Practical Radiation Oncology (2015) 5, e223-e228
www.practicalradonc.org
Original Report
The impact of hormonal therapy on sexual quality of life in men receiving intensity modulated radiation therapy for prostate cancer Christina H. Son MD a , Sravana K. Chennupati MD b , Rangesh Kunnavakkam MS c , Stanley L. Liauw MD a,⁎ a
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon c Department of Health Studies, University of Chicago, Chicago, Illinois b
Received 28 July 2014; revised 13 October 2014; accepted 15 October 2014
Abstract Purpose: Sexual function is an important concern in men receiving intensity modulated radiation therapy (IMRT) for prostate cancer. Our aim was to study the impact of IMRT and androgen deprivation therapy (ADT) on sexual function over time and to report the effectiveness of sexual medications or aids. Methods and materials: A total of 179 men, median age 69, received definitive IMRT for prostate cancer and completed 2 surveys (Expanded Prostate Cancer Index Composite-26 and a sexual medicines/devices survey) for at least 2 time points. Surveys were prospectively collected at baseline (before all therapy), and 2, 6, 12, 18, and 24 months after IMRT. Median dose was 76 Gy to the prostate. ADT was administered to 59% of patients (median duration 5 months, initiated 2 months before IMRT). Global scores were generated for the Expanded Prostate Cancer Index Composite-26 questions. Longitudinal analysis was performed by constructing a generalized estimation equations model, and clinical variables were tested for association with global scores. Results: Overall, there was a significant decline in global sexual score through 2 years. Men receiving ADT had a lower sexual score at 2 and 6 months, but this difference disappeared at 24 months. Analysis of individual sexual symptoms showed no significant difference at 24 months except that men on ADT were less likely to be sexually active (P = .02); this difference was not observed for men receiving short-term ADT only. Longitudinal analysis revealed that duration of ADT was the only factor associated with global sexual score. Phosphodiesterase inhibitors were attempted by roughly half of all men, with 66% experiencing benefit, whereas other aids were attempted by roughly 5% of men. Conclusions: Although ADT adversely affected short-term sexual function, there was no significant difference in global score and most sexual symptoms by 24 months. These data are useful for anticipatory guidance regarding expectations after IMRT. © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Conflicts of interest: None. ⁎ Corresponding author. Department of Radiation and Cellular Oncology, University of Chicago, 5758 South Maryland Avenue, MC 9006, Chicago, IL 60637. E-mail address: [email protected] (S.L. Liauw). http://dx.doi.org/10.1016/j.prro.2014.10.003 1879-8500/© 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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we report on the utility of sexual aids, including PDE inhibitors, in both groups of men.
Introduction Prostate cancer is the most common cancer diagnosed in men in the United States. 1 Several treatment options exist, including radical prostatectomy, brachytherapy, or external beam radiation therapy, and many men choose to undergo external beam radiation. Multiple randomized trials have demonstrated a survival advantage with the addition of androgen deprivation therapy (ADT) to radiation in those with higher risk disease: for those with intermediate-risk prostate cancer, short-term ADT (4-6 months) is often prescribed, 2,3 whereas for those with highest risk disease, long-term ADT (N 2 years) has become standard of care. 4,5 Unfortunately, both ADT and radiation therapy (RT) can cause sexual dysfunction, leading to a significant impact on quality of life (QOL) for many men. Medications such as phosphodiesterase-5 (PDE) inhibitors or sexual aids, such as vacuum erection devices, are commonly prescribed to manage sexual symptoms. Although worsening of sexual QOL may be expected with the addition of ADT to RT, there are few, if any, prospective reports studying the impact of ADT on sexual function and response to sexual aids in men who receive dose-escalated intensity modulated RT (IMRT). Prior studies using older radiation techniques and lower doses confirm an overall worsening of sexual function after RT, with varying conclusions regarding the effect of ADT on sexual QOL and response to medication. 6 -12 In this study, we report the results of prospectively obtained longitudinal data in patients who underwent dose-escalated IMRT with or without ADT. Additionally, Table 1
Methods and materials Men treated with definitive RT for prostate cancer between 2001 and 2010 at an academic institution were identified in an institutional database. Written informed consent was obtained from all patients with ongoing follow-up. This study was approved by the hospital’s institutional review board. All men completed 2 surveys, the Expanded Prostate Cancer Index Composite-26 (EPIC) 13 and a sexual medicines/devices survey, for at least 2 time points. Surveys were prospectively collected at baseline (before initiation of RT or ADT), and 2, 6, 12, 18, and 24 months following completion of RT. To assign post-RT follow-up periods to the actual survey date of completion, the closest follow-up period was chosen, but the survey was never assigned to a period that was later than the actual survey. For example, in the absence of a 12-month survey, an available 15-month survey would be recorded under the “12-month” time point. Global scores were generated for the EPIC-26 sexual questions, ranging from 0 to 100 (full health). Table 1 describes the patient population. All men were treated with IMRT. The planning target volume (PTV) was generally 0.5-0.8 cm around the prostate; the proximal 2 cm of the seminal vesicles were also included in an initial PTV for men with intermediate-risk disease. Pelvic lymph nodes were treated in 31% of men using IMRT at physician discretion based on risk of pelvic lymph node
Baseline patient characteristics
Median age (IQR) Race Caucasian African American Other History of tobacco use Diabetes Median dose, Gy (IQR) Median ADT duration, mo (IQR) T stage T1-T2a T2b-T2c T3-T4 Median PSA (IQR) Gleason score 6 7 8 9
Total (N = 179)
No hormonal therapy (N = 79)
Hormonal therapy (N = 100)
P value
69 (63-74)
69 (64-73)
67.5 (63-74)
.99
26% 72% 2% 67% 18% 76 (75.6-78)
18% 77% 5% 69% 21% 76 (75.6-78) 0
32% 68% 0% 65% 16% 76.4 (76.5-78) 5 (3.1-19.6)
.01
69% 15% 15% 9 (5.7-14.9)
89% 10% 0% 7.1 (5.0-10.5)
53% 20% 27% 11.11 (6.9-25.3)
b .0001
31% 46% 14% 9%
52% 46% 1% 0%
14% 46% 24% 16%
b .0001
ADT, androgen deprivation therapy; IQR, interquartile range; PSA, prostate-specific antigen.
