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Predictive factors for erectile dysfunction in men with prostate cancer after brachytherapy: Is dose to the penile bulb important?
Int. J. Radiation Oncology Biol. Phys., Vol. 63, No. 1, pp. 155–163, 2005 Copyright © 2005 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/05/$–see front matter
doi:10.1016/j.ijrobp.2004.12.056
CLINICAL INVESTIGATION
Prostate
PREDICTIVE FACTORS FOR ERECTILE DYSFUNCTION IN MEN WITH PROSTATE CANCER AFTER BRACHYTHERAPY: IS DOSE TO THE PENILE BULB IMPORTANT? A. GRAHAM MACDONALD, M.D.,* MIRA KEYES, M.D.,* ALEXANDRA KRUK, R.T.T.,† GRAEME DUNCAN, M.D.,* VERONIKA MORAVAN, M.SC.,‡ AND W. JAMES MORRIS, M.D.* Departments of *Radiation Oncology and †Radiation Therapy, Vancouver Cancer Centre, BC Cancer Agency; ‡Population and Preventive Oncology, BC Cancer Agency, Vancouver, BC, Canada Purpose: To determine predictive factors for postimplant erectile dysfunction (ED) in a cohort of patients, according to prospectively collected data; specifically, to assess the impact of penile bulb volume and D50 and D95 (dose covering 50% and 95% of the penile bulb volume, respectively) on ED. Methods and Materials: Three hundred forty-two patients were identified who were potent before implant and who had at least 2 years’ follow-up. Patient, tumor, treatment, and dosimetric data were collected on all patients. Postimplant ED was defined according to both physician-documented and patient-documented outcome data. Binary logistic regression analysis was used to create multivariable models of predictors for ED at 1, 2, and 3 years after implant. Results: Physician-documented rates of ED were 57%, 48%, and 38% at 1, 2, and 3 years after implant, respectively. Patient-documented rates of ED were 70% and 66% at 1 and 2 years, respectively. Multivariable analyses revealed age and degree of preimplant erectile function to be consistently significant predictors of ED. Use of hormones was significant at the 1-year physician-documented ED endpoint but not thereafter, in keeping with the time course of testosterone recovery. Penile bulb volume, D50, and D95 were not found to be predictive for ED at any time point, in contrast to previous studies. In addition, planning ultrasound target volume, number of needles, and institutional case sequence number were significant predictors of ED at various time points, consistent with a traumatic etiology of ED. Conclusions: We found no evidence to support penile bulb dosimetry as an independent predictive factor for ED after implant, using physician-documented or patient-documented outcomes. © 2005 Elsevier Inc. Prostate carcinoma, Brachytherapy, Erectile dysfunction, Penile bulb.
INTRODUCTION
quence, the choice of treatment is often decided by patient and physician preference and local availability. One of the reported advantages of BT is a lower incidence of erectile dysfunction (ED) compared with surgery or EBRT. An updated meta-analysis of rates of ED after radical treatment for prostate cancer reported potency preservation rates at 1 year of 76% for BT, 55% for EBRT, and 34% for nervesparing radical prostatectomy (2). In contrast, Merrick et al. (3) reported a lower potency preservation rate of 39% from a series of 209 men at a median follow-up of 40.6 months, using a validated questionnaire (the International Index of Erectile Function) to assess postimplant erectile function (EF) (4). Litwin et al. (5) have published data suggesting
Carcinoma of the prostate is the most common noncutaneous malignancy diagnosed in British Columbia (BC), Canada in men, with an annual incidence of 142 per 100,000 men (BC Cancer Registry data) (1). Management options for early prostate cancer include surgery, external beam radiotherapy (EBRT), prostate brachytherapy (BT), hormone therapy, and watchful waiting. No prospective randomized trial evidence exists to guide patients and physicians as to which of the potentially curative treatment options (surgery, EBRT, and BT) is most efficacious in terms of biochemical, disease-free, and overall survival and quality of life. In conse-
physicians: W. James Morris, M.D. (head of the prostrate brachytherapy program), Mira Keyes, M.D. (QA committee chair), Alexander Agranovich, M.D., Eric Barthelet, M.D., Mitchell Liu, M.D., Michael McKenzie, M.D., Tom Pickles, M.D., and Jonn Wu, M.D.; and the support of the brachytherapy physicists Robert Harrison, M.Sc., Ingrid Spadinger, Ph.D., and William Kwa, Ph.D. Received Aug 31, 2004, and in revised form Dec 2, 2004. Accepted for publication Dec 17, 2004.
Reprint requests to: A. Graham MacDonald, M.D., Aberdeen Royal Infirmary, ANCHOR Unit, Foresterhill, Aberdeen, Scotland AB25 2ZN, United Kingdom. Tel: (⫹44) 1224-681818; Fax: (⫹44) 1224-554183; E-mail: [email protected] Acknowledgments—We wish to acknowledge the assistance of Yulia D’yachkova and Barb Baerg in the design and data collection for this study, and Monty Martin, M.D., for his assistance with defining the penile bulb on CT and MRI. We acknowledge the support of the BC Cancer Agency Prostate Brachytherapy Program 155
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that physician documentation might underestimate the incidence of ED compared with patient-completed documentation. The variation in reported ED rates might therefore be due in part to differing time points for analysis of outcomes and in part due to differing methods of documenting ED. Normal EF requires a functional autonomic and somatic nerve supply to the penis, an adequate arterial supply from the pudendal arteries, intact corpora cavernosa and spongiosum function, and adequate pelvic floor muscle function (6). The National Institutes of Health have defined ED as “the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance” (7). The etiology of ED is multifactorial, with psychological, neurogenic, arterial, and venous factors all potentially contributing. The incidence of ED is age related, with 25% of men older than 65 years suffering from loss of potency. In addition, pharmacologic (e.g., -blockers, methyl dopa, clonidine), diseaserelated (diabetes, hypertension, chronic illness), and lifestyle factors (smoking, alcohol use) might all increase the risk of ED (6). The specific etiology of BT-induced ED is not well understood. In a study of 209 men who were potent before BT, preimplant potency (full vs. partial), delivery of EBRT in addition to BT, and diabetes were statistically significant predictors for the development of ED (3). Some investigators have suggested that dose-related damage to the neurovascular bundles is likely to contribute to ED (8, 9); however, Merrick et al. have reported no such relationship (10, 11). More recently, attention has focused on the penile bulb as a potential critical organ for the development of BTinduced ED, with small retrospective studies showing higher penile bulb doses levels in patients with ED compared with those who retained potency after BT (12) or EBRT (13, 14). Until now, there have been no large-scale cohort studies evaluating the relationship between penile bulb dose and ED in detail. We designed the current study to determine the predictive factors for ED in a large cohort of uniformly treated BT patients, and in particular to assess whether penile bulb dosimetry is an independent predictive factor.
METHODS AND MATERIALS Vancouver Cancer Centre Prostate Brachytherapy Program protocol All patients were treated with an I-125 permanent prostate implant. Patients with low-risk prostate cancer (prostate-specific antigen [PSA] ⱕ10 ng/mL, Gleason score ⱕ3 ⫹ 3 ⫽ 6, Union Internationale Contre le Cancer 1997 clinical stage T1–T2b) and prostate volume ⬍50 cm3 were treated with implant alone. All patients with intermediate-risk prostate cancer (PSA 10 –15 ng/mL and Gleason score 6, or Gleason score 7 and PSA ⱕ10 ng/mL) and those patients with prostate volumes ⬎50 cm3 were implanted with 3 months of neoadjuvant and 3 months of adjuvant androgen suppression. Patients with a previous history of transurethral resection of the prostate were not implanted. No patients received supplemental EBRT.
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Implant planning and procedure A transrectal ultrasound volume study was used to generate a customized treatment plan (VariSeed; Varian Medical Systems, Palo Alto, CA). Pretreatment planning volumes followed American Brachytherapy Society (ABS) recommendations (15). Initially, 0.33 mCi (National Institute of Standard and Technology [NIST99]) I-125 loose seeds (model 6711; Nycomed Amersham, Arlington Heights, IL) were used for all implants; however, since November 2000 all patients have been implanted with RAPID strand (model 6711) OncoSeed I-125 seeds, with loose seeds used only for a special load and periurethral needles. The planning ultrasound target volume (PUTV) was generated on the basis of the transrectal ultrasound results and included the entire prostate with a 0.5–1-cm margin superiorly and inferiorly to include the base of the seminal vesicles, periapical soft tissues, and perivesical soft tissues. We used a modified peripheral loading technique, whereby the 150% isodose (which typically covers 60 – 65% of the prostate volume) is limited to the peripheral zones of the prostate. The dose to the central and periurethral prostate was maintained at ⬍150% of the prescription dose. The minimum peripheral dose was prescribed as 144 Gy and was planned to cover ⬎99% of the PUTV. The radioactive seeds were implanted with a real-time ultrasound-guided transperineal technique, as described by the Seattle group (16). At the end of the procedure, 2–5 additional seeds were frequently deposited into the biopsy-positive prostatic zones or into any “cool areas,” as seen on fluoroscopy or ultrasound images. Patients were routinely prescribed terazosin (1 mg orally for 7 days, then 2 mg daily for 7 days) a fortnight before implantation and were prescribed terazosin (5 mg daily for ⱖ6 weeks) and dexamethasone (16 mg daily for 4 days, then reducing to zero over 2 weeks) starting on the day of implant.
Postimplant dosimetry Approximately 30 days after implantation, all patients underwent pelvic CT (3.0-mm slice thickness, 2.5-mm slice interval). The images were uploaded into the VariSeed software, and a radiation oncologist contoured the prostate and critical structures (bladder and rectum). The seeds were identified on the CT images by a combination of manual selection and the automated redundancy checks available on the VariSeed software system. The postoperative dose covering 90% of the prostate (D90) and the volumes of the prostate covered by 80%, 90%, 100%, 150%, and 200% of the prescription dose were calculated and recorded.
