Affiliations of authors: Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD; Medical Service, Department of Veterans Affairs Medical Center, Albuquerque, NM; Division of Urology, Department of Surgery, University of Utah, Salt Lake City; Division of Urology, University of Connecticut Health Center, Farmington; Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles; Fred Hutchinson Cancer Research Center, Seattle, WA.
Correspondence to: Arnold L. Potosky, Ph.D., Applied Research Program, NCI, EPN Rm. 4005, 6130 Executive Blvd., MSC 7344, Bethesda, MD 208927344 (e-mail: potosky{at}nih.gov).
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ABSTRACT |
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INTRODUCTION |
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Androgen deprivation therapy (ADT) has been proposed as an alternative to "watchful waiting" for men with clinically localized disease electing less aggressive management (2). Estrogens, such as diethlystilbestrol, and surgical orchiectomy have been standard palliative treatments for metastatic prostate cancer for the past several decades. However, the cardiovascular risks associated with oral antiandrogenic agents and the invasiveness of surgery made them unacceptable options for many men with localized disease. In the last decade, safer antiandrogenic agents have been developed, particularly injectable luteinizing hormone-releasing hormone (LHRH) agonists. Community urologists now include ADT as a potential treatment option for some men with clinically localized prostate cancer as a means of preventing or delaying progression while avoiding complications associated with local therapies (3). However, there is no definitive evidence that early ADT alone improves length or quality of life in men with clinically localized prostate cancer, though there are randomized trials ongoing in Europe that evaluate this issue.
However, ADT is costly (4,5), and previous outcomes studies have shown that androgen deprivation adversely affects quality of life and leads to increased fatigue, difficulties with erection, and declines in sexual interest and enjoyment (69). To date, researchers have focused on outcomes of metastatic disease or have sampled cases from single institutions. Using data from a randomly sampled population-based cohort, we investigated the prevalence of ADT and the factors associated with its use among men recently diagnosed with clinically localized prostate cancer. After adjusting for disease and sociodemographic characteristics, we compared multiple outcomes within 1 year after initial diagnosis, including sexual function, general health status, and satisfaction with treatment between men receiving ADT and those receiving no therapy.
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SUBJECTS AND METHODS |
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In 1994, the Prostate Cancer Outcomes Study (PCOS) was initiated within the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)1 Program (1) to investigate variations in the initial treatment of prostate cancer and to describe health outcomes in a socioeconomically heterogeneous cohort of newly diagnosed prostate cancer patients treated primarily in community medical practices (10). The PCOS enrolled men who were diagnosed as having primary invasive prostate cancer from October 1, 1994, through October 31, 1995, and who were residents of areas covered by six population-based registries participating in the SEER Program (Connecticut, Utah, and New Mexico and the metropolitan areas of Atlanta, GA , Los Angeles, CA, and SeattlePuget Sound, WA).
The PCOS randomly sampled a total of 5672 men from 11 137 eligible men residing in these areas, of whom 3486 (62%) participated by completing a 6-month and/or a 12-month self-administered questionnaire and consenting to medical record reviews. Men under age 60 and case subjects with African American or Hispanic background were sampled in higher proportions than were white case subjects over age 60 to permit a higher representation of these subgroups in all PCOS analyses. Details of the sampling plan and data collection and a comparison of respondents to nonrespondents are described elsewhere (10).
For the present study of men with clinically localized prostate cancer, 413 men diagnosed with metastatic prostate cancer were excluded, including men with positive distant lymph nodes, positive bone scans or other imaging studies, or other evidence of distant metastases. Men receiving the following local therapies were excluded: 1620 men who received a radical prostatectomy, 734 men who received radiation therapy, and 18 men who had cryosurgery, all within the first 12 months following initial diagnosis. These exclusions left 701 men with clinically localized prostate cancer who did not receive local therapy. An additional 40 patients were excluded because the timing of ADT could not be determined, leaving a final sample of 661 patients (245 receiving ADT and 416 receiving no primary therapy).
