The primary treatments for clinically localized prostate cancer confer equivalent cancer control for most patients but disparate side effects. In the current study, the authors sought to compare health-related quality of life (HRQOL) outcomes after the most commonly used treatments.
A total of 580 men completed the Medical Outcomes Study Short Form-36, the University of California-Los Angeles (UCLA) Prostate Cancer Index, and the American Urological Association Symptom Index before and through 24 months after treatment with radical prostatectomy (RP), external beam radiation therapy (EBRT), or brachytherapy (BT).
General HRQOL did not appear to be affected by treatment. Obstructive and irritative urinary symptoms were more common after BT (P < .001). Urinary control and sexual function were better after EBRT than BT (P < .001 and P = .02, respectively) and better after BT than RP (P < .001 and P = .01, respectively). Among potent men, recovery of sexual function was best after EBRT and was equivalent after bilateral nerve-sparing surgery or BT. Sexual bother was more common than urinary or bowel bother after all 3 treatments. Bowel dysfunction was more common after EBRT or BT than RP (P < .001).
In 2006, greater than 234,000 American men were diagnosed with prostate cancer.1 Despite advances in the primary treatments for localized prostate cancer, no randomized controlled trial to date has proven the superiority of 1 modality in terms of cancer control.2 Hence, attention has been directed toward the side effects of treatment. Several investigations have included longitudinal health-related quality of life (HRQOL) outcomes after treatment for localized prostate cancer3–18; however, most have used retrospective, cross-sectional analyses. Among the studies presenting longitudinal recovery trends, most either lacked baseline data or acquired it retrospectively, thereby introducing recall bias.6–16 Assessing baseline function (known to be highly correlated with posttreatment outcomes) allows subjects to serve as their own controls.8, 10, 19
Impairments in HRQOL after treatment for clinically localized prostate cancer can be substantial. Utilities studies have shown that men devalue time gained from curative treatment if it is associated with diminished QOL.20, 21 With such an arresting impact on patient perception, the effects of treatment on HRQOL need to be characterized more accurately. We prospectively evaluated general and disease-specific HRQOL after treatment for localized prostate cancer with radical prostatectomy (RP), external beam radiation therapy (EBRT), or brachytherapy (BT).
MATERIALS AND METHODS
Participants were recruited from March 1999 through January 2003. Eligible men had clinically localized (clinical TNM classification T1, T2, or limited T3), biopsy-proven adenocarcinoma of the prostate and chose curative treatment with RP (n = 307 patients), EBRT (n = 78 patients), or interstitial seed BT (n = 90 patients). Exclusion criteria included prior treatment for prostate cancer, the presence of metastatic disease on imaging studies, the receipt of neoadjuvant androgen ablation before registration, and an inability to read or understand English.
All recruitment and research protocols were approved by the University of California-Los Angeles (UCLA) Institutional Review Board and were Health Insurance Portability and Accountability Act (HIPAA)-compliant; informed consent was obtained from each participant. Clinical information collected from the medical record included pretreatment serum prostate-specific antigen (PSA) level, clinical T classification, and biopsy Gleason score. For recipients of EBRT, we collected total radiation dose and noted the use of neoadjuvant or adjuvant hormone therapy. For recipients of BT, we noted the isotope used, the number of seeds delivered, and the use of neoadjuvant or adjuvant hormone therapy. Recipients of combination BT with EBRT were grouped with BT recipients for analysis.
Follow-up assessments were completed 1 month, 2 months, 4 months, 8 months, 12 months, 18 months, and 24 months after treatment. Subjects who sought primary treatment elsewhere or did not return follow-up questionnaires beyond the initial assessment were excluded from this analysis.