.66 .34 .0016
.02
Practical Radiation Oncology: May-June 2015
Sexual function after prostate cancer RT
Figure 1 Median global sexual function score over time for all patients. The diamond marker represents scores that were significantly different (P b .05) at each time point from baseline score. SE, standard error.
involvement, with a PTV defined by a 1.5-cm expansion around the pelvic vessels. ADT was administered at the discretion of the treating physician to 59% of patients and generally initiated 2 months before IMRT. Duration of therapy was known in 85 of 100 patients who received ADT, and 84% of these patients received ≤ 12 months of therapy. Neoadjuvant and concurrent ADT typically consisted of dual androgen blockade with an antiandrogen and luteinizing hormone-releasing hormone agonist. Adjuvant ADT consisted of the luteinizing hormonereleasing hormone agonist only.
Statistical analysis Percentages of men with moderate/severe distress in each EPIC-26 QOL domain were tabulated at each time point and tested for an association with ADT, tobacco use, diabetes, and age by chi-square analysis. The global health score was tested for an association with ADT at each time point. Categorical groups were compared by chi-square analysis,
Table 2
and continuous variables were compared by the 2-sided t-test, with statistical significance defined as P b .05. We performed a longitudinal analysis to assess the QOL measures at baseline and each visit following RT. All analyses were performed using generalized estimation equations (GEE) with patients as the grouping variable and with an exchangeable correlation structure. This technique addresses the within-person correlation structure and provides robust standard errors. 14 Separate GEE models were conducted for the end points of “overall sexuality problem,” sexual function global score, and likelihood of benefit from a PDE inhibitor. Univariate modeling using the GEE was used to identify factors associated with changes in QOL over time. Although the GEE model controls for missing data points (including baseline surveys), separate GEE analyses were also conducted incorporating baseline sexual function as a covariate to verify that overall conclusions were not altered by inclusion of men without baseline surveys.
Results Fig 1 describes global sexual function score over time for all patients. Table 2 describes the median global scores and proportion of patients with symptoms based on whether they were treated with or without ADT. There was a significant difference between those who received ADT and those who did not across multiple sexual function domains at the time points of 2-6 months. However, by 24 months, the only significant difference was in the likelihood to be sexually active. Including men who received ≤ 12 months of ADT only, 34% of men treated with combined ADT and RT (n = 54) were sexually active at 24 months, compared to 46% of men treated with RT alone (n = 67, P = .16). Meanwhile, for men who had good sexual function at baseline (n = 41), the proportion of men with poor sexual function was 44% at 2 months, 43% at 6 months, 34% at 12 months, 38% at 18 months, and 51% at 24 months.
Percent of symptomatic men, with/without androgen deprivation therapy
Median global score (0-100) Poor erections Difficulty with orgasm Erections not firm Sexually active Poor sexual function Considered a problem a
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P b .05.
Baseline (n = 79)
2 mo (n = 99)
6 mo (n = 106)
12 mo (n = 116)
18 mo (n = 129)
24 mo (n = 158)
46/52 46/49 50/37 64/59 41/60 49/47 46/41
21/44 a 75/49 a 70/42 a 86/56 a 20/61 a 73/43 a 39/35
21/39 71/54 64/46 85/65 a 25/53 a 70/52 37/26
32/39 58/61 52/57 74/72 31/39 63/56 33/27
32/39 61/61 58/48 63/68 34/49 62/57 59/33
27/35 63/58 62/53 78/68 27/46 a 68/63 39/43
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Use of sexual medications and devices (percentage) reported at each time point a Baseline (n = 79)
2 mo (n = 99)
6 mo (n = 106)
12 mo (n = 116)
18 mo (n = 129)
24 mo (n = 158)
Patients attempting use of PDE inhibitor Benefited from PDE inhibitor
40 72
33 82
39 70
40 65
46 66
50 66
Patients attempting use of vacuum erection device Benefited from vacuum erection device
2 50
1 100
4 50
5 80
6 71
9 36
Patients attempting use of urethral suppository Benefited from urethral suppository
4 33
2 50
4 75
3 0
3 0
1 0
1 0
1 100
4 75
2 50
3 33
3 66
Patients attempting use of penile injection Benefited from penile injection
PDE, phosphodiesterase. a Includes all experience using medications or devices prior to survey time point.
