Grace L. Lu-Yao

Outcomes of Localized Prostate Cancer Following Conservative Management

CONTEXT Most newly diagnosed prostate cancers are clinically localized, and major treatment options include surgery, radiation, or conservative management. Although conservative management can be a reasonable choice, there is little contemporary prostate-specific antigen (PSA)-era data on outcomes with this approach. OBJECTIVE To evaluate the outcomes of clinically localized prostate cancer managed without initial attempted curative therapy in the PSA era. DESIGN, SETTING, AND PARTICIPANTS A population-based cohort study of men aged 65 years or older when they were diagnosed (1992-2002) with stage T1 or T2 prostate cancer and whose cases were managed without surgery or radiation for 6 months after diagnosis. Living in areas covered by the Surveillance, Epidemiology, and End Results (SEER) program, the men were followed up for a median of 8.3 years (through December 31, 2007). Competing risk analyses were performed to assess outcomes. MAIN OUTCOME MEASURES Ten-year overall survival, cancer-specific survival, and major cancer related interventions. RESULTS Among men who were a median age of 78 years at cancer diagnosis, 10-year prostate cancer-specific mortality was 8.3% (95% confidence interval [CI], 4.2%-12.8%) for men with well-differentiated tumors; 9.1% (95% CI, 8.3%-10.1%) for those with moderately differentiated tumors, and 25.6% (95% CI, 23.7%-28.3%) for those with poorly differentiated tumors. The corresponding 10-year risks of dying of competing causes were 59.8% (95% CI, 53.2%-67.8%), 57.2% (95% CI, 52.6%-63.9%), and 56.5% (95% CI, 53.6%-58.8%), respectively. Ten-year disease-specific mortality for men aged 66 to 74 years diagnosed with moderately differentiated disease was 60% to 74% lower than earlier studies: 6% (95% CI, 4%-8%) in the contemporary PSA era (1992-2002) compared with results of previous studies (15%-23%) in earlier eras (1949-1992). Improved survival was also observed in poorly differentiated disease. The use of chemotherapy (1.6%) or major interventions for spinal cord compression (0.9%) was uncommon. CONCLUSIONS Results following conservative management of clinically localized prostate cancer diagnosed from 1992 through 2002 are better than outcomes among patients diagnosed in the 1970s and 1980s. This may be due, in part, to additional lead time, overdiagnosis related to PSA testing, grade migration, or advances in medical care.

Contemporary Risk Profile of Prostate Cancer in the United States

National-level data that characterize contemporary prostate cancer patients are limited. We used 2004-2005 data from the Surveillance, Epidemiology, and End Results Program to generate a contemporary profile of prostate cancer patients (N = 82 541) and compared patient characteristics of this 2004-2005 population with those of patients diagnosed in 1998-1989 and 1996-1997. Among newly diagnosed patients in 2004-2005, the majority (94%) had localized (ie, stage T1 or T2) prostate cancer and a median serum prostate-specific antigen (PSA) level of 6.7 ng/mL. Between 1988-1989 and 2004-2005, the average age at prostate cancer diagnosis decreased from 72.2 to 67.2 years, and the incidence rate of T3 or T4 cancer decreased from 52.7 per 100 000 to 7.9 per 100 000 among whites and from 90.9 per 100 000 to 13.3 per 100 000 among blacks. In 2004-2005, compared with whites, blacks were more likely to be diagnosed at a younger age (mean age: 64.7 vs 67.5 years, difference = 2.7 years, 95% confidence interval [CI] = 2.5 to 2.9 years, P < .001) and to have a higher PSA level at diagnosis (median PSA level: 7.4 vs 6.6 ng/mL, difference = 0.8 ng/mL, 95% CI = 0.6 to 1.0 ng/mL, P < .001). In conclusion, more men were diagnosed with prostate cancer at a younger age and earlier stage in 2004-2005 than in earlier years. The racial disparity in cancer stage at diagnosis has decreased statistically significantly over time.

