Use of Hormonal Therapy in Men With Metastatic Prostate Cancer

Use of Hormonal Therapy in Men With Metastatic Prostate Cancer Grace Lu-Yao, Dirk F. Moore, John Oleynick, Robert S. DiPaola* and Siu-Long Yao†,‡ From the Department of Environmental and Occupational Medicine (GLY) and Cancer Institute of New Jersey (GLY, DFM, JO, RSDP, SLY), Robert Wood Johnson Medical School and Department of Biostatistics, School of Public Health (DFM, JO), University of Medicine and Dentistry of New Jersey, Piscataway and Dean and Betty Gallo Prostate Cancer Center (GLY, DFM, JO, RSDP, SLY), New Brunswick, New Jersey

Purpose: Bilateral orchiectomy or luteinizing hormone releasing hormone agonists represent the standard of care for metastatic prostate cancer. In this population based study we assessed the use rates of these therapies in men who died of prostate cancer. Material and Methods: A total of 9,110 men 65 years or older who died of prostate cancer in 1991 to 2000 were identified through the population based Surveillance, Epidemiology and End Results, and Medicare linked database to determine hormonal therapy use rates. A modified Poisson regression model was used to estimate the adjusted effects of various factors associated with hormone use. Results: Approximately 38% of black and 25% of white men did not receive hormonal therapy before dying of prostate cancer. After adjusting for cancer status at diagnosis and other potential confounding factors black race and residence in low income areas were associated with lower hormonal therapy use (relative risk 0.73, 95% CI 0.67 to 0.80 and 0.91, 95% CI 0.85 to 0.98, respectively). Hormonal therapy use was most comprehensive in the Northeast. Conclusions: A substantial number of men who die as a consequence of prostate cancer never receive hormonal therapy. The use of hormonal therapy varies significantly. Further studies are warranted to determine factors that may be associated with the incomplete use of hormonal therapy for metastatic prostate cancer. Key Words: prostate; prostatic neoplasms; Medicare; SEER program; antineoplastic agents, hormonal

rostate cancer is the most common nonskin cancer and the second most common cause of cancer death in men. In men with metastatic disease hormonal therapy, ie DES, orchiectomy or LHRH agonist, has been the mainstay of treatment since recognition of its effectiveness in studies for which Huggins was ultimately awarded the 1966 Nobel Prize in Medicine. Indeed, almost every contemporary textbook, review or clinical guideline recognizes hormonal therapy as the standard of care in men with metastatic disease.1

Remarkably and despite this a modern phase III trial that compared early vs delayed hormonal therapy showed that in practice many patients randomized to delayed treatment never received the prescribed hormonal therapy.2 It has generally been assumed that these results are not reflective of current practice in the United States and almost all patients with metastatic disease receive hormonal therapy before dying of prostate cancer.3 However, empirical data to support this assumption have been limited. We performed a population based study to assess the use of hormonal therapy in men who ultimately died of prostate cancer, a population in which hormonal therapy is indicated. We also examined potential factors associated with failure to administer hormonal therapy in these men.

P

Submitted for publication August 29, 2005. Study received Institutional Review Board approval from the University of Medicine and Dentistry of New Jersey, SEER program, and Center for Medicare and Medicaid Services. Supported by Award DAMD17-01-1-0755 from the United States Army Medical Research Acquisition Activity, Fort Detrick, Maryland and by the Cancer Institute of New Jersey. The performance and design of this study was reviewed and approved by the National Cancer Institute, and Center for Medicare and Medicaid Services. This study used the Linked SEER-Medicare Database. The interpretation and reporting of these data are the sole responsibility of the authors. The content of the information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. * Financial interest and/or other relationship with Aventis, Sanofi, Novartis, Abbott, BUS, Therion, Dendreon, Schering and Cellgurency. † Correspondence and requests for reprints: Dean and Betty Gallo Prostate Cancer Center, 195 Little Albany St., Room 5544, New Brunswick, New Jersey (telephone: 732-235-8830; FAX: 732-2358808; e-mail: [email protected]). ‡ Financial interest and/or other relationship with ScheringPlough.