Patient follow-up After permanent implant BT, all patients were reviewed at 6 weeks, 6 months, and biannually thereafter. Erectile function was scored on each visit by the attending physician. Baseline EF was scored with a three-tier scale, which defined normal function, partial function (suboptimal but sufficient for penetration), and impotence. Follow-up assessments of EF were scored as normal (erections adequate for intercourse) or impotent (erections inadequate for intercourse). Quality of life (QoL) questionnaires were filled out by patients on each visit and retrieved either at the end of the clinic visit or by mail. The questionnaire comprised the European Organization for Research and Treatment of Cancer QLQ C-30 questionnaire, as well as additional specific questions relating to urinary, rectal, and sexual function. The sexual health questions are shown in Table 1. The two specific questions used to define “patient-documented
Erectile dysfunction after prostate brachytherapy
Table 1. Quality of life questionnaire sexual health questions
During the past 2 weeks: 1A Have you been able to have an erection? 1B If YES, have you been able to keep an erection? 2 Have you been sexually active? If you answered NO to question 2, jump to question 5. 3 Have you been able to ejaculate?
4 5
Have you been satisfied with your sexual functioning? Has your present condition affected your sex life?
Yes
No
1
2
1
2
1
2
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ability of data thereafter precluded patient-documented outcome analysis at 3 years. For both the physician-documented and patient-documented outcomes, the “1-year” data were taken from the follow-up visit closest to 12 months of any visits between 8 and 18 months after the implant. “Two years” after implant was taken as the follow-up visit closest to 24 months of any visit between 19 and 30 months after implant, and “3 years” was taken as the follow-up visit closest to 36 months of any visit between 31 and 42 months.
Contouring of the penile bulb and bulb dosimetry 1
2
Not at all
A little
Quite a bit
Very much
1
2
3
4
1
2
3
4
erectile function” in this study were 1A (“During the past 2 weeks, have you been able to have an erection?”) and 1B (“If yes, have you been able to keep an erection?”). Patients were considered to have normal EF if both questions were answered “Yes.” The results for the other questions are to be the subject of a separate report.
Study design Patients were identified from the prostate BT database, a prospectively updated resource containing patient, tumor, treatment, and dosimetry factors. Patients were included in the study if they had EF sufficient for vaginal penetration before therapy and at least 24 months’ follow-up from the date of BT implant. Patients who received a “reimplant” (17) were excluded. Patient, tumor, treatment, and dosimetry factors were collected from the BT database on all patients in the study. These included age, relevant comorbidity (vascular disease [including any of ischemic heart disease, cerebrovascular disease, or peripheral vascular disease], diabetes mellitus, and hypertension), smoking habit (current smoker, ex-smoker, or nonsmoker), degree of preimplant potency, clinical T stage, Gleason score, and presenting PSA level, use of -blockers, hormone therapy, PUTV, number of seeds implanted, number of needles used, implant number (i.e., institution case sequence number), physician performing the procedure, and ratio of prostate volume on postimplant CT to PUTV (CT/ PUTV). Data on prostate dosimetry (derived from the postimplant CT scan) included the D90 and D80 and the V100 and V150 (volume of the prostate covered by the 100% [144 Gy] and the 150% [216 Gy] isodoses, respectively). These parameters have been chosen on the basis of reports from the literature suggesting that D90 (18) and V100 (3) were significant predictors of ED. Penile bulb factors included volume, D95, and D50. Physician-documented outcome data regarding EF were retrieved from the follow-up database for the 1-year, 2-year, and where available, the 3-year time points. Patient-documented outcome data (i.e., the sexual function questions from the QoL questionnaire) were retrieved for the 1-year and 2-year time points, but the limited avail-
Two observers independently contoured the penile bulb (A.G.M. and A.K.), each blinded to the other’s contour and to the patient’s outcome. Both observers had performed contours on this organ on 30 postimplant CT scans before the study, so that none of the study patients were contoured on the steep part of either observer’s learning curve. Expert radiologic advice and training was given by one of the BC Cancer Agency radiologists in identifying the penile bulb on CT scan and on MRI studies. The penile bulb was defined on the 4-week postimplant CT scan; landmarks were the paired crura laterally, corpora cavernosa anteriorly, and the levator ani posteriorly (19). The isodose curves covering 50% and 95% of the volume (D50 and D95, respectively) were calculated for each contour. The choice of these parameters was partly based on the available evidence in the literature, in which D50 has been found to be the most significant penile bulb dose parameter in predicting ED (12, 20). Other studies on this topic consistently use D50 in reporting their findings (14, 21, 22). A parameter that approximates the minimum dose delivered to the penile bulb was also chosen (D95), because the investigators considered that any association between penile bulb dose and ED is likely to have a significant volume effect. In addition, because the superior extent of the bulb is often difficult to define compared with the inferior extent, D50 and D95 were considered to be more accurate than the dose to ⬍50% of the bulb. Merrick et al. (12) have previously shown that all penile bulb dosimetric parameters correlate significantly with each other, hence the choice of parameter is unlikely to affect the findings of the study.
Statistical analyses The consistency between the two observers regarding penile bulb contouring (for volume, D50, and D95) was assessed by plotting the difference between the values (i.e., Observer 1 value ⫺ Observer 2 value) against the mean value (i.e., [Observer 1 value ⫹ Observer 2 value]/2), to assess any systematic difference in contouring with respect to volume, D50, and D95. Erectile function (physician-documented data) was assessed at 1 year, 2 years, and 3 years after implant. Each factor was first tested independently for association with erectile dysfunction, with the chi-square test for categoric factors, the Mantel-Haenszel chisquare test for ordered categoric factors, and binary logistic regression for continuous factors. Variables that demonstrated borderline or actual statistical significance (p ⬍ 0.1) were included in a multiple variable logistic regression model, with the forward selection method. The best models were chosen for each time point. Penile bulb volume and dosimetry data were then included in the model to check for independent significance. All data were used for creating the best multiple variable model, and the data set was then limited to those in whom penile bulb data were available for the addition of penile bulb data into the model. Patient-documented EF (QoL data) at 1 year and 2 years was
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similarly assessed with the above-mentioned univariate and multiple variable techniques, with questions 1A and 1B (Table 1) used as outcomes.
RESULTS Patient, tumor, and treatment characteristics Five hundred ninety-eight patients underwent prostate BT at the Vancouver Cancer Centre between July 1998 and January 2002, of whom 342 were eligible for analysis in the study (i.e., potent before implant and with ⬎2 years’ followup). Of these, 330 patients had prostate dosimetric data available for use in the analysis. However, in 93 patients, the CT scan did not extend sufficiently inferiorly to allow the whole penile bulb to be contoured, and in a further 11 cases the postimplant CT images could not be retrieved from the archive, leaving 226 patients with CT scans on which the penile bulb could be contoured. The patient, tumor, and treatment characteristics are displayed in Table 2. Consistency of penile bulb contouring between observers A systematic difference in the way the two observers contoured the penile bulb was noted when difference in penile bulb volume was plotted against mean penile bulb volume. There was a tendency for one observer to contour larger volumes than the other, especially in cases in which the penile bulb volume was small. Logistic regression for this effect was significant, with an estimate of  for mean volume of ⫺0.34 (p ⬍ 0.001). Although statistically significant, the practical impact of this systematic difference in contouring is negligible, because the mean overall difference in bulb volumes was 0.31 ⫾ 3.21 mL. However, in view of this potential bias, the penile bulb volumes, D50, and D95 were entered into the regression models as the mean values for the two observers and as the values for each observer separately. The mean (median) penile bulb D50 was 54.1 Gy (49.2 Gy) and 51.1 Gy (45.1 Gy) for Observers 1 and 2, respectively. The equivalent values for penile bulb D95 were 26.8 Gy (23.9 Gy) and 25.2 Gy (23.0 Gy). Physician-documented and patient-documented outcomes The percentages of patients with physician-assessed ED after prostate BT at 1, 2, and 3 years were 57%, 48%, and 38%, respectively. Patient-documented ED rates at 1 and 2 years were 70% and 66%, respectively (Table 3). Potency preservation rates are displayed graphically in Fig. 1. Potency was seen to change with time in a substantial proportion of patients (physician-documented data). Some previously potent patients became impotent (12–17% per year), but a larger proportion of impotent patients recovered their sexual function regardless of previous use of hormones (23–29% per year). This is summarized in Table 4 and displayed graphically in Fig. 2. To clarify, in those patients for whom data were available for both years 1 and 2 (332 patients), 145 (44%) were potent and 187 (56%) were impotent at year 1. Of 145 potent patients, 24 (17%) became
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Table 2. Patient, tumor, and treatment characteristics (n ⫽ 342) Age (y) Preimplant erectile function Normal Partial Diabetes mellitus Present Absent Unknown Vascular disease Present Absent Unknown Hypertension Present Absent Use of -blocker Yes No Unknown Smoking status Current smoker Ex-smoker Never smoked Unknown T stage T1 T2 Gleason score 3 4 5 6 7 Presenting PSA level (ng/mL) Mean (SD) Range Use of neoadjuvant hormones Yes No Implant factors No. of needles No. of seeds PUTV (mL) Postimplant CT volume (mL) CT/PUTV ratio Prostate dosimetry (n ⫽ 330) V100 (%) V150 (%) D80 (Gy) D90 (Gy) Penile bulb dosimetry (n ⫽ 226) Mean volume (mL) Mean D50 (Gy) Mean D95 (Gy)
65 (49–80) 256 (75) 86 (25) 24 (7) 316 (92) 2 (1) 48 (14) 293 (86) 1 (0) 79 (23) 263 (77) 29 (8) 278 (81) 35 (10) 150 (44) 37 (11) 144 (42) 11 (3) 156 (46) 186 (54) 1 (0) 13 (4) 33 (10) 244 (71) 51 (15) 6.7 (3.3) 0.3–9.9 232 (68) 110 (32) 29 (18–42) 94 (57–130) 36.2 (17.0–56.0) 34.6 (17.4–75.9) 0.99 (0.60–1.66) 92.0 (57.4–99.8) 57.8 (17.3–89.3) 174 (117–245) 149 (94–212) 6.83 (3.73–12.91) 47.8 (13.2–160.9) 23.7 (7.4–99.1)
Abbreviations: PSA ⫽ prostate-specific antigen; SD ⫽ standard deviation; PUTV ⫽ planning ultrasound target volume; CT ⫽ computed tomography. Data are presented as n (%) or median (range), unless otherwise noted.
impotent by year 2. Of 187 impotent patients, 50 (27%) became potent by year 2 (40% with the use of aids and 60% spontaneously). Potency recovery was also observed in the patient-
Erectile dysfunction after prostate brachytherapy
Total no. of evaluable patients No. of patients with ED Percentage of patients with ED Percentage of patients using potency aids
159
Table 4. Results of physician-documented change in erectile function with time
Table 3. Results of physician-documented and patient-documented rates of ED Physiciandocumented
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Patientdocumented
1y
2y
3y
1y
2y
334
338
197
246
164
189 57
161 48
75 38
171 70
108 66
31
36
35
NA
NA
Abbreviations: ED ⫽ erectile dysfunction; NA ⫽ not available.
