The Prostate Cancer Outcomes Study (PCOS) was initiated in 1994 by the National Cancer Institute (NCI) to investigate patterns of treatment and HRQOL outcomes in American men diagnosed with prostate cancer. Enrollment occurred during 12 months between 1994 and 1995, from 6 of the 10 Surveillance, Epidemiology and End Results (SEER) cancer registries. A total of 11,137 men who were diagnosed with prostate cancer during this time in this catchment area were eligible for the PCOS.[5] The study restricted eligibility to white, African-American, and Hispanic men. A prespecified random sampling design, weighted to enhance accession of African-American and Hispanic men and those under 60 years of age, was used to determine which of the eligible men would be contacted for enrollment. PCOS HRQOL data were ascertained via a survey questionnaire administered at 6, 12, and 24 months after initial diagnosis. A mixed-mode survey approach was used to ensure high response rates: Initial contact comprised a mailed HRQOL questionnaire with a cover letter. Nonresponders were followed-up with a telephone call and remailing of the questionnaire if necessary. As a final resort, a telephone interview was attempted. The response rate differed by individual SEER registry, ranging from 54% to 76%. Nonresponders were more likely to be older, nonwhite residents of areas with lower median household income and lower prevalence of college education, and to have undergone radical prostatectomy (42% of responders vs 26% of nonresponders).[5] The mailed questionnaire, the PCOS prostate cancer-specific HRQOL index, was a novel tool derived from previously validated instruments such as the University of California, Los Angeles (UCLA) prostate cancer index. Based on three such instruments used in the prostate cancer literature, the urinary, bowel, and sexual domains were addressed. Other variables included the presence and severity of comorbid conditions (based on Medical Outcomes Study Short Form-36 [SF-36] responses), socioeconomic status, demographic data, and satisfaction with treatment chosen. Because more than 14% of men were Hispanic, this PCOS scale was translated into Spanish and pretested in Spanish- speaking men with prostate cancer. Overall, 5,672 men were sampled, with 3,533 (62%) responders and 2,139 (38%) nonresponders.[5] More information about the PCOS can be obtained at http:// healthservices.cancer.gov/pcos. CPDR
In 1994, the Department of Defense Center for Prostate Disease Research (CPDR) began collecting data on prostate cancer patients treated within the medical systems of the military services, first at Walter Reed Army Medical Center, and since 1997, at eight other military sites around the country; three other sites initially participated but were excluded due to poor performance. In 1999, a uniform database entry form was developed. Data quality is ensured by dedicated study coordinators at each participating site in the CPDR. Unique among the registries, the CPDR project seeks to standardize clinical practice across the various military sites rather than simply to collect clinical data. The mean age at diagnosis fell from 68 in 1991 to 65 in 1999. Of CPDR patients, 39% elected radical prostatectomy, 32% underwent externalbeam radiation therapy, 29% primary androgen-deprivation therapy, and the remainder, miscellaneous therapy (brachytherapy, cryotherapy, etc).[6] Including 13,878 patients as of June 2002, CPDR is the only registry to have reported a significant number of men who underwent radical perineal prostatectomy (finding similar oncologic results to those undergoing retropubic prostatectomy).[7] More information on CPDR can be obtained at www.cpdr.org/database.html. CaPSURE
The Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) was initiated in 1995 with the aims of tracking prostate cancer epidemiologic trends, practice patterns, and oncologic and HRQOL outcomes. A total of 40 urologic practice sites are represented, 31 of which are actively enrolling patients. The sites are primarily community based, although 4.8% and 3.2% of patients are treated, respectively, at four university- based and three Veterans Affairs (VA) medical centers. At each practice site, all men with biopsy-proven prostate cancer are invited consecutively to join CaPSURE. CaPSURE collects approximately 1,000 clinical and patient-reported variables. The clinical information, collected by the treating urologist at baseline and each time the patient returns for care, includes history of prostate cancer diagnosis, biopsies, pathology, staging tests, primary and subsequent treatments, clinic procedures, Karnofsky performance status scores, and medications. At enrollment and every 6 months thereafter, each patient completes a questionnaire addressing sociodemographic parameters, comorbidities, and baseline HRQOL. The HRQOL components of the questionnaires include extensively validated survey instruments: the SF-36 for general HRQOL and the Prostate Cancer Index (PCI) for disease- specific HRQOL. Since 1999, the questionnaires have also included a survey on patient satisfaction with care and an assessment of fear of cancer recurrence. Other sections of the patient questionnaires assess all use of health services. Patient-reported hospitalizations and emergency department use are verified via review of discharge summaries. Patients are treated according to their physicians' usual practices and are followed until time of death or withdrawal from the study. Completeness and accuracy of the data are ensured by random sample chart review at periodic intervals. Additional details of the project methodology have been reported previously.[8] The database is managed by the Urology Outcomes Research Group of the Department of Urology at the University of California, San Francisco (UCSF) and has been funded since its inception by a grant from TAP Pharmaceutical Products, Inc.
