Survivorship Beyond Convalescence: 48-Month Quality-of-Life Outcomes After Treatment for Localized Prostate Cancer

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1 BRIEF COMMUNICATION Survivorship Beyond Convalescence: 48-Month Quality-of-Life Outcomes After Treatment for Localized Prostate Cancer John L. Gore, Lorna Kwan, Steve P. Lee, Robert E. Reiter, Mark S. Litwin Decision making for treatment of localized prostate cancer is often guided by therapeutic side-effect profiles. We sought to assess health-related quality-of-life outcomes for patients 48 months after treatment for localized prostate Men treated for localized prostate cancer (N = 475) were evaluated before treatment and at intervals during the 48 months after intervention. Changes in mean healthrelated quality-of-life scores and the probability of regaining baseline levels of health-related quality of life were compared between treatment groups. All statistical tests were two-sided. Urinary incontinence was more common after prostatectomy (n = 37) than after brachytherapy (n = 9) or external beam radiation therapy (n = 78) (both P <.), whereas voiding and storage urinary symptoms were more prevalent after brachytherapy than after prostatectomy (both P <.). Sexual dysfunction profoundly affected all three treatment groups, with a lower likelihood of regaining baseline function after prostatectomy than after external beam radiation therapy or brachytherapy ( P <.). Bowel dysfunction was more common after either form of radiation therapy than after prostatectomy. These results may guide decision making for treatment selection and clinical management of patients with health-related quality-of-life impairments after treatment for localized prostate J Natl Cancer Inst 9;: In 9, the immense public health burden of prostate cancer perseveres. Because no treatment has proven superiority in prostate cancer control, treatment side-effect profiles often determine treatment choices ( ). Prospective studies ( 2, 3 ) have characterized 2-year health-related quality-of-life outcomes among patients who were treated for clinically localized prostate cancer and have demonstrated treatment-specific impairments in urinary function, sexual function, and bowel function. Patient recovery profiles marked this 2-year period as one of convalescence. We hypothesized that the recovery documented in those prospective assessments would continue for surgical patients. Conversely, we hypothesized that the third and fourth years after radiation therapy would capture the onset of progressive functional decline as a result of cumulative radiation-induced injury. Herein, we describe the health-related quality-of-life outcomes for patients 48 months after treatment for localized prostate This analysis expands on previous work ( 2 ) that examined 2-year outcomes for patients treated for localized prostate cancer with radical prostatectomy (n = 37), external beam radiation therapy (n = 78), or brachytherapy (n = 9). Participant inclusion and exclusion criteria have been described previously ( 2 ). Briefly, subjects completed a comprehensive assessment of generic and prostate cancer specific healthrelated quality of life before treatment and completed follow-up questionnaires at, 2, 4, 8, 2, 8, 24, 3, 36, 42, and 48 months after treatment to capture maximal fluctuations in functional convalescence. All statistical tests were two-sided. Subjects who completed a 48-month survey were older (mean age ± SD = 63.7 ± 8. years) than those who did not (.2 ± 7. years) ( P <.); responders and nonresponders did not differ in other sociodemographic or clinical characteristics. We assessed generic health-related quality of life with the Medical Outcomes Study Short Form-36 ( 4 ), from which we derived physical and mental composite summary scores. The physical and mental composite scores measure generic, physical, and mental health and are standardized to the general US population with a normative mean of 5 and standard deviation of. Thus, a score of less than 5 denotes physical or mental function that is worse than the US average. We evaluated prostate cancer specific health-related quality of life with the University of California Los Angeles (UCLA) Prostate Cancer Index and the American Urological Association Symptom Index (AUASI) ( 5, 6 ). The Prostate Cancer Index quantifies urinary, sexual, and bowel dysfunction, with a higher score indicating better function. Conversely, higher scores on the AUASI indicate worse storage