Table 3 describes the use of sexual medications and devices and the likelihood of benefit. Fewer than 50% of patients attempted use of PDE inhibitors at any time point, although more than two-thirds of those who did reported benefit. At 2 months and 6 months, patients on ADT were less likely to attempt use of PDE inhibitors (22% vs 49% at 2 months and 30% vs 50% at 6 months, all P b .05). However, there was no statistically significant difference between those who received ADT versus no ADT in terms of likelihood of benefit from PDE inhibitors at any time point. Only a very small proportion of patients (b 10%) attempted use of other interventions, including vacuum erection device, urethral suppository, or penile injection, despite the routine offer to try these or be referred to urology. GEE longitudinal analysis of global sexual score revealed changes over time between the ADT and no ADT patients
(Fig 2). Using the end point of global sexual score, there was an association with duration of hormone therapy (P = .002, coefficient − 0.656). There was no association with diabetes, race, risk category, Gleason grade (P = .054), tobacco history, or use of hormone therapy. A bivariate analysis incorporating baseline sexual function confirmed that there was an association with duration of ADT in those receiving ADT (P = .05, coefficient − 0.637) as well as use of hormone therapy (P = .005, coefficient − 12.2), but no association with other covariates. Analyzing the end point of overall sexuality problem, the GEE model revealed an association with diabetes (odds ratio 2.45, P = .05). Race, Gleason grade, risk category, ADT duration, tobacco history, and use of hormone therapy were not associated with the overall sexuality problem. After incorporating the baseline score, the GEE model revealed no association with diabetes. Of note, patients with a baseline score available had no difference in tobacco history, diabetes history, use of ADT, or length of ADT compared with men without a baseline score available. There was no clinical variable that was associated with greater likelihood of response to PDE inhibitor therapy.
Discussion
Figure 2 Median global sexual function score over time by androgen deprivation therapy (ADT) use. The diamond marker represents scores that were significantly different (P b .05) at each time point from baseline score for the ADT and no ADT patients. The cross marker represents scores that were significantly different between the ADT and no ADT patients at that time point. Error bars indicate standard error (SE).
Although several reports describe sexual function after RT, many of these were published in the era of standard dose, 3-dimensional conformal RT and are derived from retrospectively collected patient data. 6 -12 More recently published studies address QOL post-IMRT, 15 -17 but few report specifically on sexual function using the EPIC scale, the impact of ADT on sexual medicines, or the time to recovery. In this study, we report the results of prospective, longitudinally obtained data (using the validated EPIC questionnaire) in patients who underwent dose-escalated IMRT with or without ADT. Overall, we did observe a mild decline in sexual function in the 2-year period
Practical Radiation Oncology: May-June 2015
following IMRT. ADT (median 5 months) did negatively impact sexual function, but this effect appeared to be limited to the 2-6 months post-RT. Meanwhile, PDE inhibitors were commonly used and helpful for the majority of patients, whether or not they received ADT. Notably, other non-oral medications or sexual aids were much less commonly used, despite the fact that these alternatives were routinely presented to patients. Regarding the impact of RT on sexual function, large cohort studies by Sanda et al. and Ferrer et al. using the EPIC survey demonstrated similar results, with an approximately 10-point drop in global sexual score at 2 years 18 and 5 years 19 following irradiation in a group of patients receiving no ADT. Follow-up in the study by Ferrer and colleagues demonstrated continuing decline of sexual function (as measured by the ability to have firm erections) through 5 years, although it is unclear how much increasing age and the use of salvage ADT contributed in these patients. Of note, patients receiving ADT in the study by Sanda et al. had a more marked and longer decline in sexual function compared with patients in our study. Significant differences in global sexual score persisted through 2 years of follow-up; factors associated with sexual outcome included age, prostate size, and neoadjuvant ADT. Our results suggest recovery of sexual score by 2 years, perhaps attributable to differences in duration of ADT, radiation treatment parameters, or in the patient populations. The reported magnitude of the effect of ADT is variable, with some studies showing little to no effect of ADT on sexual function, 6 whereas others note that both sexual function and the response to PDE inhibitors are significantly affected by ADT. 9 Chen et al. noted that although those receiving ADT were less likely to be potent at 1 year following radiation, they were also less likely to be potent before all therapy. After accounting for this by looking at the difference in function from baseline, they noted that the change in function between the 2 groups was not different. 6 Similarly, Zelefsky et al. reported on the use of oral sildenafil in 50 patients, 36% of whom received neoadjuvant and concurrent ADT; they noted no difference in response to sildenafil in these patients. 12 However, Teloken et al. noted that patients treated with ADT had a 47% response rate to sildenafil at a follow-up time of N 24 months compared with 61% (P = .032) in the RT-only group. 9 This discrepancy may be attributable to varying duration of ADT and follow-up times, small sample sizes, and differences in the definition of sexual function and potency. Our results (Table 2, Fig 1) demonstrate the most marked difference in the ADT patients at a time point of 2-6 months following therapy—a time point at which patients are typically castrate (median ADT duration was 5 months), leading to a loss of libido as well as function. The difference in sexual function may be partially accounted for by a difference in the proportion of patients who attempted use of a PDE inhibitor during this same
