentioned to patients willing to use tadalafil but reporting side effects at the very beginning of treatment. On the basis of a previous titration trial with sildenafil after 3D-CRT in which most patients (90%) used sildenafil 100 mg,8 we decided to use tadalafil 20 mg in the present trial. A possible criticism of this approach is that we do not know whether tadalafil 10 mg would also be effective in treating RT-induced ED.
CONCLUSIONS The results of our study have shown that tadalafil is an effective oral drug to treat men with ED after RT for PCa. The 20-mg dose was well tolerated, and the side effects were mild or moderate, decreased over time, and never led to drug discontinuation. Because of the simplicity of delivery (effective for up to 36 hours and not affected by food or alcohol intake) and the acceptable side effects, tadalafil might be the first treatment option for patients with post-RT ED, but not using nitrates. Nevertheless, the development and testing of new drugs (and combi-
UROLOGY 70 (6), 2007
nation therapies) are needed to improve the outcome in this difficult-to-treat population. Acknowledgment. To Cleo Slagter, M.D. for helping to collect the data.
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