Richard G. Stock, Department of Radiation Oncology, Mount Sinai School of Medicine, Box 1236, 1 Gustave L. Levy Place, New York, NY 10029, USA. e-mail: firstname.lastname@example.org
Study Type – Therapy (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
Previously, rates of potency preservation with or without external beam radiation and/ or hormone therapy have been published with smaller series and limited follow-up. The study provides greater numbers and longer follow-up giving patients and clinicians a better appreciation of the true potency preservation rates in this population and how various factors such as age, hormone use and external beam affect those rates.
• To assess potency preservation in men following brachytherapy for prostate cancer with or without external beam radiation therapy (EBRT) and/or androgen deprivation therapy (ADT).
• To evaluate the factors that significantly impact this rate.
PATIENTS AND METHODS
• In all, 1063 potent men with T1–T3 prostate cancer were treated from 1990 to 2007 with seed implantation alone (103Pd or 125I) (69.6%) or combined modality treatment consisting of a partial dose 103Pd implant followed 6–8 weeks later by EBRT (45 Gy, prostate/seminal vesicles only) (30.4%). ADT was used in 49.1% of cases (range 1–27 months).
• Patients were required to have a minimum of 2 years follow-up and to be off ADT for a minimum of 1 year.
• Erectile function was assessed prior to seed implantation and at each follow-up visit using the physician-assigned Mount Sinai Erectile Function Score (MSEFS): 0, unable to have erections; 1, erections insufficient for intercourse; 2, suboptimal erections but sufficient for intercourse; 3, normal erectile function. Potent was defined as a score of greater than or equal to 2 with or without use of a phosphodiesterase type 5 inhibitor.
• The potency rate was calculated using actuarial methods with comparisons tested by log-rank and Cox regression analysis.
• The 5-year and 10-year actuarial rate of potency preservation was 68.0% and 57.9%, respectively, at last follow-up.
• On multivariate analysis, 5- and 10-year potency was 87.6% (79.5%) for men younger than 60, 68.0% (57.5%) for age 60–70, and 42.2% (31.0%) for men older than 70 (P < 0.001).
• Pretreatment MSEFS of 2 had a potency rate of 51.7% (37.2%) vs 74.2% (65.2%) for an MSEFS of 3 (P < 0.001).
• There was a 75.8% (62.6%) potency rate without ADT vs 60.0% (53.0%) with ADT (P < 0.001).
• Five-year potency was 76.4% for implant alone, 71.0% for implant with EBRT, 62.2% for implant with ADT, and 57.9% for implant with EBRT and ADT (P < 0.001).
• Increasing initial age at implant, diminished pretreatment erectile function and the use of combination therapy with EBRT and/or ADT significantly increases erectile dysfunction following brachytherapy.
Patients are often influenced by the associated quality of life issues when choosing a treatment for their prostate. Preservation of erectile function is an important consideration for many patients when deciding on the optimal management of their prostate cancer. Detecting differences in sexual function rates following the various treatment modalities is difficult since no prospective randomized trials have been done. In addition, the analysis of potency rates is frequently confounded by the multiple factors that can affect sexual function. A recent paper on quality of life and satisfaction among prostate cancer survivors demonstrated a benefit of brachytherapy over prostatectomy or external beam radiation therapy (EBRT) for potency preservation . Since 1990, our institution has prospectively collected data on erectile dysfunction to better understand the effects of prostate brachytherapy on potency. The unique aspect of this data set is that it contains information on patients treated using a uniform technique (real-time ultrasound-guided) and by one radiation oncologist (R.G.S.). In the following analysis, we assess erectile function following brachytherapy in potent men prior to treatment as well as the effects of multiple prognostic variables.
PATIENTS AND METHODS
A total of 2036 patients with T1–T3 prostate cancer were treated from October 1990 to November 2007 at the Mount Sinai Medical Center with permanent radioactive seed implantation. Patients were followed prospectively under the approval of the Mount Sinai Institutional Review Board for human subjects. Erectile function was assessed prior to seed implantation and at each follow-up visit using the physician-assigned Mount Sinai Erectile Function Score (MSEFS): 0, unable to have erections; 1, erections insufficient for intercourse; 2, suboptimal erections but sufficient for intercourse; 3, normal erectile function . This scoring system has been validated using correlation studies with the patient assessed potency tool, the sexual health inventory for men . Potent was defined as an MSEFS ≥ 2 with or without the use of a phosphodiesterase type 5 inhibitor. In total, 1867 patients had pre-implant erectile function assessment and post-implant potency evaluation. Of the initial cohort, 1063 patients were potent prior to undergoing implantation, had more than 2 years of post-treatment potency follow-up, and had discontinued androgen deprivation therapy (ADT) for a minimum of 1 year (Table 1). This group made up the study cohort for this analysis. All patients with a Phoenix failure were excluded from the analysis due to the likelihood of subsequent salvage hormonal therapy as well as the potential emotional impact of biochemical failure on sexual interest and function. Follow-up time was calculated from completion of treatment to last available follow-up date. The median follow-up was 5.7 years (range 2–17.3 years).