We evaluated general HRQOL with the Medical Outcomes Study Short Form-36 (SF-36).22 The SF-36 consolidates 8 individual domains into Physical (PCS) and Mental (MCS) Composite Summary scores, which are standardized to the general population with a normative mean of 50 and a standard deviation of 10. The SF-36 has been extensively tested and shown to be reliable and valid in various populations (test-retest reliability coefficients ≥0.78 and internal consistency Cronbach α coefficients of 0.78–0.93).22, 23
We evaluated disease-specific QOL using the UCLA Prostate Cancer Index (PCI) and the American Urological Association Symptom Index (AUASI).24, 25 The PCI measures urinary, sexual, and bowel habits with function and bother scores. The urinary function domain reflects dryness rather than general voiding function, and is more accurately termed the urinary control domain. Bother scores measure the distress associated with dysfunction. Responses are scored from 0 to 100, with a higher score indicating better HRQOL. The PCI is reliable and valid in men with and without prostate cancer (test-retest reliability coefficients ≥0.77 and internal consistency Cronbach α of 0.65–0.93).24 The AUASI measures obstructive and irritative urinary symptoms and is scored from 0 to 35, with a higher score indicating worse symptoms. A score <8 indicates mild symptoms, a score between 8 and 19 indicates moderate symptoms, and a score >19 indicates severe obstructive and irritative urinary symptoms. The AUASI demonstrates excellent reliability, validity, and responsiveness (test-retest reliability coefficient of 0.92 and internal consistency Cronbach α coefficient of 0.86).25
Subjects who opted for surgical therapy underwent an anatomic radical retropubic prostatectomy.26 The decision to perform cavernosal nerve-sparing was made by the patient and surgeon. The degree to which the surgeon preserved the nerves was categorized as nonnerve-sparing (n = 28 patients; 9.1%), unilateral nerve-sparing (n = 31 patients; 10.1%), or bilateral nerve-sparing (n = 248 patients; 80.8%).
Subjects who selected EBRT received either 3-dimensional conformal therapy or intensity-modulated radiation therapy, designed to maximize the radiation dose to the prostate and minimize exposure to surrounding structures, including the bladder and rectum.27, 28 Radiation to the prostate was delivered in fractionated doses divided over multiple treatments for a total dose to the prostate of 68 to 77 gray (Gy), in doses per fraction of 180 to 200 centigray (cGy) prescribed at 90% to 100% of the isodose line. Short-term androgen deprivation therapy was administered concurrently to 46 EBRT subjects (59.0%).
Subjects who selected BT received either BT monotherapy (n = 67 patients; 74.4%) or BT in combination with EBRT (n = 23 patients; 25.6%) depending on the risk stratification of their prostate cancer. After preoperative volumetric analysis as a separate outpatient procedure, BT was performed through a transperineal approach with transrectal ultrasound guidance. According to preoperative dosimetric planning, a mean of 89 ± 34 radioactive seeds were implanted into the prostate. Plain radiography in the supine position confirmed seed placement. For high dose rate BT, transperineal catheters were placed for postoperative dosimetric planning. High-dose radiation was then delivered through the catheters, which were removed after the completion of therapy. In subjects who received combination BT and EBRT, BT was preceded by an attenuated EBRT total dose of 45 Gy to the low pelvis, centered on the prostate. Two to 4 weeks after treatment, computed tomography (CT) imaging of the pelvis verified postimplant dosimetry. Short-term androgen deprivation therapy was administered to 21 (23%) of the BT recipients.
Demographic and clinical variables were compared among treatment arms with chi-squared analysis for categorical variables and analysis of variance (ANOVA) for continuous variables. General and disease-specific HRQOL were assessed using the principle of survival analysis with Cox proportional hazards models to characterize recovery trends. Models were created based on the occurrence of subjects' return to baseline score. A subject was considered to have returned to baseline if his domain score was at least 90% of his baseline. For the AUASI, in which a higher score indicates a worse outcome, a subject was considered to have returned to baseline if his domain score was ≤110% of his pretreatment score. Once a subject returned to baseline, his time to return was censored. Cox proportional hazards ratios were compared to detect differences in the return to baseline among treatment groups. When no significant difference was noted in the outcome measure between 2 treatment modalities, they were collapsed.
We performed a subset analysis of sexual function in men who were potent prior to treatment, defining potency as a sexual function score of at least 70.29 RP subjects were stratified into bilateral versus nonnerve-sparing (unilateral nerve-sparing cases were grouped with nonnerve-sparing cases).