documented EF data: of 56 patients who were potent at year 2 after BT, 20 had documented ED at year 1 (17 of these had received prior hormone therapy and 3 had not). In those patients who were partially potent before implant, 76% had ED at year 1, 63% at year 2, and 48% at year 3 (physician-documented data). As expected, the ED rate was higher in this subgroup compared with the whole population; however, the same trend in recovery of potency was observed. Compliance in completion of patient-documented EF data Follow-up QoL questionnaires were available for 334 patients at 1 year; however, only 263 (79%) completed any of the sexual health questions shown in Table 1. The compliance rates at years 2 and 3 were 52% and 19%, respectively, for these questions. In those patients who did not answer the sexual health questions, the physician-documented levels of potency were 45%, 50%, and 60% at years 1, 2, and 3, respectively. This compares to the physiciandocumented levels of potency of 43%, 52% and 62% for all patients. Use of potency aids The use of potency aids or medications to achieve EF was documented in 31%, 36%, and 35% of potent patients at years 1, 2, and 3, respectively. When the type of assistance
Change in erectile function
From year 1 to From year 2 to year 2 year 3
All patients From potent to impotent 24 of 145* (17) 13 of 110† (12) From impotent to potent 50 of 187‡ (27) 24 of 87§ (28) Recovering potency with 20 of 50 (40) 12 of 24 (50) use of potency aids Patients who received hormone therapy From potent to impotent 13 of 80 (16) 9 of 78 (12) From impotent to potent 40 of 144 (28) 17 of 63 (27) Recovering potency with 17 of 40 (42) 8 of 17 (47) use of potency aids Patients who did not receive hormone therapy From potent to impotent 11 of 65* (17) 5 of 32 (16) From impotent to potent 10 of 43 (23) 7 of 24 (29) Recovering potency with 3 of 10 (30) 4 of 7 (57) use of potency aids Numbers in parentheses are percentages. * Potent patients for whom erectile function (EF) data were available at both years 1 and 2. † Potent patients for whom EF data were available at both years 2 and 3. ‡ Impotent patients for whom EF data were available at both years 1 and 2. § Impotent patients for whom EF data were available at both years 2 and 3.
used was documented, it was found to be sildenafil in 85% and alprostadil (intracavernosal or urethral) or a pump device in the remainder. Univariate analyses of postimplant ED The results for the statistical tests for association between the patient-related, tumor-related, and treatment-related factors are shown in Table 5, for both the physician-documented and patient-documented outcomes, and are displayed separately for years 1, 2, and 3 of follow-up. Factors predictive of ED on univariate analysis included age, pretreatment EF, smoking status, hormone therapy, PUTV, number of needles, postimplant CT volume, and implant number (order of implant). Penile bulb volume, D95, or D50 were not found to predict for BT-induced ED on univariate analysis in our data set.
Preservation of potency (%)
70 60 50 40 30 20 10 0 All patients
Patients following HT
Patients without HT
Fig. 1. Physician-documented postimplant potency rates at 1 year (solid bars), 2 years (hatched bars), and 3 years (striped bars) in all patients, in those who received hormone therapy (HT), and in those who received no HT.
Multivariate analyses of postimplant ED The best multivariable models for the data using physiciandocumented and patient-documented outcome are displayed in Tables 6 and 7, respectively. Age and preimplant EF were found to be consistent factors in the models. Use of hormones was significant only at the year 1 time point (Table 6). The number of needles used was a significant predictor for ED in two of the models (Table 6), and the PUTV was significant in a further two models (Table 7). When penile bulb volume, D50, and D95 were entered into these models, there was no evidence of an association with ED. This procedure was repeated separately for the
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Fig. 2. Physician-documented potency recovery at 2 and 3 years after implant, displaying percentages of patients who were impotent but previously potent (striped areas), patients who were impotent and previously impotent (light gray areas), patients who were potent and previously potent (dark gray areas), and patients who were potent but previously impotent (i.e., patients who recovered potency) (black areas). HT ⫽ hormone therapy.
data set from both observers, again with no evidence of an association. DISCUSSION The principal aim of this study was to determine patient, treatment, and dosimetric variables predictive of ED after prostate BT; in particular, we investigated whether dose to the penile bulb was predictive for ED after implant. Our main finding was that, with two independent investigators to contour the penile bulb and with the use of both physiciandocumented and patient-documented outcome data, there was no evidence that dose to the penile bulb is predictive for ED after prostate BT. It has been suggested that planning lower doses to the proximal penis might lead to potential gains in potency preservation in EBRT and prostate BT (13, 22). Although such an approach might be appropriate in EBRT planning, if used in prostate BT it raises the possibility of underdosing the prostatic apex and increasing the risk of treatment failure, without any potential gains in sexual function. We have found that at 1, 2, and 3 years after implant, different factors become predictive on multivariate analysis, with patient age being a dominant factor at all follow-up points and pretreatment EF being significant at 1 and 2 years. These have been found to be significant factors in previous studies of postimplant ED (3, 12, 18, 20, 21), and this finding is biologically plausible. Other patient-related factors (hypertension, diabetes, smoking) appear in only one model each and might represent relatively weak predictors of ED, as previously reported (3, 23, 24). The patient, tumor, and treatment characteristics in our study are broadly similar to those in other studies of postimplant ED (3, 12, 18, 20). Our data (Fig. 1) show that EF rates improve from year 1
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(43%) to year 3 (62%) and that this effect is primarily due to the majority of patients receiving hormone therapy. Consistent with this, in the multivariable models for physiciandocumented outcome, use of hormones was significant at the 1-year time point but not thereafter, in keeping with the time course of testosterone recovery. In patients who receive no hormone therapy, the percentage who have normal EF is stable at 59 – 61% over this time course. However, whereas some of these patients become impotent, others have shown steady recovery of potency (in the range of 20 –30% per year [Table 4]) from years 1 to 2 and from years 2 to 3. This is seen in patients regardless of whether hormone therapy was given. Cessation of androgen ablation alone cannot therefore explain the potency recovery in all patients. To our knowledge, recovery of sexual potency after prostate BT in a significant number of patients in the absence of androgen suppression has never before been described. Spontaneous potency recovery in the postprostatectomy setting has been reported, although recovery is significantly greater with early erectogenic therapy (25). In our study, no more than 50% of patients who recovered potency were using potency aids, which suggests that treatment of ED is not solely responsible for this trend either. From our data, other significant factors predictive for ED include number of needles used, PUTV, and implant order, and these deserve further comment. Number of needles and PUTV are positively correlated, as expected (Pearson correlation coefficient 0.65, p ⬍ 0.001), and it is conceivable that both might be surrogate factors for trauma to the erectile tissues. Both have previously been found to predict for ED (or timing of ED) on univariate analysis (3, 18, 20, 26). In addition, implant number appeared as a significant factor at 1 year after implant. This might represent an “institutional learning curve” for prostate implants, possibly as a result of reduced trauma in patients treated in the later years of the program. Over the time course of the BT program, there has been a deliberate attempt to reduce the number of needles used for each implant. At the same time, because of better operating skills, we have reduced the operating room time substantially and reduced the amount of trauma during the procedure by minimizing the number of “stabs” per needle. In keeping with this, implant number is negatively correlated with number of needles used (p ⫽ 0.036) and CT/PUTV ratio (p ⫽ 0.005) in our data set. We have also noted this learning curve effect in the development of postimplant urinary obstruction in our institution (27), which suggests that better outcomes and lower toxicity profile might be achieved in institutions with greater experience in prostate BT. All these findings support the hypothesis that trauma is a contributor to ED. Therefore, we believe that potency recovery might be partly explained by recovery from trauma induced at implant. This might explain the previously mentioned potency recovery in years 2 and 3 in patients treated without androgen suppression. In conclusion, we believe that recovery of potency in our cohort is undoubtedly related to testosterone recovery in patients who also received androgen suppression with their implant, and is also related to use of aids. However, as
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Table 5. Significance of test results (reported as p values) for univariate analyses of physician-documented and patient-documented erectile dysfunction Physician-documented outcome
Patient-related factors Age Preimplant erectile function Diabetes mellitus Vascular disease Hypertension Use of -blocker Smoking status Tumor-related factors T stage Gleason score Presenting PSA level Treatment-related factors Use of neoadjuvant hormones Implant factors No. of needles No. of seeds PUTV Postimplant CT volume CT/PUTV ratio Implant number Implant physician Prostate dosimetry V100 V150 D80 D90 Penile bulb factors Penile bulb volume Penile bulb D50 Penile bulb D95
Patient-documented outcome
1y
2y
3y
1y
2y
⬍0.0001* ⬍0.0001* 0.19 0.035* 0.027* 0.41 0.34
⬍0.0001* 0.0007* 0.056 0.11 0.21 0.34 0.42
0.0002* 0.18 0.88 0.087 0.66 0.51 0.55
⬍0.0001* ⬍0.0001* 0.12 0.53 0.68 0.91 0.45
0.0034* 0.0047* 0.53 0.82 0.97 0.38 0.016*
0.45 0.10 0.66
0.97 0.77 0.95
0.44 0.82 0.58
0.12 0.56 0.29
0.28 0.08 0.63
0.065
0.92
0.17
0.59
0.0027* 0.45 0.091 0.019* 0.40 0.0019* 0.26
0.21 0.24 0.11 0.15 0.76 0.80 0.33
0.024* 0.14 0.045* 0.12 0.37 0.32 0.33
0.018* 0.0094* 0.002* 0.055 0.079 0.93 0.33
0.027* 0.0023* 0.0006* 0.041* 0.20 0.41 0.36
0.37 0.17 0.22 0.46
0.74 0.74 0.04 0.76
0.10 0.78 0.48 0.43
0.54 0.99 0.67 0.19
0.53 0.24 0.36 0.13
0.85 0.35 0.45
0.57 0.66 0.93
0.26 0.68 0.85
0.98 0.21 0.14
0.33 0.77 0.44
⬍0.0001*
Abbreviations as in Table 1. * p ⬍ .05.
discussed above, trauma to the erectile tissues might be the cause of ED after prostate BT, and recovery from trauma might offer an explanation for the documented spontaneous potency recovery in our patient population.