Data Collection
After notifying physicians, PCOS investigators at each site contacted patients by mail approximately 6 months after initial diagnosis. Respondents were asked to complete a self-administered questionnaire and provide consent for access to medical records. Respondents to the 6-month survey were contacted to complete identical questionnaires 6 months later, i.e., approximately 12 months after diagnosis. Approximately 90% (percentage reflects those who responded to surveys at 6 and/or 12 months) completed the mailed survey, with the remaining 10% completing interviews by phone or in person. The PCOS study was approved by local Institutional Review Boards at the six participating cancer registries.
The survey instrument obtained information on demographics, satisfaction with treatment, comorbidity, and both general and disease-specific measures of health-related quality of life (HRQOL) and functional status. Disease-specific HRQOL was measured with the use of a newly adapted prostate-cancer-specific instrument, based on items from three existing instruments (1113). The disease-specific component of the instrument contained six scales that used 18 items covering urinary, bowel, and sexual functioning; the instrument is reprinted elsewhere (10). The sexual function items analyzed in this study include questions about level of sexual interest, frequency of activity, and the ability to achieve and maintain an erection firm enough for intercourse. Other items asked respondents about overall physical discomfort, worry, limitations in daily activities, and bother due to prostate cancer or treatments.
Because surveying all case subjects before initial treatment was not possible (we were unable to obtain physician consent to contact all eligible patients immediately following initial diagnosis), respondents were asked on the 6-month survey about urinary, bowel, and sexual function just before prostate cancer diagnosis and about their functional status during the month prior to survey. Of the 661 case subjects in the study, 544 completed the initial survey 6 months after diagnosis and provided retrospective assessments of prediagnostic sexual function that were used as baseline measures. The accuracy of the 6-month retrospective recall of sexual function (and urinary and bowel function) was evaluated in a separate validation study (14).
We assessed general HRQOL by selecting five domains (bodily pain, depression/anxiety, vitality, role limitations due to physical health, and role limitations due to emotional health) and a global item on overall health status from the Medical Outcomes Study (MOS) 36-item generic health status questionnaire. This instrument, which has excellent reliability and validity, has been used in numerous studies to measure general HRQOL (15).
Written informed consent was obtained from all subjects for medical record review. Centrally trained, experienced abstractors from each registry abstracted medical records from hospitals, free-standing radiological or surgical centers, Veterans Affairs centers, health maintenance organizations, and private physicians' officesusually the treating urologist or radiation oncologist. The outpatient medical record abstractions obtained information not routinely collected by SEER registries, such as Gleason grade, baseline prostate-specific antigen (PSA), baseline symptoms, and type and dates of specific hormonal agents given.
Statistical Analysis
Baseline sociodemographic, clinical, and quality-of-life factors associated with the use of primary ADT, versus no therapy, were evaluated by means of logistic regression analysis. Primary ADT was defined as the implementation of surgical (orchiectomy) or medical (LHRH agonist injections) central androgen blockade, with or without combined androgen blockade (flutamide or bicalutamide), preceding the completion of the 12-month postdiagnosis patient survey.
A cross-sectional analysis of health outcomes that compared men receiving ADT with men receiving no therapy was performed using responses from the 12-month postdiagnosis survey. Responses to questionnaire items were rescaled from the original three to five response categories to either binary or trichotomous variables, based on both the clinical co-investigators' judgments and the distributions of responses. Responses from the 6-month survey were used (carried forward) for 117 patients (49 patients with ADT and 68 watchful waiting patients) who did not complete the 12-month survey. Few differences in baseline sociodemographic, clinical, or quality-of-life measures were detected between 12-month responders and nonresponders for whom 6-month surveys were used. We found that 12-month nonresponders included a slightly higher percentage of African Americans, a higher concentration of respondents with a Gleason score of 6, and a higher number of respondents from the Los Angeles area.
