Weichung Shih

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.

Survival following primary androgen deprivation therapy among men with localized prostate cancer.

CONTEXT Despite a lack of data, increasing numbers of patients are receiving primary androgen deprivation therapy (PADT) as an alternative to surgery, radiation, or conservative management for the treatment of localized prostate cancer. OBJECTIVE To evaluate the association between PADT and survival in elderly men with localized prostate cancer. DESIGN, SETTING, AND PATIENTS A population-based cohort study of 19,271 men aged 66 years or older receiving Medicare who did not receive definitive local therapy for clinical stage T1-T2 prostate cancer. These patients were diagnosed in 1992-2002 within predefined US geographical areas, with follow-up through December 31, 2006, for all-cause mortality and through December 31, 2004, for prostate cancer-specific mortality. Instrumental variable analysis was used to address potential biases associated with unmeasured confounding variables. MAIN OUTCOME MEASURES Prostate cancer-specific survival and overall survival. RESULTS Among patients with localized prostate cancer (median age, 77 years), 7867 (41%) received PADT, and 11,404 were treated with conservative management, not including PADT. During the follow-up period, there were 1560 prostate cancer deaths and 11,045 deaths from all causes. Primary androgen deprivation therapy was associated with lower 10-year prostate cancer-specific survival (80.1% vs 82.6%; hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.03-1.33) and no increase in 10-year overall survival (30.2% vs 30.3%; HR, 1.00; 95% CI, 0.96-1.05) compared with conservative management. However, in a prespecified subset analysis, PADT use in men with poorly differentiated cancer was associated with improved prostate cancer-specific survival (59.8% vs 54.3%; HR, 0.84; 95% CI, 0.70-1.00; P = .049) but not overall survival (17.3% vs 15.3%; HR, 0.92; 95% CI, 0.84-1.01). CONCLUSION Primary androgen deprivation therapy is not associated with improved survival among the majority of elderly men with localized prostate cancer when compared with conservative management.

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.

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.

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.

Cancer-specific Survival After Metastasis Following Primary Radical Prostatectomy Compared with Radiation Therapy in Prostate Cancer Patients: Results of a Population-based, Propensity Score–Matched Analysis

BACKGROUND Data regarding the difference in the clinical course from metastasis to prostate cancer-specific mortality (PCSM) following radical prostatectomy (RP) compared with radiation therapy (RT) are lacking. OBJECTIVE To examine the association between primary treatment modality and prostate cancer-specific survival (PCSS) after metastasis. DESIGN, SETTING, AND PARTICIPANTS We used the Surveillance Epidemiology and End Results-Medicare linked database from 1994 to 2007 for patients diagnosed with localized prostate cancer (PCa). We used cancer stage and Gleason score to stratify patients into low and intermediate-high risks. INTERVENTION Radical prostatectomy or radiation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Our outcome is time from onset of metastases to PCSM. Propensity score matching and Cox regression were used to analyze the PCSM hazard for the RP group compared with the RT group. RESULTS AND LIMITATIONS Our study consisted of 66,492 men diagnosed with PCa, 51,337 men receiving RT, and 15,155 men undergoing RP within 1 yr of cancer diagnosis. During the study period, 2802 men were diagnosed as having metastatic disease. A total of 916 men with metastases were included in the propensity-matched cohort; of these men, 186 died from PCa. During the follow-up, for the low-risk patients, the adjusted PCSS after metastasis was 86.2% and 79.3% in the RP and RT groups, respectively; for the intermediate-high-risk patients, the PCSS after metastasis was 76.3% and 63.3% in the RP and RT groups, respectively. The hazard ratios estimating the risk of PCSM between the RP and RT groups were 0.64 (95% confidence interval [CI], 0.36-1.16) and 0.55 (95% CI, 0.39-0.77) for the low- and intermediate-high-risk groups, respectively. Because of the nature of observational studies, the results may be affected by residual confounders and treatment indication. CONCLUSIONS Following the development of metastases, men who received primary RP have a longer PCSS than men who received primary RT. Our results may have implications for the timing and nature of local PCa treatment.

Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications

Receipt of androgen deprivation therapy (ADT) has been associated with an increased risk of skeletal‐associated complications, such as a decrease in bone mineral density and an increase in fracture risk. Many men with pre‐existing health conditions receive ADT as their primary treatment because they are considered to be inappropriate candidates for attempted curative treatments. However, several chronic health conditions, such as diabetes, rheumatoid disease and chronic liver disease, are strong predictors for osteoporosis and fractures. We undertook the present study aiming to quantify the impact of treating men with ADT who carry known risk factors for skeletal complications. Among these high‐risk men, more than 58% develop at least one fracture after ADT within the 12 years of follow‐up. Men who sustained a fracture within 48 months experienced an almost 40% higher risk of mortality than those who did not. Our findings suggest that treating men with a high fracture risk at baseline with long‐term ADT may have serious adverse consequences.

Severe Genitourinary Toxicity Following Radiation Therapy for Prostate Cancer—How Long Does it Last?

PURPOSE Radiation therapy is a common treatment for localized prostate cancer but long-term data are sparse on treatment related toxicity compared to observation. We evaluated the time course of grade 2-4 genitourinary toxicities in men treated with primary radiation or observation for T1-T2 prostate cancer. MATERIALS AND METHODS We performed a population based cohort study using Medicare claims data linked to SEER (Surveillance, Epidemiology and End Results) data. Cumulative incidence functions for time to first genitourinary event were calculated based on the competing risks model with death before any genitourinary event as a competing event. The generalized estimating equation method was used to evaluate the risk ratios of recurrent events. RESULTS Of the study patients 60,134 received radiation therapy and 25,904 underwent observation. The adjusted risk ratio for genitourinary toxicity was 2.49 (95% CI 2.00-3.11) for 10 years and thereafter. Patients who had required prior procedures for obstruction/stricture, including transurethral prostate resection, before radiation therapy were at significantly increased risk for genitourinary toxicity (risk ratio 2.78, 95% CI 2.56-2.94). CONCLUSIONS This study demonstrates that the increased risk of grade 2-4 genitourinary toxicities attributable to radiation therapy persists 10 years after treatment and thereafter. Patients who required prior procedures for obstruction/stricture were at higher risk for genitourinary toxicity than those without these preexisting conditions.

Does Primary Androgen-Deprivation Therapy Delay the Receipt of Secondary Cancer Therapy for Localized Prostate Cancer?

BACKGROUND Despite evidence that shows no survival advantage, many older patients receive primary androgen-deprivation therapy (PADT) shortly after the diagnosis of localized prostate cancer (PCa). OBJECTIVE This study evaluates whether the early use of PADT affects the subsequent receipt of additional palliative cancer treatments such as chemotherapy, palliative radiation therapy, or intervention for spinal cord compression or bladder outlet obstruction. DESIGN, SETTING, AND PARTICIPANTS This longitudinal population-based cohort study consists of Medicare patients aged ≥ 66 yr diagnosed with localized PCa from 1992 to 2006 in areas covered by the Surveillance Epidemiology and End Results (SEER) program. SEER-Medicare linked data through 2009 were used to identify the use of PADT and palliative cancer therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Instrumental variable analysis methods were used to minimize confounding effects. Confidence intervals were derived from the bootstrap estimates. RESULTS AND LIMITATIONS This study includes 29 775 men who did not receive local therapy for T1-T2 PCa within the first year of cancer diagnosis. Among low-risk patients (Gleason score 2-7 in 1992-2002 and Gleason score 2-6 in 2003-2006) with a median age of 78 yr and a median follow-up of 10.3 yr, PADT was associated with a 25% higher use of chemotherapy (hazard ratio [HR]: 1.25; 95% confidence interval [CI], 1.08-1.44) and a borderline higher use of any palliative cancer treatment (HR: 1.07; 95% CI, 0.97-1.19) within 10 yr of diagnosis in regions with high PADT use compared with regions with low PADT use. Because this study was limited to men >65 yr, the results may not be applicable to younger patients. CONCLUSIONS Early treatment of low-risk, localized PCa with PADT does not delay the receipt of subsequent palliative therapies and is associated with an increased use of chemotherapy.