Dose to the penile bulb also deserves further comment. We found that the mean penile bulb D50 and D95 values were 52.6 Gy and 26.0 Gy, respectively. These compare to values in the published literature for BT patients of 43– 69
Table 6. Best multivariate models for erectile dysfunction for physician-documented outcomes at 1 year, 2 years, and 3 years after implant 1y
2y
Variable
OR
p
Age Use of hormones Preimplant EF No. of needles Implant number Hypertension Above model with inclusion of: PB volume PB D95 PB D50
1.09 2.34 2.59 1.08 0.998 1.83
⬍0.0001 0.0020 0.0022 0.0048 0.011 0.050
1.07 1.01 1.00
0.52 0.64 0.83
Variable Age Preimplant EF Diabetes
Above model with inclusion of: PB volume PB D95 PB D50
3y OR
p
1.08 2.04 2.52
⬍0.0001 0.0075 0.0044
0.96 1.00 1.00
0.64 0.88 0.53
Abbreviations: EF ⫽ erectile function; OR ⫽ estimated odds ratio; PB ⫽ penile bulb.
Variable
OR
p
Age No. of needles
1.09 1.08
0.0003 0.024
Above model with inclusion of: PB volume PB D95 PB D50
0.81 1.00 1.00
0.13 0.99 0.76
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Table 7. Best multivariate models for erectile dysfunction for patient-documented outcomes at 1 year and 2 years after implant 1y Variable Preimplant EF Age PUTV Above model with inclusion of: PB volume PB D95 PB D50
2y OR
p
Variable
OR
p
20.14 1.09 1.05
⬍0.0001 0.0003 0.0086
2.79 1.07 1.06 2.86 3.37
0.048 0.018 0.015 0.018 0.018
0.90 1.01 1.00
0.43 0.60 0.81
Preimplant EF Age PUTV Current smoking Former smoking Above model with inclusion of: PB volume PB D95 PB D50
1.06 1.01 1.00
0.70 0.67 0.95
Abbreviations as in Tables 1 and 5.
Gy and 20.5–29 Gy (12, 20, 21). The equivalent values in the EBRT patient population are less well established but range from a median of 48.5 Gy to 67.3 Gy for D50 and 14 Gy to 51.1 Gy for D95 (13). Although these doses seem to be broadly similar for BT and EBRT, the much lower dose rate with BT theoretically should result in sparing of late radiation toxicity when compared with EBRT. The doses to the proximal 1 cm of the corpora cavernosa with BT are much lower (25.5 Gy for D50 and 14.5 Gy for D95) (20) than those reported for EBRT (mean dose of 59.4 Gy) (28). The corpora cavernosa are the main vascular structures in the penis and represent the true erectile tissue. This is supported by the finding that vascular leak is implicated in the pathophysiology of EBRT-caused ED (29). Therefore, it is likely that dose to the penile bulb is simply a surrogate for dose to the proximal crura in patients receiving EBRT (30). Whereas the dose to the proximal crura is high enough to be a plausible contributor to ED in EBRT, the much lower doses to these structures from BT (with the added effect of low dose rate) make dose to the crura an unlikely candidate for causing ED in this context. However, unlike EBRT, trauma to the crura undoubtedly occurs during implantation and might be implicated as a causative factor for ED. This is supported by our finding that number of needles is an independent predictor for ED and by the recovery of erectile function seen in patients regardless of whether they received hormone therapy. Methods of reporting ED have not been standardized in the literature, and the ABS has recently published recommendations for reporting late morbidity after prostate implants (31). The ABS-preferred instrument for reporting sexual function is the “sexual health inventory for men,”
which differs from the sexual health questions used in the QoL questionnaire at our institution. Most of our data were collected before the 2002 recommendations. We collected data on ability to achieve and maintain an erection (as well as data on ejaculatory function, current level of sexual activity, and satisfaction with sexual function, to be reported elsewhere), and we believe that this represents a reasonable assessment of potency as expressed by the patient. The physician-reported ED rates were lower than those from the patient-documented data, in keeping with previous studies (5). Noncompliance rates for completion of the sexual health questions were high; however, the physician-documented potency rates were similar regardless of whether patients completed these questions, arguing against a systematic bias in patient potency in completion of the QoL forms. We are confident that the use of both physician- and patient-documented potency as endpoints ensures that any bias of methods of reporting potency would not influence the robustness of the study findings. CONCLUSIONS In our study, factors predictive for ED included age, pretreatment EF, hypertension, diabetes, and smoking, as well as implant order, PUTV, and number of needles, which might ultimately point to trauma to the bulb as an important factor predicting ED after prostate BT. None of penile bulb volume, D50, or D95 was found to predict for ED at any time point by physician-documented or patient-documented outcomes. In addition, recovery of potency was seen in a proportion of patients, regardless of whether they had received prior hormone therapy or used potency aids.
REFERENCES 1. BC Cancer Agency. Crude cancer rates—incidence. Available at: www.bccancer.bc.ca/HPI/CancerStatistics/FF/Rates/Inc/ default.htm. Website accessed June 30, 2004. 2. Robinson JW, Moritz S, Fung T. Meta-analysis of rates of erectile function after treatment of localized prostate carcinoma. Int J Radiat Oncol Biol Phys 2002;54:1063–1068. 3. Merrick GS, Butler WM, Galbreath RW, et al. Erectile func-
tion after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002;52:893–902. 4. Rosen RC, Riley A, Wagner G, et al. The international index of erectile function (IIEF): A multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822– 830. 5. Litwin MS, Lubeck DP, Henning JM, et al. Differences in urologist and patient assessments of health related quality of
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6. 7. 8.
9. 10.
11. 12.
13.
14.
15.
16. 17. 18.
life in men with prostate cancer: Results of the CaPSURE database. J Urol 1998;159:1988 –1992. Tierney LM, MacPhee SJ, Papadakis MA, eds. Current medical diagnosis and treatment. 43rd ed. New York: Lange Medical Books/McGraw-Hill; 2004. NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA 1993;270:83–90. Bradley KA, Chappell R, Yuan Z, et al. Erectile dysfunction and prostate brachytherapy doses to the penile bulb and neurovascular bundles [abstract]. Int J Radiat Oncol Biol Phys 2003;57(Suppl.):S399 –S400. DiBiase SJ, Wallner K, Tralins K, et al. Brachytherapy radiation doses to the neurovascular bundles. Int J Radiat Oncol Biol Phys 2000;46:1301–1307. Merrick GS, Butler WM, Dorsey AT, et al. A comparison of radiation dose to the neurovascular bundles in men with and without prostate brachytherapy-induced erectile dysfunction. Int J Radiat Oncol Biol Phys 2000;48:1069 –1074. Merrick GS, Wallner K, Butler WM, et al. Short-term sexual function after prostate brachytherapy. Int J Cancer 2001;96: 313–319. Merrick GS, Wallner K, Butler WM, et al. A comparison of radiation dose to the bulb of the penis in men with and without prostate brachytherapy-induced erectile dysfunction. Int J Radiat Oncol Biol Phys 2001;50:597– 604. Fisch BM, Pickett B, Weinberg V, et al. Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer. Urology 2001;57:955–959. Pickett B, Fisch BM, Weinberg V, et al. Dose to the bulb of the penis is associated with the risk of impotence following radiotherapy for prostate cancer [Abstract]. Int J Radiat Oncol Biol Phys 1999;45(Suppl.):263. Nag S, Ellis RJ, Merrick GS, et al. American Brachytherapy Society recommendations for reporting morbidity after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002;54: 462– 470. Blasko JC, Mate T, Sylvester JE, et al. Brachytherapy for carcinoma of the prostate: Techniques, patient selection, and clinical outcomes. Semin Radiat Oncol 2002;12:81–94. Keyes M, Pickles T, Agranovich A, et al. 125-I reimplantation in patients with poor initial dosimetry after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2004;60:40 –50. Stock RG, Kao J, Stone NN. Penile erectile function after permanent radioactive seed implantation for treatment of prostate cancer. J Urol 2001;165:436 – 439.
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19. Wallner KE, Merrick GS, Benson ML, et al. Penile bulb imaging. Int J Radiat Oncol Biol Phys 2002;53:928 –933. 20. Merrick GS, Butler WM, Wallner KE, et al. The importance of radiation doses to the penile bulb vs. crura in the development of postbrachytherapy erectile dysfunction. Int J Radiat Oncol Biol Phys 2002;54:1055–1062. 21. Kiteley RA, Lee WR, deGuzman AF, et al. Radiation dose to the neurovascular bundles or penile bulb does not predict erectile dysfunction after prostate brachytherapy. Brachytherapy 2002;1:90 –94. 22. Merrick GS, Butler WM. The dosimetry of brachytherapyinduced erectile dysfunction. Med Dosim 2003;28:271–274. 23. Wright JL, Newhouse JH, Laguna JL, et al. Localization of neurovascular bundles on pelvic CT and evaluation of radiation dose to structures putatively involved in erectile dysfunction after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2004;59:426 – 435. 24. Selek U, Cheung R, Lii M, et al. Erectile dysfunction and radiation dose to penile base structures: A lack of correlation. Int J Radiat Oncol Biol Phys 2004;59:1039 –1046. 25. Montorsi F, Guazzoni G, Strambi LF, et al. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: Results of a prospective, randomized trial. J Urol 1997;158:1408 –1410. 26. Ghilezan M, Vargas C, Gustafson G, et al. Erectile dysfunction (ED) after prostate cancer brachytherapy as sole treatment modality. The William Beaumont Hopsital’s experience with HDR vs. LDR (Pd103 permanent implants) [Abstract]. Radiother Oncol 2004;71(Suppl.):S56. 27. Schellenberg D, Keyes M, Bucci J, et al. Decreased incidence of urinary retention after prostate brachytherapy: The effect of the learning curve? [Abstract]. Radiother Oncol 2004;71(Suppl.): S55–56. 28. Mulhall JP, Yonover P, Sethi A, et al. Radiation exposure to the corporeal bodies during 3-dimensional conformal radiation therapy for prostate cancer. J Urol 2002;167:539 –542. 29. Zelefsky MJ, Eid JF. Elucidating the etiology of erectile dysfunction after definitive therapy for prostatic cancer. Int J Radiat Oncol Biol Phys 1998;40:129 –133. 30. Mulhall JP, Yonover PM. Correlation of radiation dose and impotence risk after three-dimensional conformal radiotherapy for prostate cancer [Letter]. Urology 2001;58:828. 31. Nag S, Ellis RJ, Merrick GS, et al. American Brachytherapy Society recommendations for reporting morbidity after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002;54: 462– 470.