and voiding urinary symptoms. We examined mean scores over time and the subject s likelihood of regaining baseline function after treatment, as defined by a score within % of the baseline score. We modeled this binary outcome with nonlinear mixed models with random slopes and intercepts to evaluate the association between treatment modality and the likelihood of regaining baseline function. Other covariates were included in the models as fixed effects. In addition, we incorporated an interaction between treatment type and the duration of follow-up and between treatment type and the squared value of the duration of follow-up to control for the time dependence of functional recovery. Affiliations of authors: VA Greater Los Angeles Healthcare System Division of General Internal Medicine, Los Angeles, CA (JLG); UCLA Robert Wood Johnson Clinical Scholars Program, Division of General Internal Medicine and Health Services Research, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, CA (JLG); Jonsson Comprehensive Cancer Center (LK, RER, MSL), Department of Urology (JLG, RER, MSL), and Department of Radiation Oncology (SPL), David Geffen School of Medicine at University of California, Los Angeles, (UCLA), Los Angeles, CA. Correspondence to: John L. Gore, MD, Robert Wood Johnson Clinical Scholars Program, University of California, Los Angeles, 9 Broxton Ave, 3rd Floor, Los Angeles, CA 924 ( jgore@mednet.ucla.edu ). See Funding and Notes following References. DOI:.93/jnci/djp4 The Author 9. Published by Oxford University Press. All rights reserved. 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2 Table. Demographic and clinical characteristics of the study sample (N = 475) * Characteristic Prostatectomy (n = 37) (n = 78) (n = 9) P value Mean age (±SD), y. ± ± ± 6.9 <. Race or ethnicity, No. (%).34 White 262 (85.3) 66 (84.6) 7 (78.9) Not white 45 (4.7) 2 (5.4) 9 (2.) Married or partnered, No. (%) 256 (83.4) 64 (82.) 72 (8.).75 Education level, No. (%).4 Less than college 8 (26.4) 22 (28.2) 36 (.4) College or more 223 (73.6) 56 (7.8) 53 (59.6) Comorbidity count, No. (%). 7 (38.) 22 (28.2) 3 (34.4) 9 (35.5) 32 (4.) 34 (37.8) 2 8 (26.4) 24 (3.8) 25 (27.8) Mean PSA level (±SD), ng/ml 7.3 ± ± ± 4.6 <. Mean biopsy Gleason 6.3 ± ±. 6.2 ±.8.2 score (±SD) Tumor stage, No. (%).3 T 26 (7.4) 42 (53.9) 7 (78.9) T2 9 (29.3) 34 (43.6) 7 (8.9) T3 (.) 2 (2.6) 2 (2.2) * = external beam radiation therapy; PSA = prostate-specific antigen. Categorical variables were compared with 2 analysis and Fisher exact test. Continuous variables were compared with independent samples t tests. All statistical tests were two-sided. After estimation, we calculated the interval probability of regaining baseline function from the model coefficients and created smoothed probability plots ( 7 ). All protocols were approved by the UCLA institutional review board and were compliant with the Health Insurance Portability and Accountability Act. Each participant provided written informed consent. Patients who underwent prostatectomy were younger, more highly educated, and had fewer comorbid conditions than those who underwent external beam radiation therapy or brachytherapy ( Table ). External beam radiation therapy patients had more aggressive tumor characteristics at baseline, with higher pretreatment mean levels of prostate-specific antigen and a higher prevalence of prostate cancers that were palpable on rectal examination (ie, stage classification T2 or greater) at presentation. Physical and mental well-being were largely unaffected by treatment for clinically localized prostate cancer ( Figures, A and B, and 2, A and B ). We identified a higher burden of storage and voiding symptoms among those who underwent brachytherapy than among those treated with external beam radiation therapy or radical prostatectomy ( P <.) ( Figures, C, and 2, C ). Although brachytherapy was associated with a lower likelihood of regaining baseline AUASI score than radical prostatectomy, the probability of regaining baseline function improved throughout the 48-month study period. Conversely, subjects who underwent external beam radiation therapy demonstrated progressive worsening of urinary function related to storage and voiding symptoms. Patients treated with either type of radiation therapy experienced minor impairments in urinary control ( Figures, D, and 2, D ); continence was most profoundly affected among prostatectomy patients ( P <.). After prostatectomy, the likelihood of continued functional