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Long-term erectile function following permanent seed brachytherapy treatment for localized prostate cancer

Radiother Oncol. 2014 Jul;112(1):72-6.

Comment from Henk van der Poel: The more gradual development of erectile dysfunction after brachytherapy as compared to prostatectomy render short term comparisons in erectile function outcome between the two approaches cumbersome.  At 5 years 41% reported erectile dysfunction. Interestingly, Gleason score was predictive of postoperative erectile function recovery.

Abstract

Background and purpose

Erectile function (EF) is commonly affected following prostate cancer treatment. We aim to evaluate the long-term EF following seed brachytherapy (BT) treatment.

Materials and methods

The study consisted of 366 patients treated with BT at our institution, who completed the IIEF-5 questionnaire and reported no or mild erectile dysfunction (ED) pre-BT. The probability of EF preservation post-BT was estimated using the Kaplan–Meier methods. The difference in EF preservation by patient-, tumour- and treatment-related factors was assessed using the log-rank test. Multivariate Cox regression was used to estimate the effect of each factor on EF preservation.

Results

Of the 366 patients, 277 (76%) reported normal EF, and 89 (24%) reported mild ED. The patients were followed-up for a median of 41 months (range: 3–124), and the 5-year actuarial rate of EF preservation was 59%. Age at BT seed implant, presence of medical comorbidities, Gleason score and the biologically effective dose (BED) are associated with EF preservation (P < 0.005). The association for these four factors remains statistically significant in multivariate analysis, with Gleason score having the strongest effect (HR = 3.7; 95% CI = 2.6–5.4).

Conclusion

The 5-year actuarial rate of EF preservation post-BT in our cohort is 59%, and is influenced by multiple factors.

Keywords: Prostate cancer, Brachytherapy, Erectile function.

The main treatment modalities for localized prostate cancer are radical prostatectomy (RP), external beam radiotherapy (EBRT) and permanent seed implant brachytherapy (BT); however, none has been proven to be superior to the others in terms of cancer control [1] . This has made the understanding of the health related quality of life (HRQOL) outcomes, including sexual, urinary and bowel function, associated with each treatment modalities important. Each of these treatment modalities is associated with distinct pattern of changes in the HRQOL outcomes [2] , and patients make decision on their treatment based on this information[3] and [4].

It has been suggested that sexual function is the most commonly impaired of all the HRQOL outcome domains, and is closely related with outcome satisfaction [5] . However, it is difficult to precisely quantify treatment-related erectile dysfunction. There were inconsistent findings as to which treatment modalities are associated with worse sexual function in short term follow-up studies (less than 2 years)[6] and [7]. Longer follow-up studies of 3–4 years appeared to suggest that patients treated with BT have better sexual function preservation compared to EBRT and RP[5], [8], and [9]. Even among patients treated with BT, erectile function post-treatment has yet to be fully characterized, with a wide range of post-treatment erectile dysfunction incidence reported, possibly due to differences in patient selection for treatment and erectile function assessment methods[10], [11], [12], and [13].

The primary aim of this study is to prospectively evaluate the long-term erectile function (EF) in an Australian cohort of patients with localized prostate cancer treated with BT. The secondary aim is to determine the patient-, tumour- and treatment-factors influencing EF preservation following BT.

Material and methods

Between 1998 and 2011, 822 patients with biopsy-confirmed localized prostate cancer were treated with BT at the William Buckland Radiation Oncology Service (WBRO), Alfred Health. As part of the on-going treatment monitoring, patients completed the International Index of Erectile Function five-item (IIEF-5) questionnaire pre-treatment and at regular follow-up post-treatment. The IIEF-5 is a validated patient-administered diagnostic tool for erectile function [14] . Normal erectile function (EF) was defined as IIEF-5 score of 22–25, mild erectile dysfunction (ED) 17–21, mild-moderate ED 12–16, moderate ED 8–11, and severe ED 0–7 [15] . We reviewed the 389 men who completed the IIEF-5 questionnaire and reported no or mild ED (i.e. IIEF-5 ⩾ 17) prior to treatment. Patients who developed erectile dysfunction at follow-up were assessed clinically with investigations and managed with counselling, medication, vacuum pumps, injectable prostaglandins, or implanted devices as deemed clinically appropriate.