doi:10.1016/j.ijrobp.2004.12.056
CLINICAL INVESTIGATION
Prostate
PREDICTIVE FACTORS FOR ERECTILE DYSFUNCTION IN MEN WITH PROSTATE CANCER AFTER BRACHYTHERAPY: IS DOSE TO THE PENILE BULB IMPORTANT? A. GRAHAM MACDONALD, M.D.,* MIRA KEYES, M.D.,* ALEXANDRA KRUK, R.T.T.,† GRAEME DUNCAN, M.D.,* VERONIKA MORAVAN, M.SC.,‡ AND W. JAMES MORRIS, M.D.* Departments of *Radiation Oncology and †Radiation Therapy, Vancouver Cancer Centre, BC Cancer Agency; ‡Population and Preventive Oncology, BC Cancer Agency, Vancouver, BC, Canada Purpose: To determine predictive factors for postimplant erectile dysfunction (ED) in a cohort of patients, according to prospectively collected data; specifically, to assess the impact of penile bulb volume and D50 and D95 (dose covering 50% and 95% of the penile bulb volume, respectively) on ED. Methods and Materials: Three hundred forty-two patients were identified who were potent before implant and who had at least 2 years’ follow-up. Patient, tumor, treatment, and dosimetric data were collected on all patients. Postimplant ED was defined according to both physician-documented and patient-documented outcome data. Binary logistic regression analysis was used to create multivariable models of predictors for ED at 1, 2, and 3 years after implant. Results: Physician-documented rates of ED were 57%, 48%, and 38% at 1, 2, and 3 years after implant, respectively. Patient-documented rates of ED were 70% and 66% at 1 and 2 years, respectively. Multivariable analyses revealed age and degree of preimplant erectile function to be consistently significant predictors of ED. Use of hormones was significant at the 1-year physician-documented ED endpoint but not thereafter, in keeping with the time course of testosterone recovery. Penile bulb volume, D50, and D95 were not found to be predictive for ED at any time point, in contrast to previous studies. In addition, planning ultrasound target volume, number of needles, and institutional case sequence number were significant predictors of ED at various time points, consistent with a traumatic etiology of ED. Conclusions: We found no evidence to support penile bulb dosimetry as an independent predictive factor for ED after implant, using physician-documented or patient-documented outcomes. © 2005 Elsevier Inc. Prostate carcinoma, Brachytherapy, Erectile dysfunction, Penile bulb.
INTRODUCTION
quence, the choice of treatment is often decided by patient and physician preference and local availability. One of the reported advantages of BT is a lower incidence of erectile dysfunction (ED) compared with surgery or EBRT. An updated meta-analysis of rates of ED after radical treatment for prostate cancer reported potency preservation rates at 1 year of 76% for BT, 55% for EBRT, and 34% for nervesparing radical prostatectomy (2). In contrast, Merrick et al. (3) reported a lower potency preservation rate of 39% from a series of 209 men at a median follow-up of 40.6 months, using a validated questionnaire (the International Index of Erectile Function) to assess postimplant erectile function (EF) (4). Litwin et al. (5) have published data suggesting
Carcinoma of the prostate is the most common noncutaneous malignancy diagnosed in British Columbia (BC), Canada in men, with an annual incidence of 142 per 100,000 men (BC Cancer Registry data) (1). Management options for early prostate cancer include surgery, external beam radiotherapy (EBRT), prostate brachytherapy (BT), hormone therapy, and watchful waiting. No prospective randomized trial evidence exists to guide patients and physicians as to which of the potentially curative treatment options (surgery, EBRT, and BT) is most efficacious in terms of biochemical, disease-free, and overall survival and quality of life. In conse-
physicians: W. James Morris, M.D. (head of the prostrate brachytherapy program), Mira Keyes, M.D. (QA committee chair), Alexander Agranovich, M.D., Eric Barthelet, M.D., Mitchell Liu, M.D., Michael McKenzie, M.D., Tom Pickles, M.D., and Jonn Wu, M.D.; and the support of the brachytherapy physicists Robert Harrison, M.Sc., Ingrid Spadinger, Ph.D., and William Kwa, Ph.D. Received Aug 31, 2004, and in revised form Dec 2, 2004. Accepted for publication Dec 17, 2004.
Reprint requests to: A. Graham MacDonald, M.D., Aberdeen Royal Infirmary, ANCHOR Unit, Foresterhill, Aberdeen, Scotland AB25 2ZN, United Kingdom. Tel: (⫹44) 1224-681818; Fax: (⫹44) 1224-554183; E-mail: [email protected] Acknowledgments—We wish to acknowledge the assistance of Yulia D’yachkova and Barb Baerg in the design and data collection for this study, and Monty Martin, M.D., for his assistance with defining the penile bulb on CT and MRI. We acknowledge the support of the BC Cancer Agency Prostate Brachytherapy Program 155
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that physician documentation might underestimate the incidence of ED compared with patient-completed documentation. The variation in reported ED rates might therefore be due in part to differing time points for analysis of outcomes and in part due to differing methods of documenting ED. Normal EF requires a functional autonomic and somatic nerve supply to the penis, an adequate arterial supply from the pudendal arteries, intact corpora cavernosa and spongiosum function, and adequate pelvic floor muscle function (6). The National Institutes of Health have defined ED as “the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance” (7). The etiology of ED is multifactorial, with psychological, neurogenic, arterial, and venous factors all potentially contributing. The incidence of ED is age related, with 25% of men older than 65 years suffering from loss of potency. In addition, pharmacologic (e.g., -blockers, methyl dopa, clonidine), diseaserelated (diabetes, hypertension, chronic illness), and lifestyle factors (smoking, alcohol use) might all increase the risk of ED (6). The specific etiology of BT-induced ED is not well understood. In a study of 209 men who were potent before BT, preimplant potency (full vs. partial), delivery of EBRT in addition to BT, and diabetes were statistically significant predictors for the development of ED (3). Some investigators have suggested that dose-related damage to the neurovascular bundles is likely to contribute to ED (8, 9); however, Merrick et al. have reported no such relationship (10, 11). More recently, attention has focused on the penile bulb as a potential critical organ for the development of BTinduced ED, with small retrospective studies showing higher penile bulb doses levels in patients with ED compared with those who retained potency after BT (12) or EBRT (13, 14). Until now, there have been no large-scale cohort studies evaluating the relationship between penile bulb dose and ED in detail. We designed the current study to determine the predictive factors for ED in a large cohort of uniformly treated BT patients, and in particular to assess whether penile bulb dosimetry is an independent predictive factor.
METHODS AND MATERIALS Vancouver Cancer Centre Prostate Brachytherapy Program protocol All patients were treated with an I-125 permanent prostate implant. Patients with low-risk prostate cancer (prostate-specific antigen [PSA] ⱕ10 ng/mL, Gleason score ⱕ3 ⫹ 3 ⫽ 6, Union Internationale Contre le Cancer 1997 clinical stage T1–T2b) and prostate volume ⬍50 cm3 were treated with implant alone. All patients with intermediate-risk prostate cancer (PSA 10 –15 ng/mL and Gleason score 6, or Gleason score 7 and PSA ⱕ10 ng/mL) and those patients with prostate volumes ⬎50 cm3 were implanted with 3 months of neoadjuvant and 3 months of adjuvant androgen suppression. Patients with a previous history of transurethral resection of the prostate were not implanted. No patients received supplemental EBRT.
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Implant planning and procedure A transrectal ultrasound volume study was used to generate a customized treatment plan (VariSeed; Varian Medical Systems, Palo Alto, CA). Pretreatment planning volumes followed American Brachytherapy Society (ABS) recommendations (15). Initially, 0.33 mCi (National Institute of Standard and Technology [NIST99]) I-125 loose seeds (model 6711; Nycomed Amersham, Arlington Heights, IL) were used for all implants; however, since November 2000 all patients have been implanted with RAPID strand (model 6711) OncoSeed I-125 seeds, with loose seeds used only for a special load and periurethral needles. The planning ultrasound target volume (PUTV) was generated on the basis of the transrectal ultrasound results and included the entire prostate with a 0.5–1-cm margin superiorly and inferiorly to include the base of the seminal vesicles, periapical soft tissues, and perivesical soft tissues. We used a modified peripheral loading technique, whereby the 150% isodose (which typically covers 60 – 65% of the prostate volume) is limited to the peripheral zones of the prostate. The dose to the central and periurethral prostate was maintained at ⬍150% of the prescription dose. The minimum peripheral dose was prescribed as 144 Gy and was planned to cover ⬎99% of the PUTV. The radioactive seeds were implanted with a real-time ultrasound-guided transperineal technique, as described by the Seattle group (16). At the end of the procedure, 2–5 additional seeds were frequently deposited into the biopsy-positive prostatic zones or into any “cool areas,” as seen on fluoroscopy or ultrasound images. Patients were routinely prescribed terazosin (1 mg orally for 7 days, then 2 mg daily for 7 days) a fortnight before implantation and were prescribed terazosin (5 mg daily for ⱖ6 weeks) and dexamethasone (16 mg daily for 4 days, then reducing to zero over 2 weeks) starting on the day of implant.
Postimplant dosimetry Approximately 30 days after implantation, all patients underwent pelvic CT (3.0-mm slice thickness, 2.5-mm slice interval). The images were uploaded into the VariSeed software, and a radiation oncologist contoured the prostate and critical structures (bladder and rectum). The seeds were identified on the CT images by a combination of manual selection and the automated redundancy checks available on the VariSeed software system. The postoperative dose covering 90% of the prostate (D90) and the volumes of the prostate covered by 80%, 90%, 100%, 150%, and 200% of the prescription dose were calculated and recorded.
Patient follow-up After permanent implant BT, all patients were reviewed at 6 weeks, 6 months, and biannually thereafter. Erectile function was scored on each visit by the attending physician. Baseline EF was scored with a three-tier scale, which defined normal function, partial function (suboptimal but sufficient for penetration), and impotence. Follow-up assessments of EF were scored as normal (erections adequate for intercourse) or impotent (erections inadequate for intercourse). Quality of life (QoL) questionnaires were filled out by patients on each visit and retrieved either at the end of the clinic visit or by mail. The questionnaire comprised the European Organization for Research and Treatment of Cancer QLQ C-30 questionnaire, as well as additional specific questions relating to urinary, rectal, and sexual function. The sexual health questions are shown in Table 1. The two specific questions used to define “patient-documented
Erectile dysfunction after prostate brachytherapy
Table 1. Quality of life questionnaire sexual health questions
During the past 2 weeks: 1A Have you been able to have an erection? 1B If YES, have you been able to keep an erection? 2 Have you been sexually active? If you answered NO to question 2, jump to question 5. 3 Have you been able to ejaculate?