recovery of continence beyond 3 months was low. Sexual dysfunction profoundly affected all three treatment groups ( Figures, E, and 2, E ). Patients treated with external beam radiation therapy suffered progressive decline in sexual function throughout the 48 months after treatment. Alternatively, patients treated with brachytherapy demonstrated continued, if slight, improvement in sexual function over time. Interpretation of sexual function outcomes among radical prostatectomy patients was confounded by their superior baseline mean scores. Despite better mean scores, the likelihood that prostatectomy patients would regain baseline sexual function remained minimal 4 years after surgery ( P <.). Patients who were treated with either type of radiation therapy reported more bowel dysfunction than prostatectomy patients ( Figures, F, and 2, F ). CONTEXT AND CAVEATS Prior knowledge In the absence of definitive results from randomized controlled clinical trials, treatment of localized prostate cancer is often selected by use of therapeutic side effects. Study design Questionnaire-based study of health-related quality-of-life outcomes for patients 48 months after treatment for localized prostate cancer that included prostatectomy, brachytherapy, or external beam radiation therapy. Questionnaires were completed before treatment and at different times during the 48 months after treatment. Contribution Urinary incontinence was more common after prostatectomy. Voiding and storage urinary symptoms were more common after brachytherapy. Sexual dysfunction profoundly affected all three treatment groups, with the lowest likelihood of regaining baseline function after prostatectomy. Bowel dysfunction was more common after either form of radiation therapy. Implications Results from this study provide information that can be used to select the best treatments for individual patients with prostate Limitations Patients may have undergone treatments that were discordant with preexisting conditions (eg, subjects treated with radiation therapy had worse bowel function scores at baseline, which grew worse with treatment). Subjects whose cancer recurred were not analyzed separately, which might have biased the results toward poorer outcomes. From the Editors Recovery from functional impairments followed a varied trajectory after treatment for clinically localized prostate Urinary dysfunction varied statistically and clinically significantly by treatment type. Incontinence was more common after surgery, but storage and voiding symptoms were more prevalent after radiation therapy. From initial postoperative trends in prospective assessments, other investigators have projected continued improvement in urinary control beyond 24 months after radical prostatectomy ( 2, 3 ). However, we found that urinary control recovery jnci.oxfordjournals.org JNCI Brief Communication 889

3 A. Physical composite score C. AUA symptom index E. Sexual function peaked 3 months after surgery. This finding may guide clinical decision making regarding the optimal timing of secondary therapies. Reassurance may assuage the worries of those with early impairments, but it will not suffice when the dysfunction persists. Depending on the severity of the dysfunction, patients and their clinicians may consider interventions ranging from behavioral modification to medication to urethral sling or artificial urinary sphincter. Incontinence was rare after radiation, consistent with previous analyses ( 2, 3, 8 2 ). We found pronounced exacerbation of storage and voiding urinary symptoms soon after brachytherapy, with substantial timedependent recovery to baseline levels. The continued improvement throughout our study refutes a previous report ( 3 ) documenting a flare in obstructive symptoms B. Mental composite score D. Urinary control F. Bowel function Time (Months): Sample size (No.) Figure. Longitudinal mean scores for health-related quality of life as measured by various instruments. A and B ) Medical Outcomes Study Short Form-36 physical and mental composite scores. Higher scores indicate better physical and mental health. C ) American Urological Association (AUA) Symptom Index. Higher scores indicate worse storage and voiding urinary symptoms. D F ) University of California Los Angeles Prostate Cancer Index. Higher scores indicate better urinary control, sexual function, or bowel function. = radical prostatectomy; = external beam radiation therapy. 