Table 1. Presenting clinical and treatment characteristics of potent men treated at Mount Sinai Medical Center
Brachytherapy + ADT
Brachytherapy + EBRT
Brachytherapy + ADT + EBRT
In the study cohort 635 patients (59.7%) were implanted with iodine-125 (125I) and 428 patients (40.3%) were implanted with palladium-103 (103Pd), using a real-time ultrasound-guided technique. This technique and subsequent modifications have been described previously [4–6]. The range of activity for 125I and 103Pd seeds was 0.3–0.5 mCi and 1.0–1.5 mCi respectively. Patients underwent CT-based dosimetry of the prostate gland 1 month after implantation using 3 mm abutting slices. The dose delivered to the prostate was determined using dose–volume histogram analysis and was defined as the dose delivered to 90% of the prostate gland (D90). The derivation and relevance of this dose definition have been reported previously [7–9]. All doses were defined using the TG43 formalism [10,11]. Doses were converted to biologically effective doses (BEDs) using an α/β of 2, the D90 of the implant, and total EBRT dose. This calculation has been described in detail previously .
EBRT was used in 323 patients (30.4%) and was delivered 6–8 weeks after seed implantation (median dose 45 Gy, range 39.6–59.4 Gy). For patients receiving EBRT, a partial-dose 103Pd implant was performed with a median D90 of 106 Gy (range 54–162 Gy). In the earlier years of the study, lower implant doses were used with higher EBRT doses. The EBRT prescription dose was varied according to post-implant dosimetric analysis by the brachytherapist (R.G.S.). Between 1990 and June 2003, three-dimensional conformal radiation therapy was used. In June 2003, patients were treated with intensity-modulated radiation therapy. Target volume included the prostate and seminal vesicles with doses typically prescribed to the isodose line that included the entire prostate and seminal vesicles with a 5–15 mm margin.
ADT was used in 49.1% of cases and consisted of a gonadotropin-releasing hormone agonist with or without an antiandrogen. The length of ADT was at the discretion of the referring urologist (range 1–27 months) with 34.1%, 23.8%, 37.0% and 4.2% of patients receiving 1–3 months, >3–6 months, >6–9 months and >9 months of hormone therapy respectively. The duration of hormone therapy was not known for five patients. Factors assessed for impact on potency included patient age, pretreatment erectile function, addition of EBRT, use of ADT, presenting PSA, Gleason score, the disease stage and BED. Potency curves were calculated using the actuarial methods of Kaplan and Meier, with differences in potency rates assessed using the log-rank test [13,14]. For the multivariate analysis we used Cox regression .
At last follow-up, the 5-year and 10-year actuarial rates of potency preservation were 68.0% and 57.9%, respectively. Although data do not exist with regard to how many patients were using a phosphodiesterase type 5 inhibitor before brachytherapy, 740 had used a phosphodiesterase type 5 inhibitor at some time during the course of the study and 415 were using a phosphodiesterase type 5 inhibitor at last follow-up. On multivariate analysis, increased initial age, pretreatment MSEFS of 2 vs 3, ADT, and addition of EBRT had significant detrimental effects on 10-year actuarial potency rates (Table 2). Initial age had the most significant impact on 5-year (10-year) potency preservation: 87.6% (79.5%) for men younger than 60, 68.0% (57.5%) for age 60–70, and 42.2% (31.0%) for men older than 70 (P < 0.001, Fig. 1). Patients with a pretreatment MSEFS of 3 had a 5-year (10-year) potency rate of 74.2% (65.2%) vs 51.7% (37.2%) for a pretreatment MSEFS of 2 (P < 0.001, Fig. 2). The use of ADT negatively impacted 5-year (10-year) potency with 75.8% (62.6%) of men maintaining erectile function without ADT vs 60.0% (53.0%) with ADT (P < 0.001, Fig. 3). The length of hormone therapy did not significantly impact the decline in erectile function.
Table 2. Multivariate analysis of factors affecting potency
Exp B (95% CI)
MSEFS pretreatment potency
Addition of EBRT
BED 220 cutpoint
EBRT also significantly decreased erectile function. Patients receiving EBRT had a 5-year (10-year) potency rate of 60.4% (45.6%) vs 71.4% (61.1%) for those not receiving EBRT (P < 0.001). In evaluating the four treatment options that patients received, potency rates at 5 years were as follows: implant alone 76.4%; implant + EBRT 71.0%; implant + hormones 62.2%; trimodality therapy (implant + EBRT + hormones) 57.9% (P < 0.001, Fig. 4). For men receiving trimodality therapy, initial PSA, T stage and Gleason score did not significantly affect erectile function on univariate analysis.