4 5
Have you been satisfied with your sexual functioning? Has your present condition affected your sex life?
Yes
No
1
2
1
2
1
2
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ability of data thereafter precluded patient-documented outcome analysis at 3 years. For both the physician-documented and patient-documented outcomes, the “1-year” data were taken from the follow-up visit closest to 12 months of any visits between 8 and 18 months after the implant. “Two years” after implant was taken as the follow-up visit closest to 24 months of any visit between 19 and 30 months after implant, and “3 years” was taken as the follow-up visit closest to 36 months of any visit between 31 and 42 months.
Contouring of the penile bulb and bulb dosimetry 1
2
Not at all
A little
Quite a bit
Very much
1
2
3
4
1
2
3
4
erectile function” in this study were 1A (“During the past 2 weeks, have you been able to have an erection?”) and 1B (“If yes, have you been able to keep an erection?”). Patients were considered to have normal EF if both questions were answered “Yes.” The results for the other questions are to be the subject of a separate report.
Study design Patients were identified from the prostate BT database, a prospectively updated resource containing patient, tumor, treatment, and dosimetry factors. Patients were included in the study if they had EF sufficient for vaginal penetration before therapy and at least 24 months’ follow-up from the date of BT implant. Patients who received a “reimplant” (17) were excluded. Patient, tumor, treatment, and dosimetry factors were collected from the BT database on all patients in the study. These included age, relevant comorbidity (vascular disease [including any of ischemic heart disease, cerebrovascular disease, or peripheral vascular disease], diabetes mellitus, and hypertension), smoking habit (current smoker, ex-smoker, or nonsmoker), degree of preimplant potency, clinical T stage, Gleason score, and presenting PSA level, use of -blockers, hormone therapy, PUTV, number of seeds implanted, number of needles used, implant number (i.e., institution case sequence number), physician performing the procedure, and ratio of prostate volume on postimplant CT to PUTV (CT/ PUTV). Data on prostate dosimetry (derived from the postimplant CT scan) included the D90 and D80 and the V100 and V150 (volume of the prostate covered by the 100% [144 Gy] and the 150% [216 Gy] isodoses, respectively). These parameters have been chosen on the basis of reports from the literature suggesting that D90 (18) and V100 (3) were significant predictors of ED. Penile bulb factors included volume, D95, and D50. Physician-documented outcome data regarding EF were retrieved from the follow-up database for the 1-year, 2-year, and where available, the 3-year time points. Patient-documented outcome data (i.e., the sexual function questions from the QoL questionnaire) were retrieved for the 1-year and 2-year time points, but the limited avail-
Two observers independently contoured the penile bulb (A.G.M. and A.K.), each blinded to the other’s contour and to the patient’s outcome. Both observers had performed contours on this organ on 30 postimplant CT scans before the study, so that none of the study patients were contoured on the steep part of either observer’s learning curve. Expert radiologic advice and training was given by one of the BC Cancer Agency radiologists in identifying the penile bulb on CT scan and on MRI studies. The penile bulb was defined on the 4-week postimplant CT scan; landmarks were the paired crura laterally, corpora cavernosa anteriorly, and the levator ani posteriorly (19). The isodose curves covering 50% and 95% of the volume (D50 and D95, respectively) were calculated for each contour. The choice of these parameters was partly based on the available evidence in the literature, in which D50 has been found to be the most significant penile bulb dose parameter in predicting ED (12, 20). Other studies on this topic consistently use D50 in reporting their findings (14, 21, 22). A parameter that approximates the minimum dose delivered to the penile bulb was also chosen (D95), because the investigators considered that any association between penile bulb dose and ED is likely to have a significant volume effect. In addition, because the superior extent of the bulb is often difficult to define compared with the inferior extent, D50 and D95 were considered to be more accurate than the dose to ⬍50% of the bulb. Merrick et al. (12) have previously shown that all penile bulb dosimetric parameters correlate significantly with each other, hence the choice of parameter is unlikely to affect the findings of the study.
Statistical analyses The consistency between the two observers regarding penile bulb contouring (for volume, D50, and D95) was assessed by plotting the difference between the values (i.e., Observer 1 value ⫺ Observer 2 value) against the mean value (i.e., [Observer 1 value ⫹ Observer 2 value]/2), to assess any systematic difference in contouring with respect to volume, D50, and D95. Erectile function (physician-documented data) was assessed at 1 year, 2 years, and 3 years after implant. Each factor was first tested independently for association with erectile dysfunction, with the chi-square test for categoric factors, the Mantel-Haenszel chisquare test for ordered categoric factors, and binary logistic regression for continuous factors. Variables that demonstrated borderline or actual statistical significance (p ⬍ 0.1) were included in a multiple variable logistic regression model, with the forward selection method. The best models were chosen for each time point. Penile bulb volume and dosimetry data were then included in the model to check for independent significance. All data were used for creating the best multiple variable model, and the data set was then limited to those in whom penile bulb data were available for the addition of penile bulb data into the model. Patient-documented EF (QoL data) at 1 year and 2 years was
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similarly assessed with the above-mentioned univariate and multiple variable techniques, with questions 1A and 1B (Table 1) used as outcomes.
RESULTS Patient, tumor, and treatment characteristics Five hundred ninety-eight patients underwent prostate BT at the Vancouver Cancer Centre between July 1998 and January 2002, of whom 342 were eligible for analysis in the study (i.e., potent before implant and with ⬎2 years’ followup). Of these, 330 patients had prostate dosimetric data available for use in the analysis. However, in 93 patients, the CT scan did not extend sufficiently inferiorly to allow the whole penile bulb to be contoured, and in a further 11 cases the postimplant CT images could not be retrieved from the archive, leaving 226 patients with CT scans on which the penile bulb could be contoured. The patient, tumor, and treatment characteristics are displayed in Table 2. Consistency of penile bulb contouring between observers A systematic difference in the way the two observers contoured the penile bulb was noted when difference in penile bulb volume was plotted against mean penile bulb volume. There was a tendency for one observer to contour larger volumes than the other, especially in cases in which the penile bulb volume was small. Logistic regression for this effect was significant, with an estimate of  for mean volume of ⫺0.34 (p ⬍ 0.001). Although statistically significant, the practical impact of this systematic difference in contouring is negligible, because the mean overall difference in bulb volumes was 0.31 ⫾ 3.21 mL. However, in view of this potential bias, the penile bulb volumes, D50, and D95 were entered into the regression models as the mean values for the two observers and as the values for each observer separately. The mean (median) penile bulb D50 was 54.1 Gy (49.2 Gy) and 51.1 Gy (45.1 Gy) for Observers 1 and 2, respectively. The equivalent values for penile bulb D95 were 26.8 Gy (23.9 Gy) and 25.2 Gy (23.0 Gy). Physician-documented and patient-documented outcomes The percentages of patients with physician-assessed ED after prostate BT at 1, 2, and 3 years were 57%, 48%, and 38%, respectively. Patient-documented ED rates at 1 and 2 years were 70% and 66%, respectively (Table 3). Potency preservation rates are displayed graphically in Fig. 1. Potency was seen to change with time in a substantial proportion of patients (physician-documented data). Some previously potent patients became impotent (12–17% per year), but a larger proportion of impotent patients recovered their sexual function regardless of previous use of hormones (23–29% per year). This is summarized in Table 4 and displayed graphically in Fig. 2. To clarify, in those patients for whom data were available for both years 1 and 2 (332 patients), 145 (44%) were potent and 187 (56%) were impotent at year 1. Of 145 potent patients, 24 (17%) became
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Table 2. Patient, tumor, and treatment characteristics (n ⫽ 342) Age (y) Preimplant erectile function Normal Partial Diabetes mellitus Present Absent Unknown Vascular disease Present Absent Unknown Hypertension Present Absent Use of -blocker Yes No Unknown Smoking status Current smoker Ex-smoker Never smoked Unknown T stage T1 T2 Gleason score 3 4 5 6 7 Presenting PSA level (ng/mL) Mean (SD) Range Use of neoadjuvant hormones Yes No Implant factors No. of needles No. of seeds PUTV (mL) Postimplant CT volume (mL) CT/PUTV ratio Prostate dosimetry (n ⫽ 330) V100 (%) V150 (%) D80 (Gy) D90 (Gy) Penile bulb dosimetry (n ⫽ 226) Mean volume (mL) Mean D50 (Gy) Mean D95 (Gy)
65 (49–80) 256 (75) 86 (25) 24 (7) 316 (92) 2 (1) 48 (14) 293 (86) 1 (0) 79 (23) 263 (77) 29 (8) 278 (81) 35 (10) 150 (44) 37 (11) 144 (42) 11 (3) 156 (46) 186 (54) 1 (0) 13 (4) 33 (10) 244 (71) 51 (15) 6.7 (3.3) 0.3–9.9 232 (68) 110 (32) 29 (18–42) 94 (57–130) 36.2 (17.0–56.0) 34.6 (17.4–75.9) 0.99 (0.60–1.66) 92.0 (57.4–99.8) 57.8 (17.3–89.3) 174 (117–245) 149 (94–212) 6.83 (3.73–12.91) 47.8 (13.2–160.9) 23.7 (7.4–99.1)
Abbreviations: PSA ⫽ prostate-specific antigen; SD ⫽ standard deviation; PUTV ⫽ planning ultrasound target volume; CT ⫽ computed tomography. Data are presented as n (%) or median (range), unless otherwise noted.
impotent by year 2. Of 187 impotent patients, 50 (27%) became potent by year 2 (40% with the use of aids and 60% spontaneously). Potency recovery was also observed in the patient-
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Total no. of evaluable patients No. of patients with ED Percentage of patients with ED Percentage of patients using potency aids
159
Table 4. Results of physician-documented change in erectile function with time
Table 3. Results of physician-documented and patient-documented rates of ED Physiciandocumented
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Patientdocumented
1y
2y
3y
1y
2y
334
338
197
246
164
189 57
161 48
75 38
171 70
108 66
31
36
35
NA
NA
Abbreviations: ED ⫽ erectile dysfunction; NA ⫽ not available.