Multivariate models were created to determine factors associated with return to baseline for the HRQOL domains. In addition to treatment, covariates included age, ethnicity, relationship status, educational level, employment status, comorbid diseases, pretreatment serum PSA, and biopsy Gleason score. For ease of comparison, modalities were collapsed if no difference was noted in return to baseline for a given domain. Covariates were chosen a priori to incorporate variables known to influence QOL after prostate cancer treatment. Baseline scores for sexual function and AUASI, known to predict outcomes, also were included.8, 10, 19
We present PCI bother scores as the proportion of subjects reporting severe bother. We defined severe bother as a score of ≤25, which approximates 2 standard deviations below the mean baseline bother for urinary, sexual, and bowel domains. At each assessment point, chi-square analysis was used to compare the proportion of subjects reporting severe bother among treatment modalities. All statistical analyses were performed with SAS 8.02 software (SAS Institute Inc., Cary, NC).
Of the 580 eligible participants who completed a baseline assessment, 475 (81.9%) completed follow-up assessments and constitute the analytic sample (Table 1). Men undergoing surgery were younger and more frequently were employed. Although the number of comorbid conditions did not vary among treatment groups, fewer RP subjects reported a history of cardiovascular or peripheral vascular disease. EBRT subjects had a slightly higher mean PSA and biopsy Gleason score than RP subjects. Furthermore, a greater proportion of EBRT subjects had palpable disease (T2 or greater).
Table 1. Demographic and Clinical Characteristics of the Study Sample (n = 475)
RP (n = 307)
EBRT (n = 78)
BT (n = 90)
RP indicates radical prostatectomy; EBRT, external beam radiation therapy; BT, brachytherapy; SD, standard deviation; PSA, prostate-specific antigen.
Age, y (mean ± SD)
Ethnicity, no. (%)
Partner status, no. (%)
Education level, no. (%)
Less than college
College or more
Employment, no. (%)
At least part-time
Comorbidity count, no. (%)
Comorbidity, no. (%)
Mean ± SD
Biopsy Gleason score
Mean ± SD
Tumor stage, no. (%)
Figure 1 displays the domain means over time, all of which worsened noticeably at 1 month. EBRT and BT subjects fared similarly in all domains except the AUASI, with a higher proportion of BT recipients endorsing moderate to severe obstructive and irritative urinary symptoms. Although all HRQOL domains for EBRT and BT recipients soon plateaued, urinary control and sexual function scores among RP subjects continued to improve throughout the 24-month postoperative period.
Figure 2 presents Kaplan-Meier curves representing return to baseline HRQOL scores. No significant difference across treatment groups was noted for either the physical or mental domain, with nearly the entire cohort returning to baseline functioning by 4 months after treatment. Although nearly all RP and EBRT subjects quickly returned to baseline AUASI, BT subjects had greater irritative and obstructive symptoms. Subjects who underwent RP had worse urinary control and sexual function than either radiation group. Nonnerve-sparing surgery accounted for the majority of RP subjects with adverse sexual outcomes; of subjects undergoing bilateral nerve-sparing surgery (many of whom had poor pretreatment sexual function), 39% returned to baseline. Bowel dysfunction affected significantly fewer RP subjects than those who underwent either form of radiation. Sensitivity analyses using 80% and 70% as thresholds for defining return to baseline did not change the results appreciably.
Table 2 presents results from multivariate modeling of return to baseline HRQOL. No significant associations with general HRQOL were noted. For disease-specific HRQOL, treatment effects predominated. EBRT and RP subjects returned to baseline AUASI scores more rapidly. Compared with BT, urinary control and sexual function were better among EBRT recipients but were worse among those undergoing RP. Bilateral nerve-sparing RP was 2.3 times more likely to be associated with the return of baseline sexual function compared with nonnerve-sparing RP (hazards ratio [HR] of 0.66 [95% confidence interval (95% CI), 0.44–0.97] vs HR of 0.29 [95% CI, 0.15–0.57]); however, BT subjects were more likely than either of the RP groups to recover baseline sexual function (P = .03 and P < .001, respectively). Bowel function outcomes were better among RP subjects than radiation subjects (P < .001).