As of February 2004, there were
10,581 patients enrolled in CaPSURE.
The median patient age at diagnosis
is 67, and nearly 75% of the men are
between 60 and 79 years of age. The
majority are white, with roughly 10%
African-American representation, and
3.5% Hispanic, Asian, or other ethnicities.
There is a fairly even distribution
across socioeconomic strata as
assessed via education and income
level. Over half of CaPSURE patients
are covered by Medicare, with or without
supplemental policies, and the remainder
have a variety of health
coverage types.
Overall, patients are distributed
roughly evenly among low-, intermediate-,
and high-risk groups as defined
by D'Amico et al,[9] although
over time, the proportion with lowrisk
disease has been rising, and that
with high-risk has been falling.[10]
Radical prostatectomy is the most
common primary treatment, followed
sequentially by primary androgendeprivation
therapy, external-beam
radiotherapy, brachytherapy, and
watchful waiting. More information
can be obtained at www.capsure.net.
SEARCHThe Shared Equal Access Regional Cancer Hospital (SEARCH) database, the most recently inaugurated national prostate cancer registry, comprises retrospective data from consecutive patients undergoing radical prostatectomy at three California VA medical centers and the San Diego Naval Medical Center between 1988 and 2001. The VA medical center in Augusta, Ga, was added later, when one of the original SEARCH investigators transferred there. Exclusion criteria include men who had preoperative neoadjuvant androgen- deprivation therapy or radiation therapy, unknown race, pT0 disease, or unknown preoperative PSA. From 1988 to 2001, 1,547 patients were enrolled, and the racial distribution was 1,014 white (66%), 338 African-American (22%), and 195 Hispanic, Asian, or Native-American men, who were collectively termed "non-white, nonblack" (12%).[11] Variables within SEARCH include clinical and pathologic variables but no HRQOL data. A principal advantage to SEARCH is the large proportion of minority men included (34%), and the relatively equal access to care afforded by each of the participating centers. That said, it should be noted that the VA medical centers may not truly be "equal access" centers due to unmeasured factors such as distance, availability of transport, and so forth, which may be unequally distributed in a systematic fashion (eg, farmers live farther away than city dwellers, or men living in the inner city may have no access to transportation). However, on average, these centers are certainly more inclusive of patients with low socioeconomic status than those represented in the other registries. The principal features, advantages, and disadvantages of each of the registries are compared in Table 1. Trends in Prostate Cancer Presentation and Risk A recent CaPSURE analysis examined changes over time in patient risk characteristics at the time of diagnosis. Patients presenting with low-risk disease, defined by PSA ≤ 10 ng/mL, Gleason score under 7 with no pattern 4 or 5 disease on biopsy, and clinical stage T1c or T2a,[9] have increased from 31% of patients in 1989-1990 to 47% in 2001-2002. During the same time, those with high-risk disease- PSA > 20 ng/mL, Gleason 8-10 biopsy, or stage T3/4 disease[9]- decreased from 41% to 15%. T1 tumors became increasingly prevalent, as did those with Gleason 7 biopsies and those diagnosed with a PSA level of 4 to 10 ng/mL. In the early years of the study, patients were most likely to be classified as high-risk due to a high PSA level, whereas more recently, they were more likely to have a low PSA and a high Gleason score.[10] A report of trends within CPDR likewise confirms stage migration, with the percentage of patients presenting with metastatic disease declining from 14.1% in 1988 to 3.3% in 1998.[12] Diagnosis of Gleason 2-5 disease on biopsy has become quite rare.[10] Nevertheless, other investigators have demonstrated that Gleason scores have been rising over the past decade as a result of changes in pathologic grading practices,[13] suggesting that even as patients are being diagnosed less commonly with high-risk disease, a contemporary patient considered to be at high risk may have a better prognosis than a high-risk patient in the early 1990s. Interestingly, a study from SEARCH compared the time to failure for biopsy Gleason score 4 (as referent), 5, and 6 tumors, finding a monotonically increasing earlier risk of failure, with a hazard ratio of 1.31 (P = .025).[14] This finding was not borne out among CaPSURE patients. Advanced Disease