documented EF data: of 56 patients who were potent at year 2 after BT, 20 had documented ED at year 1 (17 of these had received prior hormone therapy and 3 had not). In those patients who were partially potent before implant, 76% had ED at year 1, 63% at year 2, and 48% at year 3 (physician-documented data). As expected, the ED rate was higher in this subgroup compared with the whole population; however, the same trend in recovery of potency was observed. Compliance in completion of patient-documented EF data Follow-up QoL questionnaires were available for 334 patients at 1 year; however, only 263 (79%) completed any of the sexual health questions shown in Table 1. The compliance rates at years 2 and 3 were 52% and 19%, respectively, for these questions. In those patients who did not answer the sexual health questions, the physician-documented levels of potency were 45%, 50%, and 60% at years 1, 2, and 3, respectively. This compares to the physiciandocumented levels of potency of 43%, 52% and 62% for all patients. Use of potency aids The use of potency aids or medications to achieve EF was documented in 31%, 36%, and 35% of potent patients at years 1, 2, and 3, respectively. When the type of assistance
Change in erectile function
From year 1 to From year 2 to year 2 year 3
All patients From potent to impotent 24 of 145* (17) 13 of 110† (12) From impotent to potent 50 of 187‡ (27) 24 of 87§ (28) Recovering potency with 20 of 50 (40) 12 of 24 (50) use of potency aids Patients who received hormone therapy From potent to impotent 13 of 80 (16) 9 of 78 (12) From impotent to potent 40 of 144 (28) 17 of 63 (27) Recovering potency with 17 of 40 (42) 8 of 17 (47) use of potency aids Patients who did not receive hormone therapy From potent to impotent 11 of 65* (17) 5 of 32 (16) From impotent to potent 10 of 43 (23) 7 of 24 (29) Recovering potency with 3 of 10 (30) 4 of 7 (57) use of potency aids Numbers in parentheses are percentages. * Potent patients for whom erectile function (EF) data were available at both years 1 and 2. † Potent patients for whom EF data were available at both years 2 and 3. ‡ Impotent patients for whom EF data were available at both years 1 and 2. § Impotent patients for whom EF data were available at both years 2 and 3.
used was documented, it was found to be sildenafil in 85% and alprostadil (intracavernosal or urethral) or a pump device in the remainder. Univariate analyses of postimplant ED The results for the statistical tests for association between the patient-related, tumor-related, and treatment-related factors are shown in Table 5, for both the physician-documented and patient-documented outcomes, and are displayed separately for years 1, 2, and 3 of follow-up. Factors predictive of ED on univariate analysis included age, pretreatment EF, smoking status, hormone therapy, PUTV, number of needles, postimplant CT volume, and implant number (order of implant). Penile bulb volume, D95, or D50 were not found to predict for BT-induced ED on univariate analysis in our data set.
Preservation of potency (%)
70 60 50 40 30 20 10 0 All patients
Patients following HT
Patients without HT
Fig. 1. Physician-documented postimplant potency rates at 1 year (solid bars), 2 years (hatched bars), and 3 years (striped bars) in all patients, in those who received hormone therapy (HT), and in those who received no HT.
Multivariate analyses of postimplant ED The best multivariable models for the data using physiciandocumented and patient-documented outcome are displayed in Tables 6 and 7, respectively. Age and preimplant EF were found to be consistent factors in the models. Use of hormones was significant only at the year 1 time point (Table 6). The number of needles used was a significant predictor for ED in two of the models (Table 6), and the PUTV was significant in a further two models (Table 7). When penile bulb volume, D50, and D95 were entered into these models, there was no evidence of an association with ED. This procedure was repeated separately for the
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Fig. 2. Physician-documented potency recovery at 2 and 3 years after implant, displaying percentages of patients who were impotent but previously potent (striped areas), patients who were impotent and previously impotent (light gray areas), patients who were potent and previously potent (dark gray areas), and patients who were potent but previously impotent (i.e., patients who recovered potency) (black areas). HT ⫽ hormone therapy.
data set from both observers, again with no evidence of an association. DISCUSSION The principal aim of this study was to determine patient, treatment, and dosimetric variables predictive of ED after prostate BT; in particular, we investigated whether dose to the penile bulb was predictive for ED after implant. Our main finding was that, with two independent investigators to contour the penile bulb and with the use of both physiciandocumented and patient-documented outcome data, there was no evidence that dose to the penile bulb is predictive for ED after prostate BT. It has been suggested that planning lower doses to the proximal penis might lead to potential gains in potency preservation in EBRT and prostate BT (13, 22). Although such an approach might be appropriate in EBRT planning, if used in prostate BT it raises the possibility of underdosing the prostatic apex and increasing the risk of treatment failure, without any potential gains in sexual function. We have found that at 1, 2, and 3 years after implant, different factors become predictive on multivariate analysis, with patient age being a dominant factor at all follow-up points and pretreatment EF being significant at 1 and 2 years. These have been found to be significant factors in previous studies of postimplant ED (3, 12, 18, 20, 21), and this finding is biologically plausible. Other patient-related factors (hypertension, diabetes, smoking) appear in only one model each and might represent relatively weak predictors of ED, as previously reported (3, 23, 24). The patient, tumor, and treatment characteristics in our study are broadly similar to those in other studies of postimplant ED (3, 12, 18, 20). Our data (Fig. 1) show that EF rates improve from year 1
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(43%) to year 3 (62%) and that this effect is primarily due to the majority of patients receiving hormone therapy. Consistent with this, in the multivariable models for physiciandocumented outcome, use of hormones was significant at the 1-year time point but not thereafter, in keeping with the time course of testosterone recovery. In patients who receive no hormone therapy, the percentage who have normal EF is stable at 59 – 61% over this time course. However, whereas some of these patients become impotent, others have shown steady recovery of potency (in the range of 20 –30% per year [Table 4]) from years 1 to 2 and from years 2 to 3. This is seen in patients regardless of whether hormone therapy was given. Cessation of androgen ablation alone cannot therefore explain the potency recovery in all patients. To our knowledge, recovery of sexual potency after prostate BT in a significant number of patients in the absence of androgen suppression has never before been described. Spontaneous potency recovery in the postprostatectomy setting has been reported, although recovery is significantly greater with early erectogenic therapy (25). In our study, no more than 50% of patients who recovered potency were using potency aids, which suggests that treatment of ED is not solely responsible for this trend either. From our data, other significant factors predictive for ED include number of needles used, PUTV, and implant order, and these deserve further comment. Number of needles and PUTV are positively correlated, as expected (Pearson correlation coefficient 0.65, p ⬍ 0.001), and it is conceivable that both might be surrogate factors for trauma to the erectile tissues. Both have previously been found to predict for ED (or timing of ED) on univariate analysis (3, 18, 20, 26). In addition, implant number appeared as a significant factor at 1 year after implant. This might represent an “institutional learning curve” for prostate implants, possibly as a result of reduced trauma in patients treated in the later years of the program. Over the time course of the BT program, there has been a deliberate attempt to reduce the number of needles used for each implant. At the same time, because of better operating skills, we have reduced the operating room time substantially and reduced the amount of trauma during the procedure by minimizing the number of “stabs” per needle. In keeping with this, implant number is negatively correlated with number of needles used (p ⫽ 0.036) and CT/PUTV ratio (p ⫽ 0.005) in our data set. We have also noted this learning curve effect in the development of postimplant urinary obstruction in our institution (27), which suggests that better outcomes and lower toxicity profile might be achieved in institutions with greater experience in prostate BT. All these findings support the hypothesis that trauma is a contributor to ED. Therefore, we believe that potency recovery might be partly explained by recovery from trauma induced at implant. This might explain the previously mentioned potency recovery in years 2 and 3 in patients treated without androgen suppression. In conclusion, we believe that recovery of potency in our cohort is undoubtedly related to testosterone recovery in patients who also received androgen suppression with their implant, and is also related to use of aids. However, as
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Table 5. Significance of test results (reported as p values) for univariate analyses of physician-documented and patient-documented erectile dysfunction Physician-documented outcome
Patient-related factors Age Preimplant erectile function Diabetes mellitus Vascular disease Hypertension Use of -blocker Smoking status Tumor-related factors T stage Gleason score Presenting PSA level Treatment-related factors Use of neoadjuvant hormones Implant factors No. of needles No. of seeds PUTV Postimplant CT volume CT/PUTV ratio Implant number Implant physician Prostate dosimetry V100 V150 D80 D90 Penile bulb factors Penile bulb volume Penile bulb D50 Penile bulb D95
Patient-documented outcome
1y
2y
3y
1y
2y
⬍0.0001* ⬍0.0001* 0.19 0.035* 0.027* 0.41 0.34
⬍0.0001* 0.0007* 0.056 0.11 0.21 0.34 0.42
0.0002* 0.18 0.88 0.087 0.66 0.51 0.55
⬍0.0001* ⬍0.0001* 0.12 0.53 0.68 0.91 0.45
0.0034* 0.0047* 0.53 0.82 0.97 0.38 0.016*
0.45 0.10 0.66
0.97 0.77 0.95
0.44 0.82 0.58
0.12 0.56 0.29
0.28 0.08 0.63
0.065
0.92
0.17
0.59
0.0027* 0.45 0.091 0.019* 0.40 0.0019* 0.26
0.21 0.24 0.11 0.15 0.76 0.80 0.33
0.024* 0.14 0.045* 0.12 0.37 0.32 0.33
0.018* 0.0094* 0.002* 0.055 0.079 0.93 0.33
0.027* 0.0023* 0.0006* 0.041* 0.20 0.41 0.36
0.37 0.17 0.22 0.46
0.74 0.74 0.04 0.76
0.10 0.78 0.48 0.43
0.54 0.99 0.67 0.19
0.53 0.24 0.36 0.13
0.85 0.35 0.45
0.57 0.66 0.93
0.26 0.68 0.85
0.98 0.21 0.14
0.33 0.77 0.44
⬍0.0001*
Abbreviations as in Table 1. * p ⬍ .05.
discussed above, trauma to the erectile tissues might be the cause of ED after prostate BT, and recovery from trauma might offer an explanation for the documented spontaneous potency recovery in our patient population.