Because the 6-month survey was used for the 12-month nonresponders, these patients had a shorter duration between ADT and self-reported complications. Combining responders and nonresponders could thus systematically reduce the observed rate of complications in the ADT group. To investigate the potential effects of including patients with shorter duration on ADT, we conducted an analysis of all outcomes excluding the 6-month responders. We found no important differences with the results obtained when including them. Therefore, the 12-month nonresponders were retained for all subsequent analyses.
Differences between ADT and no therapy groups were statistically evaluated using logistic (for binary outcomes) or polychotomous (for multicategory outcomes) regression models. The model of treatment patterns used receipt of ADT as the dependent variable, and models of health outcomes used summarized response categories (dichotomous or trichotomous) as the dependent variable. All regression models assessing health outcomes included baseline sociodemographic and clinical characteristics, in addition to presence of a sexual partner, baseline impotence, comorbidity, and local and metastatic symptoms.
We used the following definition for clinical stage. A patient with clinical stage T1 had no positive imaging studies, no metastatic disease, and no abnormal or suspicious digital rectal exams (no palpable disease and disease confined to the prostate). Case patients assigned to stage T2 had the same characteristics as those assigned to stage T1 except they had an abnormal or suspicious digital rectal exam (likely palpable disease).
The combined effects of treatment type and age, race/ethnicity, levels of PSA, and Gleason grade on outcomes were systematically examined using interaction terms in all regression models. Wald-type tests with the robust variance estimator were used to assess statistical significance of all estimated regression coefficients. All P values presented in the text are mainly for descriptive purposes. They are derived from the regression models and reflect adjustments for the independent variables shown in Table 1.
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RESULTS |
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Analysis of clinical characteristics demonstrates that after controlling for all other factors in Table 1, receipt of ADT was associated with clinical stage T2, with Gleason scores higher than 6, and with baseline PSA values over 20 ng/mL. Approximately two thirds of the patients receiving ADT (n = 159) had either baseline Gleason scores greater than 6 or serum PSA values above 20 ng/mL. Both groups of patients, those without any therapy and those with ADT, had similar comorbidity, baseline urinary obstructive symptoms, and weight loss, anorexia, or fatigue. Patients receiving ADT were less likely to report achieving an erection firm enough for intercourse prior to their treatment after adjusting for all other covariates in Table 1
(36.1% among those receiving ADT, 56.0% among those receiving no therapy; P = .001). Men receiving no therapy had statistically significantly more libido and more frequent sexual activity at baseline than did men who received ADT (data not shown).
We also characterized the sample according to the likelihood of pathologically organ-confined disease to facilitate comparisons of health outcomes. Following the nomograms published by Partin et al. (17), which were based on results of 4133 men undergoing radical prostatectomy, we used a combination of values for PSA, Gleason grade, and clinical stage to define this new variable. About one half of the sample (336 of 661 study subjects) had a 50% or more chance of having organ-confined disease. Among these, 74 men (25%) received ADT, while of the 325 men with less than a 50% chance of having organ-confined disease, 171 (53%) received ADT.
Sexual Function
Because of the substantial difference in function at baseline, the changes in sexual function in the ADT group were compared with those of the no therapy group by examining only those men who reported good sexual function at baseline (Fig. 1). Among men (total number of patients = 444; ADT = 149 patients; no therapy = 295 patients) reporting some interest in sexual activity at baseline, 79 (54%) of ADT patients and 35 (13%) of no therapy patients reported no interest in sexual activity approximately 1 year later (P<.001). Among potent men (total n = 311; ADT = 88 patients; no therapy = 223 patients) at baseline, 68 (80%) of ADT patients versus 60 (30%) of no therapy patients were impotent 1 year later (P<.001). The ADT group more often reported having a big or moderate problem, although not statistically significant, with their sexual function compared with patients receiving no therapy, even after adjustment for other covariates (20.1% and 15.2%, respectively, P = .51).
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These results for sexual function were not different when we analyzed the sexual outcomes among men with more than 50% probability (based on Partin nomogram) of having organ-confined disease and among men with 50% or less probability of having organ-confined disease.