0022-5347/06/1762-0526/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION

MATERIALS AND METHODS Data Sources The SEER program database was linked with Medicare files to obtain data for this study. Demographics, cancer status at diagnosis and cause of death were obtained from SEER data. Treatment information was obtained from Medicare claims. SEER regions encompass approximately 14% of the population in the United States. The Medicare database covers approximately 97% of individuals in the United States who are 65 years or older and linkage to the SEER database was complete in approximately 94% of the patients.4 Study Participants The study cohort consisted of men who were residents of SEER regions and who died of prostate cancer in 1991 to

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Vol. 176, 526-531, August 2006 Printed in U.S.A. DOI:10.1016/j.juro.2006.03.098

HORMONAL THERAPY FOR METASTATIC PROSTATE CANCER 2000. Men who died of competing causes were excluded because it could be acceptable to omit or delay treatment in a population that died of a cause other than prostate cancer. Although the clinician may not be able to predict who is going to die of a competing cause, excluding these patients was a conservative approach and biased against our hypothesis. Including patients who died of competing causes resulted in even lower use rates. The figure shows assembly of the study population. Patients younger than 65 years were excluded since Medicare did not cover them and, therefore, data on hormonal therapy use were not available. Patients who died of prostate cancer within 1 month of diagnosis were excluded since they may not have had a reasonable opportunity to receive hormonal therapy. To ensure that claims data provided a complete representation of patient care patients had to have Medicare Part A (hospitalization) and Part B coverage (physician services, laboratory and x-ray services, durable medical equipment, and outpatient and other services) as their primary health insurance coverage during the period between cancer diagnosis and the end of followup. Patients covered by a health maintenance organization or the Veterans Administration system were excluded since their Medicare data would not present a complete record of all of their medical treatments. The study received Institutional Review Board

527

approval from the University of Medicine and Dentistry of New Jersey, the SEER program, and the Center for Medicare and Medicaid Services. Use of Hormonal Therapy Using a previously described algorithm5 Medicare physician, inpatient and outpatient claims were used to identify orchiectomy (Healthcare Common Procedure Coding System codes 54520, 54521, 54522, 54530 or 54535, or International Classification of Diseases, version 9 codes 623 and 624) and use of LHRH agonists (Healthcare Common Procedure Coding System codes J1950, J9202, J9217, J9218, J9219). End Point Validation A subset of patients in this study had previously been randomly chosen to participate in PCOS.6 As part of PCOS, medical personnel reviewed the medical records of these patients, and abstracted information about hormonal therapy use and other treatments.6 For each patient the medical records examined included those from hospitals, radiological or surgical centers and physician offices. Data obtained from the actual medical records as part of the PCOS study were linked with our data using encrypted identifiers. The results of the claims based hormonal therapy use algorithm were then compared with the results of the medical records review. Other Variables for Risk Adjustment Median income in 2000 in the ZIP code area of the patient residence was used to assess socioeconomic status since it has been shown to correlate well with self-reported income. Medicare Provider Analysis and Review claims were used to calculate the Charlson index score, a validated measure of comorbidity.7 Statistical Analyses The relative risk of hormonal therapy use by race for each level of risk factors was determined by fitting each model with hormonal therapy use as the outcome variable and race as a predictor. Since hormone therapy use is not rare, the OR is not a good approximation of relative risk.8 Thus, we used a modified Poisson regression model8 rather than logistic regression to estimate the adjusted effect of the factors on hormone therapy use. The SAS® system, version 9.1 was used for statistical analysis and assumptions of all statistical models were verified. RESULTS

Cohort used in this study

Baseline Characteristics in Men Who Died of Prostate Cancer Table 1 lists baseline characteristics in 9,110 patients who died of prostate cancer during 1991 to 2000. Of patients who died of prostate cancer 60% were diagnosed at age 75 or older, 36% were diagnosed with distant stage disease and 44% had a Gleason score of 8 –10 at diagnosis. Compared with white men higher proportions of black men did not receive hormonal therapy (p ⬍0.001), had distant disease (p ⬍0.001), were younger (p ⬍0.001) and were unmarried at diagnosis (p ⬍0.001).