Sexual function after prostate cancer RT
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time frame (Table 2). However, by 2 years after IMRT, the only significant difference in function between those receiving ADT versus no ADT is in the proportion of patients that remain sexually active. Analysis of those who had ≤ 12 months of ADT revealed that, by 24 months, these patients were not less likely to be sexually active compared with those who never received ADT, suggesting there is some recovery of sexual function. At no time point was there a significant difference in the percentage of patients that perceived sexual function to be a problem. This may be due to the fact that higher risk patients may have a greater awareness of potential cancer-related morbidity and mortality, and less concern for sexual QOL. Other factors suggested to increase the risk of impotence include older age 6,8 and diabetes. 8 Good baseline sexual function is predictive of maintained potency after radiation 8 and response to sexual therapy. 12 Similarly, we found that those with good pre-IMRT function were more likely to respond to PDE inhibitors. However, there were no clinical factors other than use of hormonal therapy, or duration of hormone therapy, that were associated with the global sexuality score or likelihood of benefiting from a PDE inhibitor. In our study, we assessed the utility of a number of sexual medications and aids. Only a very small proportion of men in our study attempted use of other, non-PDE inhibitor interventions (vacuum erection device, urethral suppository, or penile injection) with variable efficacy, although it was customary to advise men in follow-up that several aids to improve sexual function exist. The cause for the relative lack of use of these non-oral medications would be presumed to be the perceived relative difficulty of use, but we did not collect data to verify this point. Further studies, and perhaps improved patient educational tools, may be valuable to maximize sexual QOL in men receiving RT and ADT. Limitations of our study include a relatively small sample size of patients as well as varying numbers of patient responses at each time point, although longitudinal analysis (GEE model) was used to minimize this effect. Our follow-up time is limited to 24 months and may not capture further deterioration that could be treatment- or age-related. Although the patients were treated over a period of 10 years, similar dose, target volume delineation methods, and treatment planning goals were in use during this time. We do not anticipate that changes in image guidance (eg, from use of ultrasound to prostatic fiducial markers) would have significantly impacted dose to the sexual organs or sexual function. Strengths of our study include prospective collection of longitudinal data in patients who are treated with current standard of care therapy (dose-escalated IMRT with or without ADT). Although the studies by Sanda et al. and Ferrer et al. included patients who received radiation using 3-dimensional conformal techniques, 18,19 all patients in this study received IMRT, and factors associated with outcome were studied.
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Conclusion The addition of ADT to dose-escalated IMRT has a modest impact on sexual function, with the most striking effect within 6 months of the completion of radiation. This appears to resolve by a time point of 24 months following RT, provided that only a short (b 12 months) course of ADT is administered. There appeared to be no difference in the efficacy of PDE inhibitors, although more patients who received IMRT alone attempted it compared with those who also received ADT. The results of this study can be useful to counsel patients regarding the anticipated impact of IMRT and ADT on sexual QOL in men with localized prostate cancer.
References 1. American Cancer Society. Cancer Facts & Figures. Available at: http:// www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/ cancer-facts-figures 2013. Accessed October 23, 2014. 2. Nguyen PL, Chen MH, Beard CJ, et al. Radiation with or without 6 months of androgen suppression therapy in intermediate- and high-risk clinically localized prostate cancer: A postrandomization analysis by risk group. Int J Radiat Oncol Biol Phys. 2010;77:1046-1052. 3. Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011;365:107-118. 4. Hanks GE, Pajak TF, Porter A, et al. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol. 2003;21:3972-3978. 5. Bolla M, de Reijke TM, Van Tienhoven F, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009;360:2516-2527. 6. Chen CT, Valicenti RK, Lu J, et al. Does hormonal therapy influence sexual function in men receiving 3D conformal radiation therapy for prostate cancer? Int J Radiat Oncol Biol Phys. 2001;50:591-595.