The median BED was 200. To analyse the effect of increasing BED on potency preservation, two BED cutpoints were made. For the BED 200 cutpoint, the 5- and 10-year actuarial potency rates were 65.6% and 54.6% for BED ≤ 200 and 71.6% and 61.7% for BED > 200, respectively (P= 0.09). With the BED 220 cutpoint, the 5- and 10-year actuarial potency rates were 67.8% and 56.3% for BED ≤ 220 and 71.2% and 65.7% for BED > 220 (P= 0.331).
For most patients with prostate cancer, maintaining erectile function is an important consideration when choosing a treatment modality. Our study is the largest prospective study to date examining erectile function following brachytherapy and the first to examine long-term 10-year actuarial potency rates. At the start of our brachytherapy experience in 1990, we developed a four-point scoring system (MSEFS) to prospectively evaluate erectile function. After the International Index of Erectile Function (IIEF) was developed approximately 10 years later, a close correlation was seen between the MSEFS and IIEF by our own group and by Merrick and colleagues [3,16]. In this study, we analysed potency rates using MSEFS alone so that all potent patients treated over the past 17 years would be included.
On multivariate analysis, age, pretreatment MSEFS, ADT and the use of EBRT all significantly impacted potency preservation. Age had the greatest impact on erectile function with a 51.8% relative decrease in 5-year potency rates for patients older than 70, compared with patients who were less than 60 years old. This finding is in concordance with multiple institutional reports. Merrick and colleagues  demonstrated 3-year potency rates following prostate brachytherapy of 60.8%, 48.6% and 32.0% for age <60, age 60–69 and age >70 respectively. In addition, Sanda et al. found that age was one of two independent variables for potency preservation in a prospective study of 271 patients receiving brachytherapy with or without hormonal therapy or external beam radiation.
We have previously reported [18,19] that potent men with an MSEFS of 3 are more likely to maintain erectile function following 125I prostate brachytherapy than men with MSEFS scores of 2 pretreatment. The present study, using a larger cohort of patients and taking into account other confounding variables such as the use of hormonal therapy and/or EBRT, confirms this finding. Patients with an initial MSEFS = 3 had a 22.5% higher rate of absolute potency preservation compared with a patient with a pre-implant MSEFS = 2. This dependence on pre-implant potency status has also been demonstrated by Merrick et al.. They showed 57.6% and 48.0% potency preservation for men with IIEF of 24–30 and IIEF of 18–23 respectively.
Approximately half of our patient cohort received ADT, the majority of whom received a short 3–9 month course. To be included in the study, patients were required to be off ADT for a minimum of 1 year in order to minimize the likelihood of androgen suppression causing erectile dysfunction. In prior analyses [18,19], we did not observe a negative impact on potency from the use of ADT. In this study, we observed a significant 20.8% relative reduction in erectile preservation with the use of neoadjuvant/adjuvant ADT independent of the duration of hormone therapy. This is in agreement with the findings by Potters et al. who found a significant decrease in the potency rate in patients who received a mean of 4.2 months of neoadjuvant hormone therapy. Likewise, Sanda et al. demonstrated that neoadjuvant hormone therapy negatively impacted potency rates in patients who received EBRT.
The effect of EBRT on potency preservation has not been previously evaluated by our group. An initial study by Merrick et al. reported that supplemental EBRT predicted for erectile dysfunction. However, their most recent study  found no significant difference with the addition of EBRT. They attributed these findings to improved planning techniques designed to limit the dose to the proximal penis. Potters et al. found a trend toward worse erectile function with the addition of EBRT to brachytherapy. The worst outcome for potency preservation was in those patients who received trimodality therapy consisting of ADT, brachytherapy and EBRT . In our cohort, we found a significant 15.4% relative decrease in potency with the addition of EBRT. This may, in large part, be due to the confounding impact of hormonal therapy, since most patients receiving supplemental EBRT also received hormonal therapy. Similar to the Potters group, patients who received trimodality therapy had the worst rate of potency preservation.
Dose escalation has been demonstrated to improve biochemical free survival. In an earlier report, we found a correlation between prostate D90 and potency in men undergoing brachytherapy alone. Specifically, we found that a D90 of 160 Gy for 125I or greater than 100 Gy for 103Pd had a negative impact on potency . In this study, BED was calculated and used in order to include those patients receiving EBRT. Dose, as measured by BED, in the current analysis did not have a significant impact on potency preservation. Patients receiving a BED of >200 or >220 did not have decreased potency.
Over one-half of all potent patients undergoing brachytherapy retain their erectile function at 10 years following treatment. Increasing age at initial implant has the largest impact on erectile dysfunction followed by a diminished pretreatment erectile function and the use of combination therapy with ADT and/or EBRT. Increased BED does not negatively impact potency.
CONFLICT OF INTEREST
Nelson N. Stone is a Consultant for Nihon Metaphysics.