Table 2. Multivariate Models Evaluating Predictors of Return to Baseline by 24 Months After Treatment for Various HRQOL Domains
Among men who were potent prior to treatment (155 in the RP group [50.5%], 14 in the EBRT group [17.9%], and 18 in the BT group [20.0%]), those who underwent bilateral nerve-sparing RP had a greater initial loss of sexual function than those undergoing EBRT or BT but greater long-term improvement (Fig. 3). Multivariate modeling revealed that EBRT recipients were more likely than BT recipients to return to baseline sexual function (HR of 3.06 [95%CI, 1.01–9.28]). Conversely, RP subjects who underwent unilateral or nonnerve-sparing procedures were less likely than those who underwent BT to return to baseline sexual function (HR of 0.14 [95% CI, 0.03–0.73]).
Bother scores, which reflect patient distress related to urinary, sexual, or bowel dysfunction, are displayed in Figure 4. Posttreatment urinary bother among RP subjects compared favorably with BT recipients, although both groups had significantly greater bother than did recipients of EBRT immediately after therapy. Beyond 4 months posttreatment, the proportions of men reporting severe urinary bother did not differ significantly among treatment groups. Similarly, despite a delayed return to baseline sexual function, beyond 8 months posttreatment the proportions of men reporting severe sexual bother did not differ significantly among treatment groups. Sexual bother was much more common than urinary or bowel bother at all time points, regardless of primary therapy. Bowel bother was most pronounced in EBRT and BT recipients.
The current study has several important findings. First, urinary function differed after the 3 treatment modalities. Men who underwent BT had moderate voiding symptoms throughout the 24 months after treatment. Urinary morbidity after BT typically involves obstructive symptoms, with urinary retention rates as high as 34% at 1 week and 10% at 6 months.30 Symptom severity is highest immediately after treatment; however, up to one-third of patients undergoing BT experience an exacerbation of obstructive symptoms 24 months after treatment.31
RP was associated with worse urinary control in the immediate postoperative period, a known side effect of surgery given the proximity of the external urinary sphincter, a structure less affected by radiation. And although urinary control continues to improve beyond 2 years after RP,32 postprostatectomy incontinence rates based on patient-centered assessments vary from 8.4% to 35%, with lower rates of severe incontinence reported among younger subjects.8, 9 Our EBRT subjects were rarely incontinent, corroborating previous investigations.4, 7, 9, 12, 17
The urinary bother scores for our RP group compared favorably with those of our BT group. Beyond 4 months, differences in urinary bother among treatment groups were negligible. Urinary bother outcomes in our sample confirmed prior investigations of urinary symptoms in recipients of RP, EBRT, and BT.4, 12, 17 Data from CaPSURE, a national prostate cancer registry, showed that urinary bother does not correlate with pad use, suggesting that bother is more affected by irritative and obstructive symptoms than by incontinence.12 Our findings highlight the need to differentiate urinary control measures from measures of obstructive and irritative symptoms because treatments differentially affect outcomes for these domains.
Second, although treatment with RP may adversely affect sexual function, surprisingly few men in all 3 groups were fully potent before treatment. Long-term sexual function scores were better among RP subjects. However, because the baseline scores of the RP subjects were so much higher, fewer were able to regain their baseline function by 24 months. Nonetheless, their mean sexual function scores continued to improve throughout the 24-month postoperative period. Return-to-baseline analyses revealed more rapid recovery of baseline sexual function in EBRT subjects than in either RP or BT subjects, regardless of the use of erectile aids. Nerve-sparing surgery was found to have a marked positive effect on sexual outcomes after RP. However, caution should be exercised when interpreting our results because so few men in our EBRT and BT groups were actually potent at baseline. Severe sexual bother was similarly prevalent in all treatment groups at 24 months.