8 among brachytherapy patients up to 2 years after treatment. After external beam radiation therapy, morbidity was initially mild, but urinary function worsened progressively beyond 24 months. Sexual dysfunction was common, regardless of primary treatment. Consistent with previous analyses, we identified a progressive decline in sexual function among patients treated with external beam radiation therapy ( 4, 5 ). Surprisingly, sexual function steadily improved among patients treated with brachytherapy. Thus, some aspect of the delivery of radiation therapy differentially affects the erectile nerves, with external beam radiation therapy inducing progressive permanent injury and brachytherapy causing initial dysfunction, but its effect was often transient. Although sexual function scores were higher among the prostatectomy cohort 2 months after surgery, the likelihood of prostatectomy subjects regaining baseline function, under a strict definition of return to baseline, remained minimal throughout the 48-month study period. Thus, a clinician may advise patients considering surgery that although they may be sexually functional, they almost certainly will not function exactly as they did before surgery. Finally, bowel dysfunction was more common among those undergoing external beam radiation therapy or brachytherapy. and external beam radiation therapy impaired bowel function equally. Other analyses ( 2, 6 ) of patient-derived assessments have corroborated the minimal impact of surgery on bowel function, with bowel dysfunction limited to those undergoing external beam radiation therapy or brachytherapy. Our results must be interpreted in the context of several potential limitations. Subjects may undergo treatment discordant with preexisting detriments in their health-related quality of life (eg, brachytherapy in men with severe baseline voiding urinary symptoms). In our sample, external beam radiation therapy and brachytherapy subjects had worse bowel function scores at baseline. These preexisting symptoms may have predisposed those who received either radiation modality to more severe bowel dysfunction after treatment. Concomitant with primary therapy, men who receive external beam radiation therapy or brachytherapy may have received androgen deprivation therapy. In our sample, hormone therapy was administered to 59% of subjects who received external beam radiation therapy and 23% of subjects who received brachytherapy. Those with more aggressive tumor characteristics more commonly receive androgen deprivation with radiation, which may impair both generic and disease-specific health-related quality of life ( 7, 8 ). Similarly, risk-stratified men may undergo brachytherapy with an external beam radiation therapy boost, which is known to confer worse health-related quality of life than either brachytherapy or external beam radiation therapy alone ( 8, 7, 9 ). Furthermore, we did not separately examine subjects whose cancer recurred, which also impacts both general well-being and cancer-specific domains ( 2, ). Inclusion of these subjects may 89 Brief Communication JNCI Vol., Issue 2 June 6, 9

4 A. Physical composite score have biased our sample toward worse outcomes. However, we sought to characterize long-term health-related quality of life after treatment for clinically localized prostate cancer, inclusive of factors inherent to the treatment choice. This method of analysis certainly introduces bias, but it also facilitates valid comparison of the expected outcomes of an average subject undergoing treatment for localized prostate We have characterized long-term health-related quality-of-life outcomes after treatment for clinically localized prostate Capturing baseline function before treatment permitted comparison of interval mean scores with pretreatment function. With assessments through 48 months after treatment, we encapsulated both the convalescent period immediately after therapy and the subsequent period B. Mental composite score C. AUA Symptom Index D. Urinary control E. Sexual function F. Bowel function characterized by functional improvement, functional plateau, or the onset of functional decline, depending on the primary therapy and the health-related quality-oflife domain assessed. These results may guide decision making for treatment selection and clinical management of patients with health-related quality-of-life impairments after treatment for localized prostate References Time (Months): Sample size (No.) Figure 2. Smoothed probability plots of the interval likelihood of returning to baseline healthrelated quality of life as measured by various instruments. A and B ) Medical Outcomes Study Short Form-36. C ) American Urological Association (AUA) Symptom Index. D F ) University of California Los Angeles Prostate Cancer Index. RTB = return to baseline; = radical prostatectomy; = external beam radiation therapy.. D Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 998 ; 28 ( ): Litwin MS, Gore JL, Kwan L, et al. Quality of life after surgery, external beam irradiation, or brachytherapy for early-stage prostate cancer. Cancer. 