Androgen deprivation exerts potent in vivo
antitumor effects in prostate cancer (21
). Like other prostate cancer treatments, however, hormonal ablation may also cause a range of short- and long-term side effects, which in the setting of monotherapy have been demonstrated to have a statistically significant impact on health-related quality of life relative to watchful waiting (4
). The combination of NADT with EBRT or brachytherapy is likewise associated with impairment of some quality of life domains relative to either treatment alone (16
). Furthermore, Penson et al. (24
) demonstrated that stage for stage, the combination of NADT with RP or EBRT is the most expensive treatment alternative for prostate cancer, regardless of which primary treatment (RP or EBRT) is used.
PADT remains the mainstay of treatment for advanced disease: a large, recent trial (2
) found a statistically significant benefit for immediate versus deferred treatment of locally advanced or metastatic prostate cancer. However, PADT has only recently been studied in localized disease. Labrie et al. (25
) tested primary combined androgen blockade in 141 patients with stage T2-3 disease who refused or were ineligible for local treatment. Disease-free survival rates among the stage T3 patients were 74.6% and 53.8% at 5 and 10 years, respectively; the disease of only one stage T2 patient progressed. Azaka et al. (26
) likewise treated 151 patients with stage T1-3a prostate cancer with PADT, again selecting patients ineligible for or refusing definitive treatment. They reported a 2-year progression-free survival of 43% and 62%, respectively, in stage T2b patients treated with a luteinizing hormone-releasing hormone agonist alone and with combined androgen blockade; rates were similar among T3 patients. Although these reports suggest a potential role for PADT, both studied highly selected patients, and neither compared PADT with watchful waiting, placebo, or other treatment alternatives. In a recent critical evaluation of hormonal therapy for prostate cancer, Chodak et al. (27
) concluded that there is insufficient evidence to support androgen deprivation as monotherapy in localized disease.
We found that rates of PADT in high-risk patients were stable—just under 50%—over the past 5 years. However, rates among low- and intermediate-risk patients increased sharply, from 4.6% to 14.2% and from 8.9% to 19.7%, respectively. Overall, patients were nearly three times as likely to receive PADT from 1999 through 2001 as they were from 1989 through 1992. Any explanation for this trend is speculative, but it seems likely that many patients who may have opted for watchful waiting earlier are now choosing PADT, perhaps in the face of earlier and more frequent PSA testing.
We found strikingly higher rates of PADT use among low-income patients. In the short term (the first year of treatment), PADT is the least expensive treatment alternative for primary prostate cancer (24
), but income was also inversely associated with the likelihood of receiving NADT, the most costly alternative. Furthermore, uninsured patients were not more likely than insured patients to receive PADT (14.9% vs. 20.5%, P
= .34 by χ2
test) and were more likely than insured patients to receive NADT (25.5% vs. 9.1%, P
<.001 by χ2
test). Although lower income patients had a higher level of serum PSA (P
<.001), a higher Gleason sum (P
<.001), and a higher tumor stage (P
= .03, all by Mantel-Haenszel χ2
), income was statistically significantly associated with the use of PADT, despite adjustment for risk: among low-risk patients, 19.4% of those earning less than $10,000 annually received PADT compared with 7.4% of those earning more than $75,000 annually. There is no readily apparent explanation for these observations, and so we urge that the question of socioeconomic determinants of hormonal therapy be subjected to more focused testing in the future.
We found that, since 1996, overall rates of NADT use among RP patients rose gradually, particularly among high-risk patients, of whom 16% received NADT before surgery. Although a survival advantage for immediate adjuvant hormonal therapy has been observed when lymph node involvement is found at the time of prostatectomy (29
), recent data do not support androgen ablation in this neoadjuvant setting. Randomized trials over the past decade, studying a variety of regimens before RP, have consistently shown decreases in preoperative PSA levels, tumor volume, positive margin rates, and pathological stage; however, none has shown any advantage in terms of PSA-defined recurrence or survival (7
Soloway et al. (10
) published the 5-year follow-up results from a multi-center trial in patients with clinical stage T2b prostate cancer. Their findings confirm the earlier studies that NADT decreased the positive margin rate from 48% to 18% (P
<.001) but had no impact on lymph node involvement or on 5-year PSA-defined recurrence-free rates (64.8% in the NADT group compared with 67.6% in the RP only group, P
= .663). Aus et al. (11
) recently reported similar outcomes at 7 years of follow-up, with no difference in progression-free survival (49.8% for NADT compared with 51.5% for RP only, P
= .588). Studies of prolonged NADT (8 months rather than 3 months before surgery) have suggested a greater effect in terms of preoperative and pathologic parameters (31
); outcomes in terms of recurrence, however, are pending. Chodak et al. (27
) argued that sufficient evidence currently exists to recommend against NADT before RP.