Procedures for BT were performed according to written unit protocol, and patients were implanted with Iodine-125 (125I) seeds, with a prescribed dose of 145 Gy. All patients underwent a CT scan for dosimetric purposes 4 weeks following the implant. The quality of BT radiation dose was quantified with D90(i.e. the minimum dose received by 90% of the prostate tissue) based on this scan, and was converted to biologically effective dose (BED) [16] . Given that the use of external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) is known to influence the erectile function outcomes [13] , 7 patients who were treated with a combination of BT and EBRT as well as 16 patients who had cytoreductive ADT were excluded from our analyses. A ‘pure’ cohort of 366 patients with BT monotherapy formed the final sample for analyses.

Patient factors assessed for association with EF preservation included: age at BT procedure, presence of medical co-morbidities and smoking histories. Medical comorbidities were defined as any history of hypertension (on anti-hypertensive medications), diabetes mellitus (use of oral hyperglycaemic agents or insulin) or ischaemic heart disease (any prior histories of coronary artery bypass grafts or coronary stent insertion). The prostate cancer characteristics included in the analysis were: Gleason score at biopsy, serum PSA level prior to BT treatment, clinical staging and prostate volume. All information was obtained from the medical records at the WBRO and Alfred Health. The study was approved by the Alfred Health Ethics Committee.

Statistical analysis

The primary outcome of interest in this study is the EF preservation. An event is defined as development of worse than mild ED (IIEF-5 < 17) at last follow-up, while the time-to-event is defined as the time from the date of BT seed implantation to last follow-up EF status. If a patient’s IIEF-5 score dropped below 17, but the score increased to 17 or greater at subsequent follow-up – and this was maintained through to the date of last follow-up – then this was not considered an event. The probability of EF preservation was plotted on the Kaplan Meier curves, stratified by each patient-, tumour- and treatment-related factor of interest. The difference in EF preservation between strata for each factor was assessed using the log-rank test, with Bonferroni correction to account for multiple testing (threshold for significance defined asP < 0.005). Univariate Cox proportional hazard regression was used to estimate the effect of each factor on EF preservation, giving a hazard ratio estimate and 95% confidence interval. All factors withP < 0.1 in univariate analysis were included as covariates in multivariate model for Cox regression. For the multivariate Cox regression, a two-sidedP < 0.05 was considered to indicate statistical significance. The proportional hazard assumption was assessed by visually examining the log–log plot and Kaplan Meier observed-predicted function plot, and tested using the Schoenfeld residual test. No evidence of violation of the proportional hazard assumption was apparent. All statistical analyses were performed using STATA/IC 11 (STATA Corp, College Station, Texas).

Results

Table 1 summarizes the demographic, clinical and treatment parameters of the cohort of patients included in our study. Of the 366 patients, 277 (76%) reported normal EF and 89 (24%) reported mild EF pre-treatment. 18 patients (5%) were using phosphodiesterase-5 inhibitors (PDE5i) prior to BT, while post BT treatment, as many as 144 (39%) patients reported to be using PDE5i at some stage during the follow-up period. All patients were followed-up for a median of 41 months (range 3–124 months).

Table 1 Demographic, clinical and treatment parameters of all patients.

Characteristics N = 366
Age of BT seed implant  
 Mean (SD) 62 (±6.7)
 Range 42–80
Smoking – no (%)  
 Never 150 (41%)
 Former (not smoked for >6 months) 125 (34%)
 Current 33 (9%)
 Unknown 58 (16%)
Medical comorbidities – no (%)  
 Type 2 diabetes (on medication/insulin) 8 (2%)
 Hypertension (on medication) 115 (31%)
 Ischaemic heart disease (CABG/stent) 18 (5%)
 T2DM/HTN/IHD 117 (32%)
Prostate size (cc)  
 Mean (SD) 36 (±9)
 Range 14–59
Pre-treatment PSA level (ng/mL) – no (%)  
 <10 354 (97%)
 10–20 12 (3%)
Gleason score – no (%)  
 <7 241 (66%)
 7 125 (34%)
cT category – no (%)  
 <T2b 338 (92%)
 ⩾T2b 28 (8%)
NCCN risk factors – no (%)  
 Low 213 (58%)
 Intermediate 153 (42%)
Use of PDE5 inhibitor – no (%)  
 Pre-treatment 18 (5%)
 Post-treatment 144 (40%)

Fig. 1 shows the proportion of patients in each IIEF-5 category at each follow-up time point. As such it is information about the prevalence of ED following BT. A common situation for our patient was that they had periods during the follow-up whereby in the “last four weeks” (the phrase used in the IIEF-5 survey items) they were not attempting sexual activity, leading to a low score. At other time points they score higher, when they are engaging in sexual activity. Overall, a notable proportion of patients develop moderate–severe ED within the first 3 months post-treatment, and this may reflect a decrease in sexual activity immediately post-BT. However, the proportion of men in each IIEF-5 category appears to stabilize after three-to-nine months. At 2-year and 5-year follow-up, the prevalence of moderate–severe ED was 46% and 53%, respectively.

gr1

Fig. 1 Proportion of men with no or mild erectile dysfunction (ED) pre-brachytherapy treatment in each IIEF-5 category over time.