7 ; 9 ( ): Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 8 ; 358 ( 2 ): Ware JE Jr. SF-36 Health Survey: Manual and Interpretation Guide. New England Medical Center ; Boston, MA : The Health Institute ; Litwin MS, Hays RD, Fink A, Ganz PA, Leake B, Brook RH. The UCLA Prostate Cancer Index: development, reliability, and validity of a health-related quality of life measure. Med Care. 998 ; 36 ( 7 ): Barry MJ, Fowler FJ Jr, O Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol. 992 ; 48 ( 5 ): ; discussion Pinheiro JC, Bates DM. Approximations to the log-likelihood function in the nonlinear mixed-effects model. J Comput Graph Stat. 995 ; 4 ( ): Brandeis JM, Litwin MS, Burnison CM, Reiter RE. Quality of life outcomes after brachytherapy for early stage prostate cancer. J Urol. ; 63 ( 3 ): Litwin MS, Pasta DJ, Yu J, Stoddard ML, Flanders SC. Urinary function and bother after radical prostatectomy or radiation for prostate cancer: a longitudinal, multivariate quality of life analysis from the Cancer of the Prostate Strategic Urologic Research Endeavor. J Urol. ; 64 ( 6 ): Potosky AL, Davis WW, Hoffman RM, et al. Five-year outcomes after prostatectomy or radiotherapy for prostate cancer: the prostate cancer outcomes study. J Natl Cancer Inst. 4 ; 96 ( 8 ): Talcott JA, Rieker P, Clark JA, et al. Patientreported symptoms after primary therapy for early prostate cancer: results of a prospective cohort study. J Clin Oncol. 998 ; 6 ( ): Wei JT, Dunn RL, Sandler HM, et al. Comprehensive comparison of health-related quality of life after contemporary therapies for localized prostate cancer. J Clin Oncol. 2 ; ( 2 ): Cesaretti JA, Stone NN, Stock RG. Urinary symptom flare following I-25 prostate brachytherapy. Int J Radiat Oncol Biol Phys. 3 ; 56 ( 4 ): Mantz CA, Nautiyal J, Awan A, et al. Potency preservation following conformal radiotherapy for localized prostate cancer: impact of neoadjuvant androgen blockade, treatment technique, and patient-related factors. Cancer J Sci Am. 999 ; 5 ( 4 ): Zelefsky MJ, Cowen D, Fuks Z, et al. Long term tolerance of high dose three-dimensional conformal radiotherapy in patients with localized prostate carcinoma. Cancer. 999 ; 85 ( ): Litwin MS, Sadetsky N, Pasta DJ, Lubeck DP. Bowel function and bother after treatment for early stage prostate cancer: a longitudinal quality of life analysis from CaPSURE. J Urol. 4 ; 72 ( 2 ): jnci.oxfordjournals.org JNCI Brief Communication 89

5 7. Hollenbeck BK, Dunn RL, Wei JT, McLaughlin PW, Han M, Sanda MG. Neoadjuvant hormonal therapy and older age are associated with adverse sexual health-related quality-of-life outcome after prostate brachytherapy. Urology. 2 ; 59 ( 4 ): Hollenbeck BK, Wei JT, Sanda MG, Dunn RL, Sandler HM. Neoadjuvant hormonal therapy impairs sexual outcome among younger men who undergo external beam radiotherapy for localized prostate cancer. Urology. 4 ; 63 ( 5 ): Speight JL, Elkin EP, Pasta DJ, et al. Longitudinal assessment of changes in sexual function and bother in patients treated with external beam radiotherapy or brachytherapy, with and without neoadjuvant androgen ablation: data from CaPSURE. Int J Radiat Oncol Biol Phys. 4 ; ( 4 ): Miller DC, Sanda MG, Dunn RL, et al. Longterm outcomes among localized prostate cancer survivors: health-related quality-of-life changes after radical prostatectomy, external radiation, and brachytherapy. J Clin Oncol. 5 ; 23 ( 2 ): Funding California Department of Health Services V-27. Notes The funding organization had no involvement in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. M. S. Litwin had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors have no financial disclosures and no conflicts of interest to report. The information contained in this manuscript was previously presented at the 8 American Urological Association Annual Meeting. Manuscript received November 9, 8 ; revised March 8, 9 ; accepted April 6, Brief Communication JNCI Vol., Issue 2 June 6, 9