Dose to the penile bulb also deserves further comment. We found that the mean penile bulb D50 and D95 values were 52.6 Gy and 26.0 Gy, respectively. These compare to values in the published literature for BT patients of 43– 69
Table 6. Best multivariate models for erectile dysfunction for physician-documented outcomes at 1 year, 2 years, and 3 years after implant 1y
2y
Variable
OR
p
Age Use of hormones Preimplant EF No. of needles Implant number Hypertension Above model with inclusion of: PB volume PB D95 PB D50
1.09 2.34 2.59 1.08 0.998 1.83
⬍0.0001 0.0020 0.0022 0.0048 0.011 0.050
1.07 1.01 1.00
0.52 0.64 0.83
Variable Age Preimplant EF Diabetes
Above model with inclusion of: PB volume PB D95 PB D50
3y OR
p
1.08 2.04 2.52
⬍0.0001 0.0075 0.0044
0.96 1.00 1.00
0.64 0.88 0.53
Abbreviations: EF ⫽ erectile function; OR ⫽ estimated odds ratio; PB ⫽ penile bulb.
Variable
OR
p
Age No. of needles
1.09 1.08
0.0003 0.024
Above model with inclusion of: PB volume PB D95 PB D50
0.81 1.00 1.00
0.13 0.99 0.76
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Table 7. Best multivariate models for erectile dysfunction for patient-documented outcomes at 1 year and 2 years after implant 1y Variable Preimplant EF Age PUTV Above model with inclusion of: PB volume PB D95 PB D50
2y OR
p
Variable
OR
p
20.14 1.09 1.05
⬍0.0001 0.0003 0.0086
2.79 1.07 1.06 2.86 3.37
0.048 0.018 0.015 0.018 0.018
0.90 1.01 1.00
0.43 0.60 0.81
Preimplant EF Age PUTV Current smoking Former smoking Above model with inclusion of: PB volume PB D95 PB D50
1.06 1.01 1.00
0.70 0.67 0.95
Abbreviations as in Tables 1 and 5.
Gy and 20.5–29 Gy (12, 20, 21). The equivalent values in the EBRT patient population are less well established but range from a median of 48.5 Gy to 67.3 Gy for D50 and 14 Gy to 51.1 Gy for D95 (13). Although these doses seem to be broadly similar for BT and EBRT, the much lower dose rate with BT theoretically should result in sparing of late radiation toxicity when compared with EBRT. The doses to the proximal 1 cm of the corpora cavernosa with BT are much lower (25.5 Gy for D50 and 14.5 Gy for D95) (20) than those reported for EBRT (mean dose of 59.4 Gy) (28). The corpora cavernosa are the main vascular structures in the penis and represent the true erectile tissue. This is supported by the finding that vascular leak is implicated in the pathophysiology of EBRT-caused ED (29). Therefore, it is likely that dose to the penile bulb is simply a surrogate for dose to the proximal crura in patients receiving EBRT (30). Whereas the dose to the proximal crura is high enough to be a plausible contributor to ED in EBRT, the much lower doses to these structures from BT (with the added effect of low dose rate) make dose to the crura an unlikely candidate for causing ED in this context. However, unlike EBRT, trauma to the crura undoubtedly occurs during implantation and might be implicated as a causative factor for ED. This is supported by our finding that number of needles is an independent predictor for ED and by the recovery of erectile function seen in patients regardless of whether they received hormone therapy. Methods of reporting ED have not been standardized in the literature, and the ABS has recently published recommendations for reporting late morbidity after prostate implants (31). The ABS-preferred instrument for reporting sexual function is the “sexual health inventory for men,”
which differs from the sexual health questions used in the QoL questionnaire at our institution. Most of our data were collected before the 2002 recommendations. We collected data on ability to achieve and maintain an erection (as well as data on ejaculatory function, current level of sexual activity, and satisfaction with sexual function, to be reported elsewhere), and we believe that this represents a reasonable assessment of potency as expressed by the patient. The physician-reported ED rates were lower than those from the patient-documented data, in keeping with previous studies (5). Noncompliance rates for completion of the sexual health questions were high; however, the physician-documented potency rates were similar regardless of whether patients completed these questions, arguing against a systematic bias in patient potency in completion of the QoL forms. We are confident that the use of both physician- and patient-documented potency as endpoints ensures that any bias of methods of reporting potency would not influence the robustness of the study findings. CONCLUSIONS In our study, factors predictive for ED included age, pretreatment EF, hypertension, diabetes, and smoking, as well as implant order, PUTV, and number of needles, which might ultimately point to trauma to the bulb as an important factor predicting ED after prostate BT. None of penile bulb volume, D50, or D95 was found to predict for ED at any time point by physician-documented or patient-documented outcomes. In addition, recovery of potency was seen in a proportion of patients, regardless of whether they had received prior hormone therapy or used potency aids.
REFERENCES 1. BC Cancer Agency. Crude cancer rates—incidence. Available at: www.bccancer.bc.ca/HPI/CancerStatistics/FF/Rates/Inc/ default.htm. Website accessed June 30, 2004. 2. Robinson JW, Moritz S, Fung T. Meta-analysis of rates of erectile function after treatment of localized prostate carcinoma. Int J Radiat Oncol Biol Phys 2002;54:1063–1068. 3. Merrick GS, Butler WM, Galbreath RW, et al. Erectile func-
tion after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002;52:893–902. 4. Rosen RC, Riley A, Wagner G, et al. The international index of erectile function (IIEF): A multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822– 830. 5. Litwin MS, Lubeck DP, Henning JM, et al. Differences in urologist and patient assessments of health related quality of
Erectile dysfunction after prostate brachytherapy
6. 7. 8.
9. 10.
11. 12.
13.
14.
15.
16. 17. 18.
life in men with prostate cancer: Results of the CaPSURE database. J Urol 1998;159:1988 –1992. Tierney LM, MacPhee SJ, Papadakis MA, eds. Current medical diagnosis and treatment. 43rd ed. New York: Lange Medical Books/McGraw-Hill; 2004. NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA 1993;270:83–90. Bradley KA, Chappell R, Yuan Z, et al. Erectile dysfunction and prostate brachytherapy doses to the penile bulb and neurovascular bundles [abstract]. Int J Radiat Oncol Biol Phys 2003;57(Suppl.):S399 –S400. DiBiase SJ, Wallner K, Tralins K, et al. Brachytherapy radiation doses to the neurovascular bundles. Int J Radiat Oncol Biol Phys 2000;46:1301–1307. Merrick GS, Butler WM, Dorsey AT, et al. A comparison of radiation dose to the neurovascular bundles in men with and without prostate brachytherapy-induced erectile dysfunction. Int J Radiat Oncol Biol Phys 2000;48:1069 –1074. Merrick GS, Wallner K, Butler WM, et al. Short-term sexual function after prostate brachytherapy. Int J Cancer 2001;96: 313–319. Merrick GS, Wallner K, Butler WM, et al. A comparison of radiation dose to the bulb of the penis in men with and without prostate brachytherapy-induced erectile dysfunction. Int J Radiat Oncol Biol Phys 2001;50:597– 604. Fisch BM, Pickett B, Weinberg V, et al. Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer. Urology 2001;57:955–959. Pickett B, Fisch BM, Weinberg V, et al. Dose to the bulb of the penis is associated with the risk of impotence following radiotherapy for prostate cancer [Abstract]. Int J Radiat Oncol Biol Phys 1999;45(Suppl.):263. Nag S, Ellis RJ, Merrick GS, et al. American Brachytherapy Society recommendations for reporting morbidity after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002;54: 462– 470. Blasko JC, Mate T, Sylvester JE, et al. Brachytherapy for carcinoma of the prostate: Techniques, patient selection, and clinical outcomes. Semin Radiat Oncol 2002;12:81–94. Keyes M, Pickles T, Agranovich A, et al. 125-I reimplantation in patients with poor initial dosimetry after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2004;60:40 –50. Stock RG, Kao J, Stone NN. Penile erectile function after permanent radioactive seed implantation for treatment of prostate cancer. J Urol 2001;165:436 – 439.
● A. G. MACDONALD et al.
163
19. Wallner KE, Merrick GS, Benson ML, et al. Penile bulb imaging. Int J Radiat Oncol Biol Phys 2002;53:928 –933. 20. Merrick GS, Butler WM, Wallner KE, et al. The importance of radiation doses to the penile bulb vs. crura in the development of postbrachytherapy erectile dysfunction. Int J Radiat Oncol Biol Phys 2002;54:1055–1062. 21. Kiteley RA, Lee WR, deGuzman AF, et al. Radiation dose to the neurovascular bundles or penile bulb does not predict erectile dysfunction after prostate brachytherapy. Brachytherapy 2002;1:90 –94. 22. Merrick GS, Butler WM. The dosimetry of brachytherapyinduced erectile dysfunction. Med Dosim 2003;28:271–274. 23. Wright JL, Newhouse JH, Laguna JL, et al. Localization of neurovascular bundles on pelvic CT and evaluation of radiation dose to structures putatively involved in erectile dysfunction after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2004;59:426 – 435. 24. Selek U, Cheung R, Lii M, et al. Erectile dysfunction and radiation dose to penile base structures: A lack of correlation. Int J Radiat Oncol Biol Phys 2004;59:1039 –1046. 25. Montorsi F, Guazzoni G, Strambi LF, et al. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: Results of a prospective, randomized trial. J Urol 1997;158:1408 –1410. 26. Ghilezan M, Vargas C, Gustafson G, et al. Erectile dysfunction (ED) after prostate cancer brachytherapy as sole treatment modality. The William Beaumont Hopsital’s experience with HDR vs. LDR (Pd103 permanent implants) [Abstract]. Radiother Oncol 2004;71(Suppl.):S56. 27. Schellenberg D, Keyes M, Bucci J, et al. Decreased incidence of urinary retention after prostate brachytherapy: The effect of the learning curve? [Abstract]. Radiother Oncol 2004;71(Suppl.): S55–56. 28. Mulhall JP, Yonover P, Sethi A, et al. Radiation exposure to the corporeal bodies during 3-dimensional conformal radiation therapy for prostate cancer. J Urol 2002;167:539 –542. 29. Zelefsky MJ, Eid JF. Elucidating the etiology of erectile dysfunction after definitive therapy for prostatic cancer. Int J Radiat Oncol Biol Phys 1998;40:129 –133. 30. Mulhall JP, Yonover PM. Correlation of radiation dose and impotence risk after three-dimensional conformal radiotherapy for prostate cancer [Letter]. Urology 2001;58:828. 31. Nag S, Ellis RJ, Merrick GS, et al. American Brachytherapy Society recommendations for reporting morbidity after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002;54: 462– 470.