Using the Kaplan Meier method, the 5-year actuarial rate of EF preservation (i.e. no worse than mild ED) was 59%. Fig. 2 shows the Kaplan Meier curves of the probability of EF preservation for each factor, which reached the statistical significance threshold ofP < 0.005 in stratified analysis using the log-rank test. At 5-year follow-up, patients who had BT seed implant at younger age (<60) have better EF preservation compared to those aged 60 and above (69% vs. 50%;P = 0.001). The 5-year actuarial rate of EF preservation for patients with medical comorbidities (hypertension, diabetes, or ischaemic heart disease) was 47% compared to 64% for those without any of the medical comorbidities (P = 0.001). Comparing patients with Gleason score of less than 7 and 7, the EF preservation at 5-year follow-up was 73% and 18%, respectively (P < 0.001). When stratified by BED, the EF preservation for patients with BED of less than 150 and 150 Gy or more was 74% and 52% respectively (P < 0.001).

gr2

Fig. 2 Kaplan Meier plot for erectile function preservation for each covariate of interest withP < 0.005.

In univariate Cox regression analysis, age at BT seed implant, pre-treatment IIEF5 score, presence of medical comorbidities, Gleason score and BED are statistically significantly associated with EF preservation among patients with mild or no ED before treatment ( Table 2 ). Higher Gleason score is most strongly associated with poorer EF preservation, with a hazard ratio of 4.4 (95% CI = 3.0–6.3). Given that the NCCN risk classifications included the Gleason score, it was not surprising that the patients with NCCN intermediate risk groups were twice more likely to report poorer EF preservation than NCCN low risk group patients (HR = 2.0; 95% CI = 1.5–2.7). For every year increase in age, there is a 5% relative increase in risk of developing worse than mild ED (95% CI = 1.03–1.08), whereas for every unit increase in pre-treatment IIEF-5 score, there is a 9% relative decrease in risk of developing worse than mild ED (95% CI = 0.85–0.96). Patients with diabetes, hypertension or ischaemic heart disease are 1.7 times (95% CI = 1.2–2.3) more likely to develop worse than mild ED. Patients with BED of more than 150 Gy have 1.8 times (95% CI = 1.3–2.4) increased risk of developing moderate or severe ED compared to patients with BED of less than 150 Gy. There is a trend towards better EF preservation with the use of PDE5i post BT treatment; however, the association is not statistically significant (HR = 0.9; 95% CI = 0.7–1.2;P = 0.4).

Table 2 Effects of patient-, tumour-, treatment-related factors on erectile function.

  Univariate Multivariate
HR 95% CI P-value HR 95% CI P-value
Age at BT implant 1.05 1.03–1.08 <0.001 1.03 1.01–1.06 0.004
Pre-treatment IIEF-5 0.91 0.85–0.96 0.001 0.95 0.89–1.01 0.09
Medical comorbidities (no/yes) 1.65 1.22–2.25 0.001 1.45 1.06–1.97 0.02
Smoking (never/ever) 1.31 0.96–1.79 0.1
Pre-treatment PSA (<10/⩾10) 0.72 0.32–1.62 0.4
Gleason Score (<7/7) 4.36 3.02–6.29 <0.001 3.70 2.55–5.37 <0.001
cT category (<T2b/⩾T2b) 0.58 0.33–1.02 0.06 0.58 0.33–1.02 0.06
NCCN risk classification (low/intermediate risk) 2.01 1.49–2.70 <0.001
Prostate volume 0.99 0.98–1.01 0.5
Use of PDE5-I (no/yes) 0.87 0.65–1.17 0.4
BED (<150 Gy/⩾150 Gy) 1.75 1.27–2.43 0.001 1.61 1.15–2.24 0.005

In a multivariate Cox regression analysis, Gleason score remains the strongest predictor of EF preservation (HR = 3.4; 95% CI = 2.3–5.1). Age at BT seed implant, presence of medical comorbidities and the biological effective dose are still statistically significantly associated with EF preservation (P < 0.05), but the pre-treatment IIEF-5 score was no longer associated with EF preservation (HR = 0.95; 95% CI = 0.89–1.01). The NCCN risk factor was not included in the multivariate model, given that it is derived from the serum PSA level, Gleason score and clinical (cT) categories.