As a population-based rather than urology-based database, PCOS includes greater numbers of patients with advanced disease. Hoffman et al described racial differences in men diagnosed with advanced prostate cancer, defined as clinical T4, N1, and/or M1 tumors.[15] The PCOS included 2,187 non-Hispanic white men, 539 African-Americans, and 447 Hispanics, of whom 8% presented with clinically advanced-stage prostate cancer. Of men in the PCOS cohort, 12.3% of African-Americans, 10.5% of Hispanics, and 6.3% of whites presented with T4 disease. Univariate analysis indicated significantly higher risk for advanced disease among African-Americans and Hispanics. Gleason 8-10 cancers also tended to be more prevalent among African-American men. Controlling for age, grade, and socioeconomic status (as measured by insurance status and educational level), African-American but not Hispanic men remained statistically significantly more likely to be diagnosed with advanced disease.[15] Higher-Risk Populations
The 241 CaPSURE patients enrolled at VA medical centers are much more likely than the general patient population to be African-American, to have lower income, less education, and more comorbidity at presentation. They also have significantly higher risk disease in terms of PSA at diagnosis and biopsy Gleason score. They are more likely to undergo watchful waiting or receive primary androgendeprivation therapy, and less likely to receive definitive local therapy.[16] African-American patients included in CaPSURE likewise have consistently higher-risk characteristics, but the trends toward better risk at presentation were identical to those seen in the general database.[10] A model of biochemical outcomes in CaPSURE found African-American ethnicity to be a predictor of recurrence in univariate analysis, with the greatest difference in outcomes between African-American and white patients with high-risk characteristics. The 5-year biochemical diseasefree survival rates were estimated at 65% among white patients and 28% among African-American patients. However, in multivariate analysis controlling for income and education- variables that associated closely with ethnicity-ethnicity was no longer an independent predictor of outcome.[17] A similar analysis from SEARCH likewise found that African-American ethnicity correlated with outcome but was not an independent predictor in multivariate analysis.[11] Amling et al reported an association among CPDR patients between obesity as measured by body mass index (BMI) and higher pathologic stage and grade and younger age at diagnosis.[18] They then correlated BMI with ethnicity, and found the highest mean BMI among African- American men. They suggest that higher BMI among African-American men may offer an explanation for the higher-risk disease and earlier age of diagnosis among these patients.[18] The relationships between ethnicity, BMI, and risk are complex and intriguing, and are the subject of numerous ongoing studies in both SEARCH and CaPSURE. National Practice Patterns Analyses dating back to the early 1990s have demonstrated minimal benefit of imaging tests for staging patients with low-risk disease characteristics such as PSA < 10 ng/mL.[19] An analysis of CaPSURE data found that rates of both bone scan and computed tomography scan use have fallen dramatically in recent years, with the greatest declines among lowerrisk patients. Indeed, whereas among early CaPSURE patients, disease risk exerted no influence on the likelihood of imaging, in more recent years, rates of imaging are strongly associated with risk characteristics.[20] Due to the extended natural history of prostate cancer and the HRQOL impact of all available active treatments, investigators have recently paid increased attention to watchful waiting as a viable alternative for the initial management of prostate tumors with favorable risk characteristics. Among PCOS patients surveyed in 1994-1995, 47.6% underwent radical prostatectomy; 23.4%, radiation therapy; 10.5%, primary androgendeprivation therapy; and 18.5%, watchful waiting.