Practical Radiation Oncology: May-June 2015 7. Ohebshalom M, Parker M, Guhring P, Mulhall JP. The efficacy of sildenafil citrate following radiation therapy for prostate cancer: Temporal considerations. J Urol. 2005;174:258-262. 8. Pinkawa M, Gagel B, Piroth MD, et al. Erectile dysfunction after external beam radiotherapy for prostate cancer. Eur Urol. 2009;55: 227-234. 9. Teloken PE, Ohebshalom M, Mohideen N, Mulhall JP. Analysis of the impact of androgen deprivation therapy on sildenafil citrate response following radiation therapy for prostate cancer. J Urol. 2007;178:2521-2525. 10. Turner SL, Adams K, Bull CA, Berry MP. Sexual dysfunction after radical radiation therapy for prostate cancer: A prospective evaluation. Urology. 1999;54:124-129. 11. Valicenti RK, Bissonette EA, Chen C, Theodorescu D. Longitudinal comparison of sexual function after 3-dimensional conformal radiation therapy or prostate brachytherapy. J Urol. 2002;168:2499-2504. 12. Zelefsky MJ, McKee AB, Lee H, Leibel SA. Efficacy of oral sildenafil in patients with erectile dysfunction after radiotherapy for carcinoma of the prostate. Urology. 1999;53:775-778. 13. Szymanski KM, Wei JT, Dunn RL, Sana MG. Development and validation of an abbreviated version of the expanded prostate cancer index composite instrument for measuring health-related quality of life among prostate cancer survivors. Urology. 2010;76:1245-1250. 14. Corbin KS, Kunnavakkam R, Eggener SE, Liauw SL. Intensity modulated radiation therapy after radical prostatectomy: Early results show no decline in urinary continence, gastrointestinal, or sexual quality of life. Pract Radiat Oncol. 2013;3:138-144. 15. Hoppe BS, Michalski JM, Mendenhall NP, et al. Comparative effectiveness study of patient-reported outcomes after proton therapy or intensity-modulated radiotherapy for prostate cancer. Cancer. 2014;120:1076-1082. 16. Spratt D, Pei X, Yamada J, Kollmeier MA, Cox B, Zelefshy MJ. Long-term survival and toxicity in patients treated with high-dose intensity modulated radiation therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2013;85:686-692. 17. Gray PJ, Paly JJ, Yeap BY, et al. Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. Cancer. 2013;119:1729-1735. 18. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 2008;358:1250-1261. 19. Ferrer M, Guedea F, Suárez JF, et al. Quality of life impact of treatments for localized prostate cancer: Cohort study with a 5 year follow-up. Radiother Oncol. 2013;108:306-313.
www.practicalradonc.org
Original Report
The impact of hormonal therapy on sexual quality of life in men receiving intensity modulated radiation therapy for prostate cancer Christina H. Son MD a , Sravana K. Chennupati MD b , Rangesh Kunnavakkam MS c , Stanley L. Liauw MD a,⁎ a
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon c Department of Health Studies, University of Chicago, Chicago, Illinois b
Received 28 July 2014; revised 13 October 2014; accepted 15 October 2014
Abstract Purpose: Sexual function is an important concern in men receiving intensity modulated radiation therapy (IMRT) for prostate cancer. Our aim was to study the impact of IMRT and androgen deprivation therapy (ADT) on sexual function over time and to report the effectiveness of sexual medications or aids. Methods and materials: A total of 179 men, median age 69, received definitive IMRT for prostate cancer and completed 2 surveys (Expanded Prostate Cancer Index Composite-26 and a sexual medicines/devices survey) for at least 2 time points. Surveys were prospectively collected at baseline (before all therapy), and 2, 6, 12, 18, and 24 months after IMRT. Median dose was 76 Gy to the prostate. ADT was administered to 59% of patients (median duration 5 months, initiated 2 months before IMRT). Global scores were generated for the Expanded Prostate Cancer Index Composite-26 questions. Longitudinal analysis was performed by constructing a generalized estimation equations model, and clinical variables were tested for association with global scores. Results: Overall, there was a significant decline in global sexual score through 2 years. Men receiving ADT had a lower sexual score at 2 and 6 months, but this difference disappeared at 24 months. Analysis of individual sexual symptoms showed no significant difference at 24 months except that men on ADT were less likely to be sexually active (P = .02); this difference was not observed for men receiving short-term ADT only. Longitudinal analysis revealed that duration of ADT was the only factor associated with global sexual score. Phosphodiesterase inhibitors were attempted by roughly half of all men, with 66% experiencing benefit, whereas other aids were attempted by roughly 5% of men. Conclusions: Although ADT adversely affected short-term sexual function, there was no significant difference in global score and most sexual symptoms by 24 months. These data are useful for anticipatory guidance regarding expectations after IMRT. © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Conflicts of interest: None. ⁎ Corresponding author. Department of Radiation and Cellular Oncology, University of Chicago, 5758 South Maryland Avenue, MC 9006, Chicago, IL 60637. E-mail address: [email protected] (S.L. Liauw). http://dx.doi.org/10.1016/j.prro.2014.10.003 1879-8500/© 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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C.H. Son et al
Practical Radiation Oncology: May-June 2015
we report on the utility of sexual aids, including PDE inhibitors, in both groups of men.