Discussion

We evaluated the long-term erectile function in a cohort of patients with localized prostate cancer and no or mild ED treated with BT in a single institution in Australia, using the IIEF-5 questionnaire. To our knowledge, this is the first prospective longitudinal study in Australia reporting on the long-term EF in patients treated with BT. An earlier Australian study on EF following BT treatment was reported by Finney et al. [17] . However, in the cross sectional study, EF was only measured at a single time point following BT and the doctor-completed LENT-SOMA (Late Effects of Normal Tissue/Somatic Objective Management Analytic) questionnaire was used to assess the pre-treatment EF. It is well recognized that clinicians’ rating of patients’ symptoms often do not correlate well with patients’ self-assessment, and clinicians tend to underestimate patients’ symptoms [18] . One of the major strengths of our study is the use of patient-administered, validated IIEF-5 questionnaire, which would provide a more unbiased assessment of patients’ EF.

We reported a 5-year actuarial EF preservation of 59% in our cohort of patients with no or mild ED pre-treatment. A wide range of EF preservation rates have previously been reported. In a cohort of 145 patients treated with BT at the Memorial Sloan Kettering Cancer Centre, Zelefsky et al. reported the 5-year actuarial EF preservation to be 47%. This was slightly lower compared to the 57% 5-year actuarial EF preservation rate reported in 137 patients treated with EBRT in the same institution [10] . In an Italian cohort of patients with localized prostate cancer, the 5-year EF preservation was reported to be 68% and 65% for those treated with BT and RP respectively [11] . In studies with longer follow-up, Taira et al. reported the 7-year actuarial EF preservation rate of 56% in 226 patients treated in Washington [12] . In a more recent larger study, Snyder et al. reported the 5-year and 10-year actuarial EF preservation rate to be 68% and 58% respectively in 1063 patients treated with BT at the Mount Sinai Medical Centre [13] . The wide range of EF preservation rates reported in the literature was largely due to differences in patient selection for the study and EF assessment methods. Different EF assessment tools used included the IIEF-5, EPIC [Expanded Prostate Cancer Index Composite), MSEFS [Mount Sinai Erectile Function Score) and EORTC-QLQ-C30 (EORTC Quality of Life Questionnaire).

Even when the same EF diagnostic tool was used, different studies defined EF preservation using different cut-off. As in our study, Merrick et al. assessed EF preservation among patients who were ‘potent’ pre-treatment using the IIEF-5 questionnaire. However ‘potency’ was defined as IIEF-5 ⩾ 11 in the study, and ‘potency’ preservation was defined as maintaining IIEF-5 score ⩾11 during the follow-up period. In the study, the 6-year ‘potency’ preservation was reported to be 39% [19]. In our study, EF preservation was defined as maintenance of IIEF-5 ⩾ 17 during the follow-up period, and we reported the 5-year actuarial EF preservation rate of 59% using this cut-off. However, it is important to appreciate that patients with IIEF-5 of <17 may still have EF sufficient for sexual intercourse. Hence, when counselling patients with no or mild ED pre-treatment, it is important to emphasize that the probability of achieving EF to remain sexually active 5 years after BT treatment is likely to be higher than the 59% EF preservation rate reported in our study.

In our analysis we showed that EF preservation post-BT is multifactorial, and was influenced by combination of patient-, tumour- and treatment-related factors. The observed effect of age at BT seed implant and medical comorbidities on EF preservation in our study is not surprising, given that these factors affect EF in the general population. It has been reported in a population-based longitudinal study of men aged 40–69 in Massachusetts that the risk of ED is higher among those with increasing age, diabetes, heart disease and hypertension [20] . In our study, we excluded men at each age with moderate to severe ED prior to treatment, thus ‘normalizing’ for age prior to treatment. Nonetheless, we observed that older men, presumably with similar quality of EF as younger men prior to BT (i.e. IIEF-5 ⩾ 17), were less likely to preserve their EF compared to younger men during the follow-up period. This is consistent with the background population risk of ED, whereby the probability of development of ED is an increasing function with age i.e. a 40 year-old man with good EF is at less risk of developing ED in the subsequent decade compared to a 60 year-old man with good EF [21] . Other studies looking at multivariate analyses of factors affecting EF after treatment have also observed that older men were more likely to develop ED than younger man[13] and [22].