Overall Perceptions, Satisfaction, and Health Status
General perceptions about the impact of prostate cancer, overall health status, and satisfaction with treatment choice are presented in Table 2. ADT patients reported statistically significantly higher levels of physical discomfort due to prostate cancer than did untreated patients (P = .02). There was little difference in men's worry about prostate cancer, but ADT patients reported more physical limitations and overall bother due to prostate cancer than did untreated patients. These differences did not remain statistically significant after adjustment for baseline characteristics. A greater proportion of untreated patients (n = 212; 53.8%) perceived themselves not to be free of prostate cancer than did ADT patients (n = 109; 46.4%) (P = .005). Eighty four (33.1%) of ADT patients reported being in poor or fair overall health compared with 91 (21.5%) of the untreated patients (P = .08).
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A cross-sectional comparison of the ADT and untreated patients on the five scales of the MOS short form (SF)-36 measuring generic outcomes of physical and mental functioning approximately 1 year after diagnosis is presented in Fig. 2. There was reduced physical role functioning (mean score was 50.2 in the ADT group versus 61.3 in the no therapy group) and vitality (mean score was 53.1 for patients treated with ADT 1 year after treatment versus 60.4 for men in the no therapy group). However, after adjusting for all other demographic and clinical characteristics, physical role function differences diminished (P = .20), while vitality differences remained, though at a borderline level of statistical significance (P = .05).
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DISCUSSION |
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In our cohort, the use of ADT was associated with high Gleason scores and a PSA in excess of 20 ng/mL but was not strongly associated with age, race, or socioeconomic status. Among those men treated with ADT, nearly 66% had prognostic factors predictive of progression, although the vast majority exhibited no symptoms of metastatic disease such as weight loss, fatigue, bone pain, or anorexia. For this group of patients with possible advanced disease, who are generally considered unlikely to benefit from surgery, the use of ADT may represent an alternative treatment to radiation therapy or "watchful waiting." Among those patients receiving ADT soon after initial diagnosis, clinicians may be treating an elevated or rising PSA as a sign of underlying advanced disease in an attempt to delay or prevent progression to symptomatic disease. There is evidence from randomized trials of ADT adjuvant to primary radiotherapy and radical prostatectomy that provide some rationale for this management strategy (18,19). For the smaller group (about one quarter) of patients in our study with more favorable prognostic factors, the use of ADT may reflect the patient's preference to take a more active treatment approach than a watch-and-wait strategy, while avoiding the treatment-related complications associated with prostatectomy or radiotherapy (20). Alternatively, some patients may have received ADT for biochemical or clinical progression during the first year after diagnosis.
Poorer baseline sexual function was associated with the use of ADT, even after adjustment for age and other demographic and clinical factors. Some men with poor sexual function may choose to undergo ADT because they perceive they are sacrificing little in return for a potentially beneficial therapy, while men with good sexual function at the time of diagnosis may elect to avoid a therapy that is known to adversely affect sexual function.
We found a large decline in multiple attributes of sexual function, including libido, erectile function, and frequency of sexual activity in men receiving ADT that was consistent with prior studies of men with metastatic prostate cancer treated with ADT (69). Declines were observed among men with good prediagnosis function after adjusting for multiple characteristics of disease severity and comorbidity. The decline in sexual function in men having no therapy suggests that diagnosis alone may have an impact on men's sexual function after prostate cancer. This apparent psychological impact may partly explain the finding that sexual dysfunction was reported as a "big problem" at nearly the same frequency by men in the ADT group and by those in the untreated group. Alternatively, some men on ADT have lowered their expectations of good sexual function after receiving ADT. It is possible that local extension of cancer into the nearby neurovascular bundles or related structures may lead to declines in sexual function among untreated men. Biased recall of prediagnosis function may also partly account for these observations.