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HORMONAL THERAPY FOR METASTATIC PROSTATE CANCER

TABLE 1. Demographic and clinical characteristics in patients 65 years or older in SEER-Medicare database Characteristic

No. White (%)

No. Black (%)

All participants Hormonal therapy: Yes No Age: 65–69 70–74 75 or Older Stage at diagnosis: Local Regional Distant Unknown Gleason score at diagnosis: 2–4 5–7 8–10 Unknown Median income in residence ZIP code: Lowest quartile Highest 3 quartiles Unknown SEER area:* North Central Northeast South West Primary treatment: Radiation alone Radical prostectomy only Radical prostectomy and radiation Watchful waiting Diagnosis yr: 1991–1994 1995–1999 Highest Charlson index:† Could not be calculated 0 1 2 3 or Greater Marital status: Married Not married

7,820 (100.0)

1,290 (100.0)

5,890 (75.3) 1,930 (24.7)

795 (61.6) 495 (38.4)

1,143 (14.6) 1,863 (23.8) 4,814 (61.6)

273 (21.2) 336 (26.0) 681 (52.8)

1,188 1,040 2,732 2,860

186 130 527 447

(15.2) (13.3) (34.9) (36.6)

(14.4) (10.1) (40.9) (34.7)

323 (4.1) 2,455 (31.4) 3,416 (43.7) 1,626 (20.8)

64 (5.0) 370 (28.7) 554 (42.9) 302 (23.4)

2,030 (26.0) 5,476 (70.0) 314 (4.0)

912 (70.7) 322 (25.0) 56 (4.3)

2,852 (36.5) 1,256 (16.1) 322 (4.1) 3,390 (43.4)

643 (49.8) 104 (8.1) 189 (14.7) 354 (27.4)

1,832 (23.4) 338 (4.3) 67 (0.9) 5,583 (71.4)

264 (20.5) 25 (1.9) 5 (0.4) 996 (77.2)

5,584 (71.4) 2,236 (28.6)

880 (68.2) 410 (31.8)

1,928 (24.7) 2,905 (37.1) 1,612 (20.6) 719 (9.2) 656 (8.4)

241 438 270 169 172

5,117 (65.4) 2,703 (34.6)

613 (47.5) 677 (52.5)

(18.7) (34.0) (20.9) (13.1) (13.3)

* North Central includes Detroit and Iowa registries; Northeast consists of Connecticut; South includes Atlanta and West consists of Hawaii, New Mexico, Seattle, Utah and San Francisco/San Jose/Los Angeles. † Calculated only in patients hospitalized in the 12-month period before death.

End Point Validation The medical records of 142 PCOS patients who had Medicare Part A and B as their primary health insurance coverage were used to validate the claims based hormonal therapy use algorithm. Of these patients 69 were identified by medical record review as having received hormonal therapy. The claims based algorithm correctly identified 66 of these patients (95.7% sensitivity). Rates of Hormonal Therapy Use A total of 38% of black and 25% of white men did not receive hormonal therapy before death from prostate cancer (tables 1 and 2). Rates of hormonal therapy use were further evaluated in various subgroups to determine the consistency of this finding (table 2). Excluding patients treated with surgery and radiation, consistently greater than 30% of black men and greater than 15% of white men had not received hormonal therapy before dying of prostate cancer across these subgroups. In every subgroup examined black patients