Natural experiment examining impact of aggressive screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and Connecticut

Abstract Objective:To determine whether the more intensive screening and treatment for prostate cancer in the Seattle-Puget Sound area in 1987-90 led to lower mortality from prostate cancer than in Connecticut. Design: Natural experiment comparing two fixed cohorts from 1987 to 1997. Setting: Seattle-Puget Sound and Connecticut surveillance, epidemiology, and end results areas. Participants: Population based cohorts of male Medicare beneficiaries aged 65-79 drawn from the Seattle (n=94 900) and Connecticut (n=120 621) areas. Main outcome measures: Rates of screening for prostate cancer, treatment with radical prostatectomy and external beam radiotherapy, and prostate cancer specific mortality. Results: The prostate specific antigen testing rate in Seattle was 5.39 (95% confidence interval 4.76 to 6.11) times that of Connecticut, and the prostate biopsy rate was 2.20 (1.81 to 2.68) times that of Connecticut during 1987-90. The 10 year cumulative incidences of radical prostatectomy and external beam radiotherapy up to 1996 were 2.7% and 3.9% for Seattle cohort members compared with 0.5% and 3.1% for Connecticut cohort members. The adjusted rate ratio of prostate cancer mortality up to 1997 was 1.03 (0.95 to 1.11) in Seattle compared with Connecticut. Conclusion: More intensive screening for prostate cancer and treatment with radical prostatectomy and external beam radiotherapy among Medicare beneficiaries in the Seattle area than in the Connecticut area was not associated with lower prostate cancer specific mortality over 11 years of follow up.

Impact of Comorbidity on Survival Among Men With Localized Prostate Cancer

PURPOSE To provide patients and clinicians more accurate estimates of comorbidity-specific survival stratified by patient age, tumor stage, and tumor grade. PATIENTS AND METHODS We conducted a 10-year competing risk analysis of 19,639 men 66 years of age and older identified by the Surveillance, Epidemiology, and End Results (SEER) program linked to Medicare program files. All men were diagnosed with localized prostate cancer and received no surgery or radiation within 180 days of diagnosis. The analysis was stratified by tumor grade and stage and by age and comorbidity at diagnosis classified using the Charlson comorbidity index. Underlying causes of death were obtained from SEER. RESULTS During the first 10 years after diagnosis, men with moderately and poorly differentiated prostate cancer were more likely to die from causes other than their disease. Depending on patient age, Gleason score, and number of comorbidities present at diagnosis, 5-year overall mortality rates for men with stage T1c disease ranged from 11.7% (95% CI, 10.2% to 13.1%) to 65.7% (95% CI, 55.9% to 70.1%), and prostate cancer-specific mortality rates ranged from 1.1% (95% CI, 0.0% to 2.7%) to 16.3% (95% CI, 13.8% to 19.4%). Ten-year overall mortality rates ranged from 28.8% (95% CI, 25.3% to 32.6%) to 94.3% (95% CI, 87.4% to 100%), and prostate cancer-specific mortality rates ranged from 2.0% (95% CI, 0.0% to 5.3%) to 27.5% (95% CI, 21.5% to 36.5%). CONCLUSION Patients and clinicians should consider using comorbidity-specific data to estimate the threat posed by newly diagnosed localized prostate cancer and the threat posed by competing medical hazards.

Risk profiles and treatment patterns among men diagnosed as having prostate cancer and a prostate-specific antigen level below 4.0 ng/ml.

BACKGROUND Despite controversy over the benefit of prostate-specific antigen (PSA) screening, little is known about risk profiles and treatment patterns in men diagnosed as having prostate cancer who have a PSA value less than or equal to 4.0 ng/mL. METHODS We used data from the Surveillance, Epidemiology, and End Results system to describe patient characteristics and treatment patterns in the cases of 123 934 men with newly diagnosed prostate cancer from 2004 to 2006. Age-standardized treatment rates were calculated in 5-year age strata. Logistic regression was used to quantify the odds ratios (ORs) of men with low- and high-risk disease and the use of radical prostatectomy (RP) or radiation therapy (RT). RESULTS Men with a PSA level of 4.0 ng/mL or lower represent 14% of incident prostate cancer cases. Fifty-four percent of men diagnosed as having prostate cancer and PSA levels lower than 4.0 ng/mL harbor low-risk disease (stage, < or =T2a, PSA level, < or =10 ng/mL, and Gleason score, < or =6), but over 75% of them received RP or RT. Men with screen-detected prostate cancer and PSA values lower than 4 ng/mL were 1.49 (95% confidence interval [CI], 1.38-1.62) and 1.39 (95% CI, 1.30-1.49) times more likely to receive RP and RT, respectively, and were less likely to have high-grade disease than men who had non-screen-detected prostate cancer (OR, 0.67; 95% CI, 0.60-0.76). CONCLUSIONS Most men diagnosed as having prostate cancer with a PSA threshold below 4.0 ng/mL had low-risk disease but underwent aggressive local therapy. Lowering the biopsy threshold but retaining our inability to distinguish indolent from aggressive cancers might increase the risk of overdiagnosis and overtreatment.