Introduction Prostate cancer is the most common cancer diagnosed in men in the United States. 1 Several treatment options exist, including radical prostatectomy, brachytherapy, or external beam radiation therapy, and many men choose to undergo external beam radiation. Multiple randomized trials have demonstrated a survival advantage with the addition of androgen deprivation therapy (ADT) to radiation in those with higher risk disease: for those with intermediate-risk prostate cancer, short-term ADT (4-6 months) is often prescribed, 2,3 whereas for those with highest risk disease, long-term ADT (N 2 years) has become standard of care. 4,5 Unfortunately, both ADT and radiation therapy (RT) can cause sexual dysfunction, leading to a significant impact on quality of life (QOL) for many men. Medications such as phosphodiesterase-5 (PDE) inhibitors or sexual aids, such as vacuum erection devices, are commonly prescribed to manage sexual symptoms. Although worsening of sexual QOL may be expected with the addition of ADT to RT, there are few, if any, prospective reports studying the impact of ADT on sexual function and response to sexual aids in men who receive dose-escalated intensity modulated RT (IMRT). Prior studies using older radiation techniques and lower doses confirm an overall worsening of sexual function after RT, with varying conclusions regarding the effect of ADT on sexual QOL and response to medication. 6 -12 In this study, we report the results of prospectively obtained longitudinal data in patients who underwent dose-escalated IMRT with or without ADT. Additionally, Table 1
Methods and materials Men treated with definitive RT for prostate cancer between 2001 and 2010 at an academic institution were identified in an institutional database. Written informed consent was obtained from all patients with ongoing follow-up. This study was approved by the hospital’s institutional review board. All men completed 2 surveys, the Expanded Prostate Cancer Index Composite-26 (EPIC) 13 and a sexual medicines/devices survey, for at least 2 time points. Surveys were prospectively collected at baseline (before initiation of RT or ADT), and 2, 6, 12, 18, and 24 months following completion of RT. To assign post-RT follow-up periods to the actual survey date of completion, the closest follow-up period was chosen, but the survey was never assigned to a period that was later than the actual survey. For example, in the absence of a 12-month survey, an available 15-month survey would be recorded under the “12-month” time point. Global scores were generated for the EPIC-26 sexual questions, ranging from 0 to 100 (full health). Table 1 describes the patient population. All men were treated with IMRT. The planning target volume (PTV) was generally 0.5-0.8 cm around the prostate; the proximal 2 cm of the seminal vesicles were also included in an initial PTV for men with intermediate-risk disease. Pelvic lymph nodes were treated in 31% of men using IMRT at physician discretion based on risk of pelvic lymph node
Baseline patient characteristics
Median age (IQR) Race Caucasian African American Other History of tobacco use Diabetes Median dose, Gy (IQR) Median ADT duration, mo (IQR) T stage T1-T2a T2b-T2c T3-T4 Median PSA (IQR) Gleason score 6 7 8 9
Total (N = 179)
No hormonal therapy (N = 79)
Hormonal therapy (N = 100)
P value
69 (63-74)
69 (64-73)
67.5 (63-74)
.99
26% 72% 2% 67% 18% 76 (75.6-78)
18% 77% 5% 69% 21% 76 (75.6-78) 0
32% 68% 0% 65% 16% 76.4 (76.5-78) 5 (3.1-19.6)
.01
69% 15% 15% 9 (5.7-14.9)
89% 10% 0% 7.1 (5.0-10.5)
53% 20% 27% 11.11 (6.9-25.3)
b .0001
31% 46% 14% 9%
52% 46% 1% 0%
14% 46% 24% 16%
b .0001
ADT, androgen deprivation therapy; IQR, interquartile range; PSA, prostate-specific antigen.
.66 .34 .0016
.02
Practical Radiation Oncology: May-June 2015
Sexual function after prostate cancer RT
Figure 1 Median global sexual function score over time for all patients. The diamond marker represents scores that were significantly different (P b .05) at each time point from baseline score. SE, standard error.
involvement, with a PTV defined by a 1.5-cm expansion around the pelvic vessels. ADT was administered at the discretion of the treating physician to 59% of patients and generally initiated 2 months before IMRT. Duration of therapy was known in 85 of 100 patients who received ADT, and 84% of these patients received ≤ 12 months of therapy. Neoadjuvant and concurrent ADT typically consisted of dual androgen blockade with an antiandrogen and luteinizing hormone-releasing hormone agonist. Adjuvant ADT consisted of the luteinizing hormonereleasing hormone agonist only.
Statistical analysis Percentages of men with moderate/severe distress in each EPIC-26 QOL domain were tabulated at each time point and tested for an association with ADT, tobacco use, diabetes, and age by chi-square analysis. The global health score was tested for an association with ADT at each time point. Categorical groups were compared by chi-square analysis,
Table 2
and continuous variables were compared by the 2-sided t-test, with statistical significance defined as P b .05. We performed a longitudinal analysis to assess the QOL measures at baseline and each visit following RT. All analyses were performed using generalized estimation equations (GEE) with patients as the grouping variable and with an exchangeable correlation structure. This technique addresses the within-person correlation structure and provides robust standard errors. 14 Separate GEE models were conducted for the end points of “overall sexuality problem,” sexual function global score, and likelihood of benefit from a PDE inhibitor. Univariate modeling using the GEE was used to identify factors associated with changes in QOL over time. Although the GEE model controls for missing data points (including baseline surveys), separate GEE analyses were also conducted incorporating baseline sexual function as a covariate to verify that overall conclusions were not altered by inclusion of men without baseline surveys.
