Faculty Bibliography

Prostate cancer is a leading cause of cancer death in men in developed countries. While early stage disease can often be cured, many patients eventually develop castration resistant prostate cancer (CRPC). The majority of CRPC patients have bone metastases, which cause significant morbidity and mortality. Although there is no cure for prostate cancer metastatic to bone, several bone-targeted agents have been approved to prevent skeletal-related events (SREs). Among them, bisphosphonates were the first class of drugs investigated for prevention of SREs. Denosumab is a recently approved agent that binds to the receptor activator of nuclear factor-kappaB ligand (RANKL) as a humanized monoclonal antibody. Both agents target prostate cancer skeletal metastasis through the inhibition of bone resorption. Alpharadin is the first radiopharmaceutical agent that has significant overall survival benefit. It has benefits in pain palliation and SREs as well. Another newly approved drug is Abiraterone acetate, which decreases circulating levels of testosterone by targeting an enzyme expressed in the testis and the adrenal, as well as in prostate cancer tissues. This review outlines the clinical and preclinical data supporting the use of these and new agents in development for CRPC with bone metastasis.

PURPOSE: To evaluate the influence of immortal time bias on observational cohort studies of postoperative radiotherapy (PORT) and the effectiveness of sequential landmark analysis to account for this bias. METHODS AND MATERIALS: First, we reviewed previous studies of the Surveillance, Epidemiology, and End Results (SEER) database to determine how frequently this bias was considered. Second, we used SEER to select three tumor types (glioblastoma multiforme, Stage IA-IVM0 gastric adenocarcinoma, and Stage II-III rectal carcinoma) for which prospective trials demonstrated an improvement in survival associated with PORT. For each tumor type, we calculated conditional survivals and adjusted hazard ratios of PORT vs. postoperative observation cohorts while restricting the sample at sequential monthly landmarks. RESULTS: Sixty-two percent of previous SEER publications evaluating PORT failed to use a landmark analysis. As expected, delivery of PORT for all three tumor types was associated with improved survival, with the largest associated benefit favoring PORT when all patients were included regardless of survival. Preselecting a cohort with a longer minimum survival sequentially diminished the apparent benefit of PORT. CONCLUSIONS: Although the majority of previous SEER articles do not correct for it, immortal time bias leads to altered estimates of PORT effectiveness, which are very sensitive to landmark selection. We suggest the routine use of sequential landmark analysis to account for this bias.

PURPOSE: Intensity-modulated radiation therapy (IMRT) requires a high degree of expertise compared with standard radiation therapy (RT). We performed a retrospective cohort study of Medicare patients treated with IMRT compared with standard RT to assess outcomes in national practice. METHODS AND MATERIALS: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, we identified patients treated with radiation for cancer of the head and neck from 2002 to 2005. We used multivariate Cox models to determine whether the receipt of IMRT was associated with differences in survival. RESULTS: We identified 1613 patients, 33.7% of whom received IMRT. IMRT was not associated with differences in survival: the 3-year overall survival was 50.5% for IMRT vs. 49.6% for standard RT (p = 0.47). The 3-year cancer-specific survival was 60.0% for IMRT vs. 58.8% (p = 0.45). CONCLUSION: Despite its complexity and resource intensive nature, IMRT use seems to be as safe as standard RT in national community practice, because the use of IMRT did not have an adverse impact on survival.

Policy makers interested in containing health care costs are targeting regional variation in utilization, including the use of advanced imaging. However, bluntly decreasing utilization among the highest-utilization regions may have negative consequences. In a cross-sectional study of prostate cancer patients from 2004 to 2005, we found that regions with lower rates of inappropriate imaging also had lower rates of appropriate imaging. Similarly, regions with higher overall imaging rates tended to have not only higher rates of inappropriate imaging, but also higher rates of appropriate imaging. In fact, men with high-risk prostate cancer were more likely to receive appropriate imaging if they resided in areas with higher rates of inappropriate imaging. This "thermostat model" of regional health care utilization suggests that poorly designed policies aimed at reducing inappropriate imaging could limit access to appropriate imaging for high-risk patients. Health care organizations need clearly defined quality metrics and supportive systems to encourage appropriate treatment for patients and to ensure that cost containment does not occur at the expense of quality.

PURPOSE: According to guidelines most men with incident prostate cancer do not require staging imaging. We determined the population level prevalence and correlates of appropriate and inappropriate imaging in this cohort. MATERIALS AND METHODS: We performed a cross-sectional study of men 66 to 85 years old who were diagnosed with prostate cancer in 2004 and 2005 from the SEER (Surveillance, Epidemiology and End Results)-Medicare database. Low risk (no prostate specific antigen greater than 10 ng/ml, Gleason score greater than 7 or clinical stage greater than T2) and high risk (1 or more of those features) groups were formed. Inappropriate imaging was defined as any imaging for men at low risk and appropriate imaging was defined as bone scan for men at high risk as well as pelvic imaging as appropriate. Logistic regression modeled imaging in each group. RESULTS: Of 18,491 men at low risk 45% received inappropriate imaging while only 66% of 10,562 at high risk received appropriate imaging. For patients at low risk inappropriate imaging was associated with increasing clinical stage (T2 vs T1 OR 1.35, 95% CI 1.27-1.44), higher Gleason score (7 vs less than 7 OR 1.80, 95% CI 1.69-1.92), increasing age and comorbidity as well as decreasing education. Appropriate imaging for men at high risk was associated with lower stage (T4, T3 and T2 vs T1 OR 0.63, 95% CI 0.48-0.82, OR 0.67, 95% CI 0.60-0.80 and OR 0.87, 95% CI 0.80-0.86) and with higher Gleason score (greater than 8 and 7 vs less than 7 OR 2.18, 95% CI 1.92-2.48 and 1.51, 95% CI 1.35-1.70, respectively) as well as with younger age, white race, higher income, lower stage and more comorbidity. CONCLUSIONS: We found poor adherence to imaging guidelines for men with incident prostate cancer. Understanding the patterns by which clinicians use imaging for prostate cancer should guide educational efforts as well as research to suggest evidence-based guideline improvements