Late Gastrointestinal Toxicities Following Radiation Therapy for Prostate Cancer

BACKGROUND Radiation therapy is commonly used to treat localized prostate cancer; however, representative data regarding treatment-related toxicities compared with conservative management are sparse. OBJECTIVE To evaluate gastrointestinal (GI) toxicities in men treated with either primary radiation or conservative management for T1-T2 prostate cancer. DESIGN, SETTING, AND PARTICIPANTS We performed a population-based cohort study, using Medicare claims data linked to the Surveillance Epidemiology and End Results data. Competing risk models were used to evaluate the risks. MEASUREMENTS GI toxicities requiring interventional procedures occurring at least 6 mo after cancer diagnosis. RESULTS AND LIMITATIONS Among 41,737 patients in this study, 28,088 patients received radiation therapy. The most common GI toxicity was GI bleeding or ulceration. GI toxicity rates were 9.3 per 1000 person-years after three-dimensional conformal radiotherapy, 8.9 per 1000 person-years after intensity-modulated radiotherapy, 5.3 per 1000 person-years after brachytherapy alone, 20.1 per 1000 person-years after proton therapy, and 2.1 per 1000 person-years for conservative management patients. Radiation therapy is the most significant factor associated with an increased risk of GI toxicities (hazard ratio [HR]: 4.74; 95% confidence interval [CI], 3.97-5.66). Even after 5 yr, the radiation group continued to experience significantly higher rates of new GI toxicities than the conservative management group (HR: 3.01; 95% CI, 2.06-4.39). Because our cohort of patients were between 66 and 85 yr of age, these results may not be applicable to younger patients. CONCLUSIONS Patients treated with radiation therapy are more likely to have procedural interventions for GI toxicities than patients with conservative management, and the elevated risk persists beyond 5 yr.

Fifteen-Year Survival Outcomes Following Primary Androgen-Deprivation Therapy for Localized Prostate Cancer

IMPORTANCE One in 6 American men will be diagnosed as having prostate cancer during their lifetime. Although there are no data to support the use of primary androgen-deprivation therapy (ADT) for early-stage prostate cancer, primary ADT has been widely used for localized prostate cancer, especially among older patients. OBJECTIVE To determine the long-term survival impact of primary ADT in older men with localized (T1/T2) prostate cancer. DESIGN, SETTING, AND PARTICIPANTS This was a population-based cohort study of 66,717 Medicare patients 66 years or older diagnosed from 1992 through 2009 who received no definitive local therapy within 180 days of prostate cancer diagnosis. The study was conducted in predefined US geographical areas covered by the Surveillance, Epidemiology, and End Results (SEER) Program. Instrumental variable analysis was used to assess the impact of primary ADT and control for potential biases associated with unmeasured confounding variables. The instrumental variable comprised combined health services areas with various usage rates of primary ADT. The analysis compared survival outcomes in the top tertile areas with those in the bottom tertile areas. MAIN OUTCOMES AND MEASURES Prostate cancer-specific survival and overall survival. RESULTS With a median follow-up of 110 months, primary ADT was not associated with improved 15-year overall or prostate cancer-specific survival following the diagnosis of localized prostate cancer. Among patients with moderately differentiated cancers, the 15-year overall survival was 20.0% in areas with high primary ADT use vs 20.8% in areas with low use (difference: 95% CI, -2.2% to 0.4%), and the 15-year prostate cancer survival was 90.6% in both high- and low-use areas (difference: 95% CI, -1.1% to 1.2%). Among patients with poorly differentiated cancers, the 15-year cancer-specific survival was 78.6% in high-use areas vs 78.5%, in low-use areas (difference: 95% CI, -1.8% to 2.4%), and the 15-year overall survival was 8.6% in high-use areas vs 9.2% in low-use areas (difference: 95% CI, -1.5% to 0.4%). CONCLUSIONS AND RELEVANCE Primary ADT is not associated with improved long-term overall or disease-specific survival for men with localized prostate cancer. Primary ADT should be used only to palliate symptoms of disease or prevent imminent symptoms associated with disease progression.