Rates in CaPSURE of NADT use before EBRT rose to 57%, 74%, and 90% of low-, intermediate-, and high-risk patients. Available evidence in fact demonstrates a clear benefit for this combined regimen in selected patients. In a multicenter randomized trial enrolling primarily patients with T3 or T4 prostate cancer, Bolla et al. (12
) found a statistically significant overall survival advantage with the addition of goserelin to EBRT (79% vs. 62% for EBRT alone, P
= .001). Two prospective trials from the Radiation Therapy Oncology Group confirmed the benefit in high-risk disease. In the RTOG 85-31 study, 977 patients were randomly assigned to EBRT with or without combined androgen blockade, and at the 4.5-year follow-up for patients with stage T3 or lymph node-positive tumors, improvements with NADT in terms of PSA-defined recurrence (16% vs. 29%, P
<.001) and disease-specific survival (60% vs. 44%, P
<.001) were observed. Overall survival was only improved among patients with Gleason scores of greater than 7 (66% vs. 55%, P
= .03) (13
In the RTOG 86-10 study, 471 patients with stage T3 or bulky (>25 cc) stage T2 tumors were randomly assigned to goserelin given 2 months before EBRT or to EBRT alone. With 8.6 years of follow-up, a benefit was demonstrated for NADT with respect to local control (42% vs. 30%, P
= .016), PSA-defined recurrence (76% vs. 90%, P
<.001), and disease-free survival (33% vs. 21%, P
= .004). In contrast to RTOG 85-31, however, an overall survival benefit was demonstrated only in patients with Gleason scores less than 7 (70% vs. 52%, P
= .015) (14
). Intermediate- and high-risk patients planning to undergo EBRT are the only localized prostate cancer patients for whom Chodak et al. (27
) found sufficient evidence to recommend routine NADT. No study has reported an advantage for EBRT with NADT in patients with lower-risk disease. The ongoing RTOG 94-08 and RTOG 94-13 studies will address this issue, as will a Canadian Uro-Oncology Group trial that is randomly assigning patients to EBRT with NADT or to hormonal therapy alone (32
Roughly one-quarter of patients undergoing brachytherapy received NADT before implantation. Although this combination is recommended by the American Brachytherapy Society for patients with a prostate volume of greater than 60 cm3
and those with a “significant risk of disease outside the implant volume”(33
), its efficacy and toxicity have not been evaluated in randomized trials. In one retrospective study, Potters et al. (15
) analyzed 612 consecutive patients with prostate cancer undergoing brachytherapy, of whom 177 (29%) were treated with NADT before implantation because of a large prostate volume. Of these, 71% were effectively cytoreduced within 3 months, and 91% were cytoreduced by 8 months of therapy. However, when compared with risk-matched patients receiving brachytherapy only, 5-year PSA-defined recurrence-free rates were essentially identical: 87.1% and 86.9% in the NADT and brachytherapy-only groups (P
= .935). Subgroup analysis did not identify any benefit for patients with specific risk characteristics, nor did NADT improve outcomes in patients receiving EBRT along with brachytherapy.
Potters et al. (15
) concluded that the addition of NADT to brachytherapy should not be considered standard treatment, but that the cytoreductive effect of androgen ablation may decrease the toxicity associated with brachytherapy and potentially can improve dosimetry. In a follow-up study (34
), however, they noted that patients who received NADT before brachytherapy had a 5-year actuarial potency rate of 52% compared with 76% for those who did not receive NADT. The effect of NADT was stronger than that of age or concurrent EBRT. Chodak et al. (27
) found insufficient evidence to support this treatment combination. Because CaPSURE physicians submitting data on brachytherapy patients do report the preimplantation prostate volume, we cannot determine whether the volume was measured before or after NADT. Therefore, we cannot comment as to whether large prostate volumes or other clinical parameters are the more common determinants of NADT use in our population.
One of the great strengths of CaPSURE is that it tracks use and outcome patterns in actual practice, without the constraints imposed by clinical trial protocols. Data are collected prospectively, irrespective of any particular research question. Although the CaPSURE practice sites have not been chosen at random and, thus, cannot be assumed to represent a statistically valid sample of the United States patient population, they do represent a broad range of geographic locales and a mixture of academic and community practices. CaPSURE data are submitted only by patients and urologists; therefore, any treatments by other practitioners that are not reported by patients either to their urologists or in their questionnaires may be missed. Extant quality assurance mechanisms, including chart review of all hospital admissions, should minimize this problem. Finally, we excluded from analysis 1399 (28.9%) of 4838 otherwise eligible patients in the database because they had not yet had at least 6 months of follow-up. This criterion was established a priori, and we do not have reason to believe it introduced bias into the analysis. It is, however, possible that, with longer follow-up, the distribution of treatments, particularly for the most recent time period, may change. Despite these cautionary notes, we believe our data provide the best available description of national practice patterns.
PADT remains the core treatment for advanced prostate cancer and offers a clear benefit in specific local disease contexts. Like other treatments, however, both PADT and NADT contribute appreciably to patient morbidity, quality of life impact, and cost of care. It is not clear from evidence to date that the growing numbers of patients opting for PADT—who tend to be older and at high risk in terms of comorbidity—are likely to reap a substantial benefit, especially given the need for prolonged therapy. Extant evidence likewise does not appear to support NADT before RP or brachytherapy, and only upholds NADT before EBRT in locally advanced disease. Nonetheless, burgeoning numbers of patients with localized disease of low- and intermediate-risks are increasingly receiving both PADT and NADT. The extent to which these trends are driven by physicians, patients, or both is a question of speculation, although a multifactorial explanation seems the most likely that plausibly includes physician financial incentives, direct-to-consumer pharmaceutical advertising, and psychological imperatives on one or both sides of the examining table—to treat cancer as aggressively as possible.
The benefits of androgen ablation in advanced prostate cancer are well demonstrated, and we hope that the upward trend in use of NADT in the context of EBRT for locally advanced disease will continue. However, prospective clinical trials must clarify the efficacy of PADT compared with watchful waiting, and must identify any potential benefit to be gained from NADT in association with brachytherapy or EBRT in lower-risk disease, particularly as new agents and regimens emerge. Such trials must assess quality of life and oncologic outcomes. Updated clinical guidelines that are based on available evidence are sorely needed; these guidelines should address the optimal role of both PADT and NADT in the initial management of localized prostate cancer.