were less likely to have received hormonal therapy than white patients (table 1). Factors Associated With Hormonal Therapy Use After adjusting for confounding factors using a modified Poisson regression model black race, localized disease at diagnosis, age 75 years or older, residence in low median income or North Central SEER areas, low Gleason score at diagnosis, high comorbidity, unmarried status at diagnosis, initial treatment with radical prostatectomy or watchful waiting was associated with lower rates of hormonal therapy use (table 3). High grade cancer and low comorbidity status were associated with increased use of hormonal therapy. Black men were 27% less likely to have received hormonal therapy than their white counterparts (p ⫽ 0.001). Compared with residents in the North Central region patients living in the Northeast were 35% more likely to receive hormonal therapy. DISCUSSION We found that 25% of white and 38% of black men had not received hormonal therapy before death from prostate cancer. These nonuse rates were lower than expected and nonclinical factors, such as race, income and geographic region, appeared to significantly impact the use of hormonal therapy. Although rates of implementation of some other medical therapies can also be suboptimal, the settings often involve earlier disease stages for which the benefit of treatment may not be immediately evident or associated toxicities may be substantial. In other instances therapies may be new or the particular disease setting may be uncommon. However, in this case the high incidence and prevalence of prostate cancer along with its marked palliative effect with limited toxicity, and the general availability of clinical expertise and consensus would have led us to expect that use rates would have been substantially closer to modern rates of ␤-blocker use after myocardial infarction9 or tamoxifen use for estrogen receptor positive breast cancer (93.5% and 98%, respectively).10 It is possible that a lack of agreement on use could form the basis for the suboptimal use rates. Direct information about the survival effects of hormonal therapy have been primarily based on 2 randomized Veterans Administration studies. Although results numerically favored hormonal therapy, the overall survival benefit of hormonal therapy was not always statistically significant in these studies, probably as a consequence of crossover. However, recent studies that compared (suboptimal) antiandrogen monotherapy with orchiectomy or DES demonstrated significant survival advantages for hormonal therapy, suggesting that hormonal therapy most likely increases survival.11,12 These studies along with the demonstrated palliative benefit of hormonal therapy have provided enough certainty for almost all authorities to consider hormonal therapy to be the standard of care and consider the performance of studies randomizing patients to placebo to be unethical, making it unlikely that suboptimal use could be attributable to widespread disagreement. The popular approach of often delaying hormonal therapy rather than initiating it upon diagnosis of metastatic disease might be another possible reason why hormonal therapy use

HORMONAL THERAPY FOR METASTATIC PROSTATE CANCER

529

TABLE 2. Rates of hormonal therapy according to race in patients 65 years or older in SEER-Medicare database who died of prostate cancer in 1991 to 1999 % Hormonal Therapy Variable All participants Age: 65–69 70–74 75 or Older Stage at diagnosis: Local Regional Distant Unknown Gleason score at diagnosis: 2–4 5–7 8–10 Unknown Median income in residence ZIP code:† Lowest quartile Highest 3 quartiles SEER area: North Central Northeast South West Primary treatment: Radiation alone Radical prostectomy only Radical prostectomy ⫹ radiation Watchful waiting Diagnosis yr: 1991–1994 1995–1999 Highest Charlson index:‡ Could not be calculated 0 1 2 3 or Greater Marital status Married Not married

No. Pts

Black

White

RR*

95% CI*

9,110

62

75

0.83

0.79–0.86

1,416 2,199 5,495

63 68 58

81 81 72

0.78 0.86 0.80

0.71–0.86 0.80–0.93 0.75–0.86

1,374 1,170 3,259 3,307

63 65 61 60

78 82 77 71

0.82 0.78 0.81 0.86

0.73–0.92 0.68–0.89 0.75–0.87 0.79–0.93

387 2,825 3,970 1,928

42 65 68 51

68 79 82 57

0.63 0.83 0.83 0.90

0.47–0.86 0.77–0.89 0.78–0.88 0.79–1.01

2,942 5,798

61 63

73 76

0.84 0.85

0.79–0.89 0.79–0.92

3,495 1,360 511 3,744

62 61 65 60

73 81 78 75

0.84 0.74 0.86 0.82

0.79–0.90 0.63–0.88 0.76–0.97 0.75–0.89

2,096 363 72 6,579

65 52 80 61

80 79 94 73

0.82 0.66 0.84 0.84

0.74–0.90 0.45–0.97 0.54–1.30 0.79–0.88

6,464 2,646

63 59

76 74

0.83 0.80

0.79–0.88 0.74–0.88

2,169 3,343 1,882 888 828

49 68 63 62 60

70 79 77 75 68

0.72 0.86 0.81 0.82 0.89

0.63–0.82 0.81–0.92 0.74–0.90 0.72–0.94 0.78–1.02

5,730 3,380

66 58

79 69

0.84 0.85

0.79–0.89 0.79–0.91

* Derived from the modified Poisson regression without adjustment for other covariates. † There were 370 patients with missing ZIP code income information. ‡ Calculated only in patients hospitalized in the 12-month period before death.