[21] After adjusting for age, clinical stage, grade, and PSA level, predictors of conservative therapy (defined as primary androgendeprivation therapy alone or watchful waiting) were age over 75, history of myocardial infarction, unmarried status, and preexisting urinary, bowel, or erectile problems. Men in Connecticut underwent aggressive treatment more frequently than did men in the other five SEER registries examined. Racial differences in treatment were absent in men less than age 60, but uniformly across age strata in men over age 60. African-American men underwent aggressive treatment (radical prostatectomy or radiation therapy) less frequently than white or Hispanic men.[21] A more recent study from PCOS focusing on the question of racial differences in treatment patterns found that African- American men with higher-risk tumors received aggressive treatment less frequently.[22] Watchful Waiting
An early cross-sectional analysis from CaPSURE found that only 8.2% of patients in the database pursued watchful waiting as primary management.[ 23] A subsequent study of temporal trends found that watchful waiting use has, in fact, fallen from 9.5% in 1992-1994 to 5.5% in 1998- 2000, with the sharpest declines among low-risk patients.[24] In the cross-sectional study, over half of the watchful waiting patients underwent secondary treatment within 5 years, especially those who were younger or had higher PSA scores at diagnosis. Most of these received androgen-deprivation therapy.[23] PSA kinetics are a strong driver of treatment decisions: Patients whose PSA levels increase > 5 ng/mL during watchful waiting were nearly four times as likely to convert to active treatment as those with an increase < 2 ng/mL. Highrisk baseline characteristics were also significant predictors of eventual active treatment.[24] Low-Risk Patients
The findings of declining watchful waiting use prompted an examination in greater detail of treatment trends among low-risk patients. Preliminary results suggest that among CaPSURE patients, use of watchful waiting in low-risk patients has fallen by more than half, from 20% of patients in 1993-1995 to 8% in 1999-2001. Over the same time, use of external-beam radiation therapy fell from 13% to 7%, while that of radical prostatectomy fell slightly, from 55% to 52%. In contrast, use of primary androgen- deprivation therapy and brachytherapy increased significantly, from 7% to 12% and 4% to 22%, respectively. Even among patients 75 years of age or older, watchful waiting use fell from 52% to 24%, while primary androgen-deprivation therapy increased from 23% to 30%, and brachytherapy from 3% to 31% of patients. Overall, roughly half of all patients over age 75 receive either primary androgen-deprivation therapy or neoadjuvant androgen-deprivation therapy. There was no significant influence of ethnicity on treatment patterns in CaPSURE.[25] Androgen Deprivation Therapy
Another CaPSURE study extended cross-sectional observations from PCOS[26] suggesting higher than expected use of primary androgen-deprivation therapy among localized prostate cancer patients. The use of primary androgen-deprivation therapy as monotherapy has risen dramatically across groups over the past decade, from 5% to 14%, 9% to 20%, and 33% to 48% among low-, intermediate-, and high-risk patients, respectively, from 1989-1990 to 2000-2001. Likewise, neoadjuvant androgen-deprivation therapy use has risen from 3% to 8% of patients undergoing radical prostatectomy, 10% to 75% of those receiving external-beam radiation therapy, and 7% to 25% of those receiving brachytherapy.[ 27] Cost Analysis
The resource utilization data in CaPSURE also offer a means of studying cost implications of various management strategies for prostate cancer. Penson et al analyzed the first-year costs associated with various treatment options based on Medicare payment schedules. They found a trend toward significantly higher costs for higher-stage patients. Costs were not different between radical prostatectomy and external-beam radiation therapy patients, but were significantly higher for patients receiving neoadjuvant androgen-deprivation therapy before either primary treatment.[28]
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
