We undertook this study to evaluate practice patterns associated with AS use in men undergoing EBRT for localized prostate cancer using a recent population-based cohort. We found that adherence to clinical guidelines with respect to use of AS varied substantially across all disease risk categories. Our results suggest overuse of AS among men within the low-risk disease category, in which approximately one third of men received AS without supporting evidence. Approximately one half of men with intermediate-risk disease received AS, which remains an area of current controversy. Finally, there was underuse of AS within the high-risk disease category, in which nearly one fifth of men did not receive AS despite evidence showing an overall survival benefit when AS is combined with EBRT.
Our results are consistent with the findings of other investigators that suggest overuse of AS, particularly with LHRH agonists, among men with low-grade nonmetastatic prostate cancer (9
). Our study extends these findings by examining patterns of AS use specifically in combination with EBRT and by disease risk category. A prior analysis using SEER-Medicare data found that the overall use of LHRH agonists among patients diagnosed with prostate cancer increased nearly fourfold between 1991 and 1999, whereas the use of LHRH agonists among patients over the age of 80 with localized, low-grade prostate cancer increased by a factor of eight (9
Several studies have suggested that financial incentives may have a significant influence on patterns of AS use (10
). Medicare expenditures for the use of LHRH agonists peaked in 2003 at nearly $1 billion, making it one of the most commonly prescribed physician-administered medications. In some cases, the administration of LHRH agonists constituted up to 40% of total urologic practice revenue. However, reimbursement policy for injectable drugs underwent a significant change after the passage of the Medicare Prescription Drug, Improvement and Modernization Act in 2003, which was associated with a reduction in Medicare reimbursement for LHRH agonists by approximately 50% (16
). A recent study reported a significant decline in the inappropriate use of AS between 2003 and 2005, which the authors defined as primary AS therapy for men with localized prostate cancer of low to moderate grade (10
). Consistent with those findings, we observed a small decline in the use of AS with EBRT between 2004 and 2005 in men within the low-risk disease category, although the absolute rate of AS in this group remained substantial.
Appropriate use of AS for men with intermediate risk disease undergoing EBRT remains controversial. We found that 56.3% of men with intermediate-risk disease received combination therapy with AS, indicating that there may be insufficient evidence to guide treatment decisions for these patients. A randomized trial by D’Amico and colleagues demonstrated an improvement in 5-year overall survival (88% vs. 78%, p
= 0.04) with the addition of 6 months of AS to EBRT for men with unfavorable disease risk features (4
). Approximately 57% of the patients enrolled in this trial had intermediate-risk disease by NCCN criteria (17
). The results from this trial were first published in August 2004, which may help explain the frequent use of AS in men within the intermediate-risk disease category. However, the NCCN guidelines did not recommend AS for men with intermediate-risk disease until 2009 (8
). Our results showed lower rates of AS use with EBRT for intermediate-risk patients in 2005 than in 2004. This may indicate that the results of the trial by D’Amico et al.
) had not yet been incorporated into widespread clinical practice. Alternatively, any increased use of AS resulting from this publication may have been counterbalanced by deterrents to AS use including lower Medicare reimbursement during the same time period. To our knowledge, currently there are no prospective randomized data that examine the use of AS exclusively in men with intermediate-risk disease, and the selection criteria for patients most likely to benefit from AS remain to be defined. This clinical question is being further investigated in the currently accruing Radiation Therapy Oncology Group Trial 0815, and our findings underscore the importance of this trial.
Among men with high-risk disease undergoing EBRT, the great majority of patients received AS, which is consistent with Level I evidence and consensus guidelines supporting its use. Published results from the European Organisation for Research and Treatment of Cancer Trial 22863 demonstrated an improvement in 5-year overall survival (78% vs. 62%, p
= 0.0002) associated with the addition of 3 years of AS combined with EBRT in comparison with EBRT alone for men with locally advanced or high-grade prostate cancer (2
). The most recent results from the Radiation Therapy Oncology Group Trial 85–31 reported an overall survival benefit at 10 years (49% vs. 39%, p
= 0.002) associated with the addition of AS continued indefinitely after EBRT for men with extraprostatic disease or lymph node involvement (5
). Although 18.5% of men with high-risk disease did not receive AS with EBRT, individual physician or patient preferences, perhaps related to the desire to avoid the potential side effects of AS, may have contributed to the decision to withhold AS. A more troubling finding is the significant decline in use of AS among high-risk patients between 2004 and 2005. This change is consistent with declines in the overall use of AS observed during the time period after changes in Medicare reimbursement policy (11
). However, these findings suggest that reductions in reimbursement may have discouraged the use of AS in patients for whom there was Level I evidence supporting its use.
Within all three disease risk categories, men aged ≥75 years or with elevated comorbidity were more likely to receive AS with EBRT. The reasons underlying these associations are uncertain, although it is possible that among men with comorbid disease, our findings reflect in part the propensity for patients with more comorbidities to have more frequent health care visits and associated procedures (18
). These findings are particularly concerning, given the potential for adverse health effects associated with AS use. A retrospective analysis of the randomized trial conducted by D’Amico et al.
indicates that patient comorbidity significantly attenuates the potential survival benefit associated with AS for patients with unfavorable disease risk features undergoing EBRT (19
). In contrast, long-term follow-up data from randomized trials combining AS with EBRT have not demonstrated an increased risk of death due to cardiovascular disease among men receiving AS (20
). Although the subject remains controversial, our results suggest that more attention to the potential adverse features of AS among older patients and those with comorbid disease may be required in making decisions about appropriate AS.
Our study has several limitations. First, our study included only patients diagnosed between January 1, 2004, and December 31, 2005 (the latest SEER-Medicare data available) to allow for stratification by disease risk category using SEER variables. The time period of our study overlaps with the enactment of the Medicare Prescription Drug, Improvement and Modernization Act between 2003 and 2005, and we do not have information about how practice patterns may have changed since 2005. In addition, we did not assess the duration of AS. The optimal duration of AS remains controversial, and the practice patterns of AS duration have not been well described. Third, although our results identify important examples of overuse and underuse of medical therapy, limited conclusions may be drawn with respect to the reasons for the existence of observed practice patterns. For example, some individuals with low-risk disease may receive a short course of AS for cytoreduction before undergoing EBRT. However, this seems unlikely to account for the majority of AS use in this patient group.
In conclusion, our study describes recent practice patterns of AS use with EBRT for patients stratified by prostate cancer disease risk category. We found that a significant proportion of men received AS with EBRT despite a lack of evidence or clinical guidelines supporting its use. Conversely, almost one fifth of men with high-risk disease did not receive AS. Our findings highlight the need for clinician and patient education regarding the appropriate use of AS. There is wide variance in the frequency of AS administration for men within the intermediate-risk disease category, which suggests a lack of sufficient evidence to guide clinical decision making. Temporal analyses regarding the patterns of AS use will remain important to enable an understanding of how available evidence and clinical guidelines are being applied by the majority of practitioners. These data may help identify important areas for intervention with the goal of improving health care quality and outcomes.