Lifestyle, Anthropometric, and Obesity-Related Physiologic Determinants of Insulin-like Growth Factor-1 in the Third National Health and Nutrition Examination Survey (1988–1994)

PURPOSE Epidemiologic studies suggest that insulin-like growth factor-1 (IGF-1) is associated with obesity and, more recently, cancer. This study investigates multiple lifestyle, physiologic, and anthropometric determinants of circulating IGF-1 concentrations. METHODS Nationally representative data were used from the cross-sectional Third National Health and Nutrition Examination (NHANES III, 1988-1994) survey, which measured IGF-1 concentrations in blood, from a subsample of participants who were examined in the morning. After exclusion of persons with missing data, 6,058 men and women 20 years of age or older were included in the study. RESULTS The mean IGF-1 concentrations were 260 ng/mL in the entire population and were higher among men as compared with women (278.8 vs. 241.3 ng/mL; p<0.0001). IGF-1 decreased with increasing age (p<0.0001), body mass index (p<0.0001), and waist circumference (p<0.0001). Individuals with metabolic syndrome had lower IGF-1 concentrations after adjustment for covariates (p=0.0008). IGF-1 was inversely associated with increasing number of metabolic syndrome abnormalities (p=0.0008). All associations were stronger among women compared with men except across concentrations of glucose. IGF-1 concentrations did not vary by any other lifestyle or physiologic factors. CONCLUSIONS Age, adiposity, hyperglycemia, and metabolic syndrome influenced circulating IGF-1 concentrations. Diet and physical activity had no impact on IGF-1 in this nationally representative population.

Associations of Lifestyle and Physiologic Factors with Prostate-Specific Antigen Concentrations: Evidence from the National Health and Nutrition Examination Survey (2001-2004)

Studies suggest inverse associations between obesity and prostate-specific antigen (PSA). However, there is little evidence whether factors related to obesity, including lifestyle (diet and physical activity) and physiologic factors (insulin resistance and metabolic syndrome), influence PSA. We used dietary, physical activity, and serum PSA, insulin, glucose, and lipid data for men >40 years from the National Health and Nutrition Examination Survey (2001-2004; N = 2,548). Energy, fat, and carbohydrate intakes were estimated from a 24-hour dietary recall. Men were considered as having metabolic syndrome based on the Adult Treatment Panel III criteria. Leisure-time physical activity and doctor-diagnosed hypertension were self-reported. Body mass index was calculated from measured weight and height. We computed the geometric mean PSA (ng/mL), adjusted for age, race, and body mass index, by tertile of energy, fat, and carbohydrate intake and level of physical activity, and among men with and without insulin resistance and metabolic syndrome in the whole population and by race. The geometric mean PSA (95% confidence interval) among men in the lowest tertile of energy was 1.05 (0.97-1.1) relative to 0.85 (0.8-0.9) in the highest tertile (P = 0.0002) in the whole population. The PSA concentrations were lower among overweight men with higher versus lower energy intake (P = 0.001). The PSA concentrations in men with insulin resistance was lower [0.87 (0.8-0.9)] relative to men without insulin resistance [0.98 (0.9-1.1)] at P = 0.04. All associations were in similar directions within racial subgroups. No associations were observed between the other lifestyle and physiologic factors. Additional studies are required to confirm these results and to investigate the potential mechanisms that may explain these relationships. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2467–72)

Patterns and Correlates of Prostate Cancer Treatment in Older Men

BACKGROUND Although elderly men, particularly patients with low-risk prostate cancer and a life expectancy less than 10 years, are unlikely to benefit from prostate cancer active therapy, treatment rates in this group are high. METHODS By using the population-based Surveillance, Epidemiology, and End Results program linked to Medicare data from 2004 to 2005, we examined the effects of clinical and nonclinical factors on the selection of prostate cancer active therapy (ie, radical prostatectomy, external beam radiation therapy, brachytherapy, or androgen deprivation therapy) in men aged≥75 years with a new diagnosis of localized prostate cancer. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for receiving prostate cancer active therapy. RESULTS The majority of men aged≥75 years were treated with prostate cancer active therapy (81.7%), which varied by disease risk level: low, 72.2%; intermediate, 83.7%; and high, 86.4%. Overall, in older men, the percentage of the total variance in the use of prostate cancer active therapy attributable to clinical and nonclinical factors was minimal, 5.1% and 2.6%, respectively. In men with low-risk disease, comorbidity status did not affect treatment selection, such that patients with 1 or 2+ comorbidities were as likely to receive prostate cancer active therapy as healthy men: OR=0.98; 95% CI, 0.76-1.27 and OR=1.19; 95% CI, 0.84-1.68, respectively. Geographic location was the most powerful predictor of treatment selection (Northeast vs Greater California: OR=2.41; 95% CI, 1.75-3.32). CONCLUSION Clinical factors play a limited role in treatment selection among elderly patients with localized prostate cancer.