Results Fig 1 describes global sexual function score over time for all patients. Table 2 describes the median global scores and proportion of patients with symptoms based on whether they were treated with or without ADT. There was a significant difference between those who received ADT and those who did not across multiple sexual function domains at the time points of 2-6 months. However, by 24 months, the only significant difference was in the likelihood to be sexually active. Including men who received ≤ 12 months of ADT only, 34% of men treated with combined ADT and RT (n = 54) were sexually active at 24 months, compared to 46% of men treated with RT alone (n = 67, P = .16). Meanwhile, for men who had good sexual function at baseline (n = 41), the proportion of men with poor sexual function was 44% at 2 months, 43% at 6 months, 34% at 12 months, 38% at 18 months, and 51% at 24 months.
Percent of symptomatic men, with/without androgen deprivation therapy
Median global score (0-100) Poor erections Difficulty with orgasm Erections not firm Sexually active Poor sexual function Considered a problem a
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P b .05.
Baseline (n = 79)
2 mo (n = 99)
6 mo (n = 106)
12 mo (n = 116)
18 mo (n = 129)
24 mo (n = 158)
46/52 46/49 50/37 64/59 41/60 49/47 46/41
21/44 a 75/49 a 70/42 a 86/56 a 20/61 a 73/43 a 39/35
21/39 71/54 64/46 85/65 a 25/53 a 70/52 37/26
32/39 58/61 52/57 74/72 31/39 63/56 33/27
32/39 61/61 58/48 63/68 34/49 62/57 59/33
27/35 63/58 62/53 78/68 27/46 a 68/63 39/43
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Use of sexual medications and devices (percentage) reported at each time point a Baseline (n = 79)
2 mo (n = 99)
6 mo (n = 106)
12 mo (n = 116)
18 mo (n = 129)
24 mo (n = 158)
Patients attempting use of PDE inhibitor Benefited from PDE inhibitor
40 72
33 82
39 70
40 65
46 66
50 66
Patients attempting use of vacuum erection device Benefited from vacuum erection device
2 50
1 100
4 50
5 80
6 71
9 36
Patients attempting use of urethral suppository Benefited from urethral suppository
4 33
2 50
4 75
3 0
3 0
1 0
1 0
1 100
4 75
2 50
3 33
3 66
Patients attempting use of penile injection Benefited from penile injection
PDE, phosphodiesterase. a Includes all experience using medications or devices prior to survey time point.
Table 3 describes the use of sexual medications and devices and the likelihood of benefit. Fewer than 50% of patients attempted use of PDE inhibitors at any time point, although more than two-thirds of those who did reported benefit. At 2 months and 6 months, patients on ADT were less likely to attempt use of PDE inhibitors (22% vs 49% at 2 months and 30% vs 50% at 6 months, all P b .05). However, there was no statistically significant difference between those who received ADT versus no ADT in terms of likelihood of benefit from PDE inhibitors at any time point. Only a very small proportion of patients (b 10%) attempted use of other interventions, including vacuum erection device, urethral suppository, or penile injection, despite the routine offer to try these or be referred to urology. GEE longitudinal analysis of global sexual score revealed changes over time between the ADT and no ADT patients
(Fig 2). Using the end point of global sexual score, there was an association with duration of hormone therapy (P = .002, coefficient − 0.656). There was no association with diabetes, race, risk category, Gleason grade (P = .054), tobacco history, or use of hormone therapy. A bivariate analysis incorporating baseline sexual function confirmed that there was an association with duration of ADT in those receiving ADT (P = .05, coefficient − 0.637) as well as use of hormone therapy (P = .005, coefficient − 12.2), but no association with other covariates. Analyzing the end point of overall sexuality problem, the GEE model revealed an association with diabetes (odds ratio 2.45, P = .05). Race, Gleason grade, risk category, ADT duration, tobacco history, and use of hormone therapy were not associated with the overall sexuality problem. After incorporating the baseline score, the GEE model revealed no association with diabetes. Of note, patients with a baseline score available had no difference in tobacco history, diabetes history, use of ADT, or length of ADT compared with men without a baseline score available. There was no clinical variable that was associated with greater likelihood of response to PDE inhibitor therapy.
Discussion
Figure 2 Median global sexual function score over time by androgen deprivation therapy (ADT) use. The diamond marker represents scores that were significantly different (P b .05) at each time point from baseline score for the ADT and no ADT patients. The cross marker represents scores that were significantly different between the ADT and no ADT patients at that time point. Error bars indicate standard error (SE).