We found a tendency for more frequent physical discomfort and limitations in daily activities due to prostate cancer or its treatment, lower general physical function and vitality scores, and slightly poorer overall self-rated health status among patients who received ADT after adjusting for disease severity, comorbidity, and patient sociodemographic characteristics. The results are consistent with those in a previous study (21), which found impaired physical and emotional health among men with nonmetastatic cancer given ADT after failure of local therapy. These findings of systemic effects are consistent with our personal clinical experience in which we have observed patients complaining of fatigue and weakness due to muscle wasting and weight gain (observed by R. A. Stephenson and P. C. Albertsen). However, while the consistency of our results supports the view that ADT likely causes clinically relevant declines in these general health domains for patients, only the difference in physical discomfort due to prostate cancer remained statistically significant after adjustment for other variables. The systemic effects of ADT may be smaller in men with clinically localized cancer than in metastatic cases or, alternatively, our study may lack the power (sample size) or instruments sensitive enough to detect differences with statistical significance. We also did not have baseline measures of these generic outcomes to assess differential changes in the treated and untreated groups. The lack of longer follow-up did not permit us to assess loss of bone density and osteoporosis, which have been documented as clinically significant complications associated with long-term use of ADT (22,23). Ongoing follow up of the PCOS cohort will permit us to assess these outcomes in future analyses.
Previous reports that compared combined androgen blockage (CAB) with orchiectomy alone revealed significantly more diarrhea and worse emotional functioning among patients receiving CAB at 6 months after therapy (24). We did not find that adding oral antiandrogens had any noticeable effect on health outcomes in our analysis.
The majority (78%) of men receiving ADT were treated with regular hormone injections (LHRH agonists), while the remaining men had an orchiectomy. In a separate analysis, we compared the effects of medical versus surgical ADT (25). In the cohort of all PCOS patients receiving ADT alone as initial therapy, we found that sexual function following surgery was similar to that following medical hormonal therapy and that stage at diagnosis (localized versus advanced stage) had little effect on outcomes 1 year after diagnosis. However, these findings must be balanced against other unmeasured concerns about orchiectomy that may influence patient preferences for LHRH agonists. Preference for injections over surgery may be associated with fear of permanent mutilation, loss of masculine self-image, and the ability to discontinue injections.
This study has the following limitations. First, the PCOS relied on 6-month retrospective recall for baseline sexual function. In a separate validation of recall accuracy, we found a 77% agreement between baseline and 6-month recall of erectile function; however, there was no consistent bias toward under- or overestimation by men of their prediagnostic function (14). No evidence supports differential recall bias by type of therapy, so it should not have substantially influenced our results. Second, the response rate to the overall PCOS study was approximately 62%, and nonresponders differed somewhat from responders in age and socioeconomic status (10). Although we adjusted for these characteristics, our results may have been biased if responders systematically differed from nonresponders regarding other variables not included in our models. Third, statistical adjustments for the confounding factors cannot definitively account for the selection bias introduced by nonrandomized comparison groups.
In summary, this study demonstrates that use of ADT among men diagnosed with clinically localized prostate cancer not receiving local therapy is common in the United States and that the use of this therapy is closely associated with clinical prognostic factors predictive of advanced disease. Given the uncertain efficacy of ADT to extend survival, patients and clinicians should discuss the possibility of substantial declines in sexual outcomes and decrements in general physical function and vitality associated with this management approach.
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NOTES |
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1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.
We thank the men who, by their participation in the PCOS, have contributed to a better understanding of the effects of prostate cancer on men's lives. J. William Eley and Jonathan M. Liff from the Atlanta registry, and Ann S. Hamilton and Dennis Deapen from the Los Angeles registry, contributed significantly to the conception and design of the study and to data collection as senior PCOS co-investigators. We thank the physicians from the six SEER areas who assisted in the collection of data from their patients and from medical records. We thank the following individuals for their outstanding efforts in data collection and management: Jennifer Stevens, Information Management Services (IMS), Inc., Silver Spring, MD, who serves as the Data Coordinator for the PCOS, and Ming Sheu and Neil Rolfes, of IMS, who assisted with the data processing.
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Manuscript received July 6, 2001; revised January 18, 2002; accepted January 24, 2002.
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