Several earlier studies among prostate cancer patients treated with BT also reported patients’ pre-treatment comorbidities to be independent predictors for development of ED post-treatment[2], [13], [19], [23], [24], and [25]. Despite the statistically significant association, the hazard ratio estimates of medical comorbidities on EF preservation in our study need to be interpreted cautiously, given the potential for misclassification of medical comorbidities in our cohort. Disease status was defined based on medical intervention (i.e. use of oral medications or insulin injection), hence patients with diabetes or hypertension on lifestyle management would have been misclassified as non-diseased thus diluting the HR estimates of medical comorbidities on EF preservation.

Another patient characteristic affecting long term EF preservation, which has been reported in earlier studies, is the pre-treatment EF[13], [19], [22], [23], [25], and [26]. In the univariate analysis in our study, the pre-treatment EF was shown to affect EF preservation (P = 0.001); however, the association was no longer statistically significant in multivariate analysis (P = 0.5). The non-significant association between pre-treatment EF and post-treatment EF preservation in our multivariate analysis could be attributed to the fact that the pre-treatment EF is influenced by age and existing medical comorbidities. Hence when all these factors were accounted for in our multivariate analysis, the effect of age and existing medical comorbidities may supersede the concurrent effect of pre-treatment EF on post-treatment EF, thus diluting the pre-treatment EF and post-treatment EF association towards null. Another reason for the non-significant association was the fact that our study was restricted to patients with no or mild ED (IIEF-5 ⩾ 17) pre-treatment. The exclusion of patients with moderate–severe ED pre-treatment in our study would have limited our ability to detect association between pre-treatment EF and post-treatment EF.

The BT radiation dose also influenced the long term EF preservation post-treatment. We observed that BED of more than 150 Gy was associated with poorer EF preservation at 5-year follow-up. One of the earliest studies showing an association between BT radiation dose and EF preservation, with comparable follow-up period as our study, was reported by Stock et al. in a cohort of 210 patients treated with I-125 BT [26] . The BT radiation dose was quantified using the D90, and the 6-year EF preservation rate was reported to be 64% in patients with D90 < 160 Gy and 58% in patients D90 ⩾ 160 Gy (P = 0.03). Over the years, there is increasing interest in exploring the association between radiation dose to specific anatomic structures within close proximity to the prostate and EF preservation [27] . BT radiation dose to the penile bulb and proximal crura has been consistently reported to be strongly associated with development of ED post-treatment[12] and [28]. Radiation dose to other structures such as the neurovascular bundles [29] and internal pudendal arteries [30] have also been suggested to play a role in EF preservation post-BT; however reports of a critical target structure have not converged on to a single anatomic structure. Also, we did not observe any significant effect of the use of PDE5i on EF preservation post-BT treatment, and this is consistent with a recently published randomized controlled trial in our institution, which did not demonstrate any long-term beneficial effects on EF preservation with early regular use of PDE5i post radiotherapy treatment among patients with no ED pre-treatment [31] .

Prostate cancer tumor characteristics were also found to affect post-treatment EF preservation in our study cohort. In fact, Gleason score of the prostate biopsy was found to be the strongest predictor for EF preservation, after adjusting for other covariates of interest. This finding has not been previously described in other cohorts of prostate cancer patients treated either with radiation or surgery. The biological mechanism as to how Gleason score could influence EF preservation following BT treatment is unclear. Higher Gleason score reflects more aggressive disease, and this will determine the prescribed radiation dose and anatomical distribution of BT seed implant during treatment planning in order to achieve optimal cancer control. It would seem more likely that the Gleason score-EF preservation association is confounded by unmeasured treatment-related factors, such as radiation dose to specific anatomical structure close to the prostate. Better quantification of the radiation dose to each of this structure might help explain, in part, the Gleason score-EF preservation association.

Conclusion

The EF preservation at 5-year follow-up post-BT treatment was 59% in our cohort of prostate cancer patients. It will be interesting to investigate the EF preservation over a longer follow-up period in future studies. We also observed that age at BT seed implant, presence of medical comorbidities, Gleason score and BED are associated with long-term EF preservation post-treatment. Understanding of these EF preservation predictors will be useful for patient counselling and guiding the clinician–patient discussion in terms of treatment decision.

Conflicts of interest

Nil to disclose.

Acknowledgement

The authors would like to thank Karen Scott for data collection and database management.

References

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Footnotes

a William Buckland Radiotherapy Centre, Alfred Health, Melbourne, Australia

b Department of Public Health and Primary Care, University of Cambridge, United Kingdom

c Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia

lowast Corresponding author at: William Buckland Radiotherapy Centre, Alfred Health, Commercial Road, Melbourne VIC 3004, Australia.