Although several reports describe sexual function after RT, many of these were published in the era of standard dose, 3-dimensional conformal RT and are derived from retrospectively collected patient data. 6 -12 More recently published studies address QOL post-IMRT, 15 -17 but few report specifically on sexual function using the EPIC scale, the impact of ADT on sexual medicines, or the time to recovery. In this study, we report the results of prospective, longitudinally obtained data (using the validated EPIC questionnaire) in patients who underwent dose-escalated IMRT with or without ADT. Overall, we did observe a mild decline in sexual function in the 2-year period
Practical Radiation Oncology: May-June 2015
following IMRT. ADT (median 5 months) did negatively impact sexual function, but this effect appeared to be limited to the 2-6 months post-RT. Meanwhile, PDE inhibitors were commonly used and helpful for the majority of patients, whether or not they received ADT. Notably, other non-oral medications or sexual aids were much less commonly used, despite the fact that these alternatives were routinely presented to patients. Regarding the impact of RT on sexual function, large cohort studies by Sanda et al. and Ferrer et al. using the EPIC survey demonstrated similar results, with an approximately 10-point drop in global sexual score at 2 years 18 and 5 years 19 following irradiation in a group of patients receiving no ADT. Follow-up in the study by Ferrer and colleagues demonstrated continuing decline of sexual function (as measured by the ability to have firm erections) through 5 years, although it is unclear how much increasing age and the use of salvage ADT contributed in these patients. Of note, patients receiving ADT in the study by Sanda et al. had a more marked and longer decline in sexual function compared with patients in our study. Significant differences in global sexual score persisted through 2 years of follow-up; factors associated with sexual outcome included age, prostate size, and neoadjuvant ADT. Our results suggest recovery of sexual score by 2 years, perhaps attributable to differences in duration of ADT, radiation treatment parameters, or in the patient populations. The reported magnitude of the effect of ADT is variable, with some studies showing little to no effect of ADT on sexual function, 6 whereas others note that both sexual function and the response to PDE inhibitors are significantly affected by ADT. 9 Chen et al. noted that although those receiving ADT were less likely to be potent at 1 year following radiation, they were also less likely to be potent before all therapy. After accounting for this by looking at the difference in function from baseline, they noted that the change in function between the 2 groups was not different. 6 Similarly, Zelefsky et al. reported on the use of oral sildenafil in 50 patients, 36% of whom received neoadjuvant and concurrent ADT; they noted no difference in response to sildenafil in these patients. 12 However, Teloken et al. noted that patients treated with ADT had a 47% response rate to sildenafil at a follow-up time of N 24 months compared with 61% (P = .032) in the RT-only group. 9 This discrepancy may be attributable to varying duration of ADT and follow-up times, small sample sizes, and differences in the definition of sexual function and potency. Our results (Table 2, Fig 1) demonstrate the most marked difference in the ADT patients at a time point of 2-6 months following therapy—a time point at which patients are typically castrate (median ADT duration was 5 months), leading to a loss of libido as well as function. The difference in sexual function may be partially accounted for by a difference in the proportion of patients who attempted use of a PDE inhibitor during this same
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time frame (Table 2). However, by 2 years after IMRT, the only significant difference in function between those receiving ADT versus no ADT is in the proportion of patients that remain sexually active. Analysis of those who had ≤ 12 months of ADT revealed that, by 24 months, these patients were not less likely to be sexually active compared with those who never received ADT, suggesting there is some recovery of sexual function. At no time point was there a significant difference in the percentage of patients that perceived sexual function to be a problem. This may be due to the fact that higher risk patients may have a greater awareness of potential cancer-related morbidity and mortality, and less concern for sexual QOL. Other factors suggested to increase the risk of impotence include older age 6,8 and diabetes. 8 Good baseline sexual function is predictive of maintained potency after radiation 8 and response to sexual therapy. 12 Similarly, we found that those with good pre-IMRT function were more likely to respond to PDE inhibitors. However, there were no clinical factors other than use of hormonal therapy, or duration of hormone therapy, that were associated with the global sexuality score or likelihood of benefiting from a PDE inhibitor. In our study, we assessed the utility of a number of sexual medications and aids. Only a very small proportion of men in our study attempted use of other, non-PDE inhibitor interventions (vacuum erection device, urethral suppository, or penile injection) with variable efficacy, although it was customary to advise men in follow-up that several aids to improve sexual function exist. The cause for the relative lack of use of these non-oral medications would be presumed to be the perceived relative difficulty of use, but we did not collect data to verify this point. Further studies, and perhaps improved patient educational tools, may be valuable to maximize sexual QOL in men receiving RT and ADT. Limitations of our study include a relatively small sample size of patients as well as varying numbers of patient responses at each time point, although longitudinal analysis (GEE model) was used to minimize this effect. Our follow-up time is limited to 24 months and may not capture further deterioration that could be treatment- or age-related. Although the patients were treated over a period of 10 years, similar dose, target volume delineation methods, and treatment planning goals were in use during this time. We do not anticipate that changes in image guidance (eg, from use of ultrasound to prostatic fiducial markers) would have significantly impacted dose to the sexual organs or sexual function. Strengths of our study include prospective collection of longitudinal data in patients who are treated with current standard of care therapy (dose-escalated IMRT with or without ADT). Although the studies by Sanda et al. and Ferrer et al. included patients who received radiation using 3-dimensional conformal techniques, 18,19 all patients in this study received IMRT, and factors associated with outcome were studied.
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Conclusion The addition of ADT to dose-escalated IMRT has a modest impact on sexual function, with the most striking effect within 6 months of the completion of radiation. This appears to resolve by a time point of 24 months following RT, provided that only a short (b 12 months) course of ADT is administered. There appeared to be no difference in the efficacy of PDE inhibitors, although more patients who received IMRT alone attempted it compared with those who also received ADT. The results of this study can be useful to counsel patients regarding the anticipated impact of IMRT and ADT on sexual QOL in men with localized prostate cancer.
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