was lower than anticipated. In the Medical Research Council study that examined early vs delayed hormonal therapy the basis of inadequate hormonal treatment in men randomized to the delayed therapy arm was never clearly understood (of 54 patients who died of cancer in the delayed treatment arm 29 died without ever having received hormonal therapy).2 However, other research has shown that clinicians often cannot accurately predict the life span of a patient with cancer.13 It may be possible that many patients with prostate cancer die of cancer earlier than anticipated and, therefore, they fail to receive hormonal therapy before death. Our observation that men often recognized as likely to die of a competing cause, ie elderly men, or those with extensive comorbidity or low Gleason score tumors at diagnosis, were less likely to receive hormonal therapy may be consistent with the notion that clinicians underestimate the effects of the cancer compared to other potential threats to life. Although our study was not designed to specifically examine racial disparities, it was noteworthy that a greater number of black men did not receive hormonal therapy before dying of prostate cancer. Similarly large racial differences have been previously described for various treatments

in Medicare patients, although the reasons for the disparities are unclear.14 Potential reasons could include more limited access to care or failure to offer certain treatments.15 There were some potential study limitations that should be noted, including the possibility that the rate of DES use (the only other commonly used drug in the United States with survival outcomes similar to those of orchiectomy or LHRH agonists) may have been underestimated. In contrast to orchiectomy or LHRH agonists, Medicare reporting of the use of nonreimbursed drugs is not legally required when no reimbursement is provided. DES and many nonchemotherapeutic oral drugs are not reimbursed. However, the profitable reimbursement rates for LHRH agonists compared with no reimbursement for DES and the publication of major studies in 1984 and 1986, well before the start of the observation period of this study in 1991, that demonstrated a superior therapeutic index for LHRH agonists16 support previous conclusions17 that DES use was minor at best during the 1990s. Failure to submit a claim could have led to an underestimation of hormonal therapy use. However, results of direct examination of medical records suggested that claims based algorithm had high sensitivity. In addition, because LHRH

530

HORMONAL THERAPY FOR METASTATIC PROSTATE CANCER

TABLE 3. Factors associated with hormonal therapy in patients 65 years or older in SEER-Medicare database who died of prostate cancer in 1991 to 1999 Factor Race: White Black Stage at diagnosis: Local Regional Distant Unknown Age: 65–69 70–74 75 or Older Median income: Highest 3 quartiles Lower quartile Gleason score at diagnosis: 2–4 5–7 8–10 Ungraded SEER area: North Central Northeast South West Highest Charlson index 12 mos before death:† 0 1 2 3⫹ Could not be calculated Primary treatment: Radiation alone Radical prostatectomy alone Radiation ⫹ radical prostatectomy Watchful waiting Diagnosis yr: 1991–1994 1995–1999 Marital status: Unmarried Married

RR*

95% CI

p Value

Referent 0.73

— 0.67–0.80

— ⬍0.001

Referent 1.11 1.13 1.03

— 0.95–1.29 1.01–1.28 0.92–1.16

— 0.185 0.036 0.605

Referent 1.07 0.84

— 0.95–1.22 0.76–0.94

— 0.267 0.002

Referent 0.91

0.85–0.98

0.017

Referent 1.53 1.71 0.84

— 1.32–1.78 1.47–1.99 0.73–0.97

— ⬍0.001 ⬍0.001 0.017

Referent 1.35 1.16 1.08

— 1.20–1.52 0.99–1.36 1.00–1.17

— ⬍0.001 0.067 0.038

Referent 0.93 0.86 0.74 0.73

— 0.84–1.02 0.76–0.98 0.66–0.83 0.67–0.79

— 0.123 0.019 ⬍0.001 ⬍0.001

Referent 0.74

— 0.60–0.92

— 0.006

2.91

1.13–7.46

0.027

0.88

0.81–0.97

0.009

Referent 1.03

0.96–1.11

0.437

Referent 1.33

— 1.24–1.42

— ⬍0.001

* Adjusted risks derived from the modified Poisson regression with all variables listed included in the model. † Calculated only in patients hospitalized in the 12-month period before death.