Our sexual function outcomes corroborated previous investigations of HRQOL after treatment for localized prostate cancer.5, 8, 16, 17 However, many of those investigations lacked baseline data regarding sexual function, an important prognosticator.8, 10 Furthermore, those investigations did not identify and analyze potent subsets. Although investigators have previously shown high rates of erectile dysfunction after RP,5, 8, 9, 11, 17, 32 our RP subjects who were potent preoperatively regained their sexual function at rates similar to those receiving BT or EBRT, especially after bilateral nerve-sparing RP. Prior analyses that have stratified the degree of nerve-sparing lacked comparison groups of men undergoing radiation.33 Our EBRT recipients had better sexual function than our RP and BT recipients; however, sexual function after EBRT declines for at least 5 years after treatment.34, 35
Third, bowel impairment was more common among subjects undergoing radiation therapy, with similar recovery profiles noted among recipients of EBRT and BT. Although urinary and sexual bother scores equilibrated with time across treatment groups, moderate bowel bother persisted in men receiving EBRT or BT. Indeed, 80% of RP subjects returned to baseline bowel function within 2 months of surgery. Our data corroborate outcomes from Wei et al.17 and from CaPSURE,13 both of which showed a minimal effect on bowel symptoms after RP. Although studies of the adverse effects of radiation therapy typically employ provider-defined QOL outcomes, limiting comparison of our results to those of other radiation series, the impairments we have documented appear to corroborate the literature.
The current study has several limitations. First, we did not control for several factors that might have biased our outcomes. Men undergoing EBRT or BT commonly receive neoadjuvant androgen ablation, especially in the presence of adverse clinical risk factors, and this can differentially impair sexual outcomes in men undergoing radiation.36, 37 In addition, men with aggressive clinical features may receive combined radiation therapy with an attenuated dose of EBRT prior to BT. Other investigations have shown that men treated with combined EBRT and BT have worse HRQOL outcomes than those treated with either one alone.4, 16, 38 That we included these subjects in our BT group may explain why our BT outcomes were slightly worse than published studies, especially with respect to bowel symptoms.13, 17 Newer EBRT protocols that apply a higher total radiation dose may further affect HRQOL results.
Second, we did not account for the impact of disease progression on the HRQOL of our subjects. Few investigations published to date have focused on HRQOL outcomes in men who experience biochemical recurrence after treatment for localized prostate cancer. Wei et al. showed that those patients who develop disease recurrence have diminished HRQOL in both general and disease-specific domains.17 Although we did not control for this factor, our intent was to describe longitudinal HRQOL outcomes after treatment for early-stage prostate cancer. Selection of a particular modality confers the risk that a patient may require concurrent or subsequent hormone therapy or salvage therapy.
Finally, although we evaluated outcomes prospectively, subjects selected their own treatment prior to study entry, a bias apparent in the demographics of our cohort. Those undergoing radiation were older, and age is associated with worse sexual and bowel outcomes after surgery and radiation.8, 10, 11, 13, 37 Furthermore, men undergoing radiation were more likely to report a history of cardiovascular or peripheral vascular disease, both of which are associated with erectile dysfunction.39 The preponderance of these comorbid conditions may have further biased our radiation cohorts toward worse sexual function.
Despite these limitations, the current study offers a prospective, longitudinal analysis of HRQOL outcomes after the 3 most commonly used treatments for early-stage prostate cancer. The study design allowed us to characterize 2-year recovery profiles in our subjects. With reliable baseline information, we were able to identify predictors of recovery of general and disease-specific HRQOL, and to differentiate treatment-related effects.
The findings of the current study address patients' clarion call for physicians to be more responsive to concerns about the quality of life, not only its quantity, after prostate cancer treatment. The remaining challenge lies in using the results of purely descriptive studies to optimize medical decision-making for future patients. To that end, it is critical to understand the difference between dysfunction and distress in the urinary, bowel, and sexual domains. Leveraging descriptive data to guide interventions that improve outcomes adds value to the clinical care we provide during the long survivorship period most patients experience. In addition, the current era of total quality improvement in medical care demands the perspicacious use of quality-of-life information to develop performance measures for providers.
Supported by a grant from the California Department of Health Services Cancer Research Program.