agonists are relatively expensive, repeatedly administered and highly profitable, it is unlikely that a provider would underreport or be able to afford underreporting. It is also possible that other nonstandard, less potent hormonal therapies were used as primary treatment, eg ketoconazole, antiandrogens, etc. However, these therapies are not considered consistent with recommendations of existing guidelines in this setting.1 For example, bicalutamide is only Food and Drug Administration approved for use in combination with LHRH agonists or orchiectomy and no consensus guidelines recognize the single use of nonLHRH agents or nonorchiectomy approaches in this setting. Another consideration is that it is possible that incorrect determination of cause of death could have led to misidentification of the population, ie all patients who died of prostate cancer, for which hormonal therapy was indicated in our study. Although several studies have demonstrated high rates of agreement (greater than 90%) between death certificate causes of death and medical record information,18,19

many were performed in patients familiar to the health care system. A lack of good ancillary health care could lead to failure to recognize the existence and role of a comorbid condition in causing death. If death was consistently more likely to be attributable to prostate cancer rather than to other conditions in such patients, and if there was a significant number of patients with prostate cancer who had little or no contact with the health care system, this could lead to underestimation of the hormonal therapy use rate. In some cases it is conceivable that there may not have been an apparent indication for hormonal therapy immediately before prostate cancer death. For example, the optimal approach to emergent, critical ureteral obstruction may be stent placement rather than hormonal therapy. In a small number of patients stent placement and/or temporary dialysis may be ineffective or impractical and the patient may die. Such a patient could justifiably have not received hormonal therapy. On the other hand, it could be argued that such a patient should have been monitored more closely, so that hormonal therapy could have been initiated earlier as it became clear that obstruction was imminent, and not receiving hormonal therapy may not have been justifiable. Although we did not observe evidence of an increase in hormonal therapy use with time (tables 1 and 3), it is possible that practice patterns could have changed in the years following the study period. Further analyses must be performed when data become available to determine if use rates are improving. Finally, the results of our study might not be applicable in younger patients since our study populations consisted of men 65 years or older. However, because greater than 70% of newly diagnosed prostate cancer occurs in men 65 years or older, the results should be generalizable to most patients. In contrast to these limitations, important advantages of our database were that it was large and based on regions (population based) rather than individual referral centers, thus, making it more comprehensive and less subject to selection biases. Indeed, the generalizability of SEER data has led to its routine use as the basis for definitive estimates of cancer incidence and survival in the United States. For these reasons the patient characteristics and results in our study are more likely to be reflective of what is actually encountered in the average medical practice. In addition, because a substantial proportion of patients were diagnosed with localized prostate cancer and the results of our multivariate analysis suggested that patients with localized disease were among the least likely to receive hormonal therapy, the results of our study should be especially important in the commonly encountered modern clinical scenario in which patients are diagnosed with localized disease through prostate specific antigen screening. CONCLUSIONS The results of our data reveal potential inadequacies of current efforts to implement hormonal therapy. The application or translation of the results of previous clinical research or guidelines into clinical practice can be challenging in some medical conditions.20 Sometimes this can be a consequence of failing to adequately appreciate the ultimate ramifications of inadequately treating an initially benign or chronic condition, eg screening, prevention and adjuvant therapy. Known prostate cancer that is advanced enough to

HORMONAL THERAPY FOR METASTATIC PROSTATE CANCER ultimately be responsible for the death of the patient is a serious condition. Few therapies for advanced cancer under such circumstances are effective, tolerable or widely available. Hormonal therapy for metastatic prostate cancer is an exception and an opportunity may exist to augment efforts directed toward taking better advantage of it. ACKNOWLEDGMENTS The Applied Research Branch, Division of Cancer Prevention and Population Science, National Cancer Institute, Office of Information Services and Office of Strategic Planning, Health Insurance Portability and Accountability Act Compliance Federation of America, Information Management Services, Inc., and SEER Program tumor registries assisted with the creation of the SEER-Medicare database. Judith Manola reviewed the manuscript.

6.

7.

8.

9. 10. 11.

12.

Abbreviations and Acronyms DES LHRH PCOS SEER

⫽ ⫽ ⫽ ⫽

diethylstilbestrol luteinizing hormone-releasing hormone Prostate Cancer Outcomes Study Surveillance, Epidemiology and End Results

13.

14.

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