Martin F. Casey

Effectiveness of Adjuvant Chemotherapy for Locally Advanced Bladder Cancer

PURPOSE Given that randomized trials exploring adjuvant chemotherapy for bladder cancer have been underpowered and/or terminated prematurely, yielding inconsistent results and creating an evidence gap, we sought to compare the effectiveness of cystectomy versus cystectomy plus adjuvant chemotherapy in real-world patients. PATIENTS AND METHODS We conducted an observational study to compare the effectiveness of adjuvant chemotherapy versus observation postcystectomy in patients with pathologic T3-4 and/or pathologic node-positive bladder cancer using the National Cancer Data Base. We compared overall survival using propensity score (-adjusted, -stratified, -weighted, and -matched) analyses based on patient-, facility-, and tumor-level characteristics. A sensitivity analysis was performed to examine the impact of performance status. RESULTS A total of 5,653 patients met study inclusion criteria; 23% received adjuvant chemotherapy postcystectomy. Chemotherapy-treated patients were younger and more likely to have private insurance, live in areas with a higher median income and higher percentage of high school-educated residents, and have lymph node involvement and positive surgical margins (P < .05 for all comparisons). Stratified analyses adjusted for propensity score demonstrated an improvement in overall survival with adjuvant chemotherapy (hazard ratio, 0.70; 95% CI, 0.64 to 0.76), and similar results were achieved with propensity score matching and weighting. The association between adjuvant chemotherapy and improved survival was consistent in subset analyses and was robust to the effects of poor performance status. CONCLUSION In this observational study, adjuvant chemotherapy was associated with improved survival in patients with locally advanced bladder cancer. Although neoadjuvant chemotherapy remains the preferred approach based on level I evidence, these data lend further support for the use of adjuvant chemotherapy in patients with locally advanced bladder cancer postcystectomy who did not receive chemotherapy preoperatively.

The Impact of Regionalization of Cystectomy on Racial Disparities in Bladder Cancer Care

PURPOSE Regionalization of surgical care has improved the quality of care for patients with bladder cancer. We explored whether regionalization has benefited white and black patients equally. MATERIALS AND METHODS We used a New York State inpatient database to identify all patients who underwent cystectomy for bladder cancer from 1997 to 2011. Hospital volume was classified in quintiles based on the number of cystectomies performed in the first 5 years of the study. Logistic regression was done to assess the association between race and low volume/very low volume hospitals. Racial disparities were further characterized using stratification by time and by the racial composition of the patient community. RESULTS A total of 8,168 patients treated with cystectomy for bladder cancer were included in analysis. Compared with white race, black race was associated with a higher likelihood of low volume/very low volume hospital use (OR 1.59, 95% CI 1.26-2.02). The disparity was most prominent in 2002 to 2006 (OR 2.51, 95% CI 1.64-3.85) but it did not persist in 2007 to 2011 (OR 1.46, 95% CI 0.92-2.32). Black patients living in a black community had the highest likelihood of low volume/very low volume hospitalization during all periods of increased regionalization (2002 to 2006 OR 4.14, 95% CI 1.84-9.34 and 2007 to 2011 OR 2.40, 95% CI 1.07-5.39). CONCLUSIONS Regionalization of cystectomy transiently worsened the racial disparity in bladder cancer care, although the disparity did not persist with time. Specific efforts may be needed to address the consequences of regionalization in particularly vulnerable subpopulations, such as black patients who live in a black community where disparities have persisted.

The Relationship between Centralization of Care and Geographic Barriers to Cystectomy for Bladder Cancer.

Background: Centralization of cystectomy treatment for bladder cancer, while associated with improved outcomes, may impose geographic barriers to care. However, whether this effect may be counterbalanced by an increased number of high volume centers has not previously been explored. Objective: To characterize changes in geographic disparities to high volume cystectomy centers over time. Methods: Data on all inpatient admissions for cystectomy in New York State (NYS) from 1997–2011 was obtained from the Department of Health. Using these data, we classified hospitals according to cystectomy volume and measured patient distance traveled to a cystectomy center. Population weights, from the US Census, were used to describe changes in minimum travel distance to high- or very high-volume (HV/VHV) facilities across the NYS population. Results: Bladder cancer patients underwent cystectomies at 195 hospitals during the study period. In 1997–2001, eleven HV/VHV facilities accounted for 37.5% of all cystectomies, while sixteen HV/VHV hospitals accounted for 71.5% of all procedures during 2007–2011. Median distance traveled by cystectomy patients to all hospitals increased from 9.6 to 14.4 miles in 1997–2001 to 2007–2011, respectively. In the same time span, the median travel distance for the NYS population to a HV/VHV center decreased by 1.9 and 9.4 miles at the median and 75th percentile, respectively. Conclusions: Our findings demonstrate a complicated relationship between centralization and geographic access. While centralization has led to a decrease in overall access to cystectomy facilities, the process simultaneously improved access to high volume centers.

Association of Glycemic Control Parameters with Clinical Outcomes in Chronic Critical Illness

OBJECTIVE Chronic critical illness (CCI) is a term used to designate patients requiring prolonged mechanical ventilation and tracheostomy with associated poor outcomes. The present study assessed the impact of glycemic parameters on outcomes in a CCI population. METHODS A retrospective case series was performed including 148 patients in The Mount Sinai Hospital Respiratory Care Unit (2009-2010). Utilizing a semi-parametric mixture model, trajectories for the daily mean blood glucose (BG), BG range, and hypoglycemia rate over time identified low- (n = 87) and high-risk (n = 61) hyperglycemia groups and low- (n = 90) and high-risk (n = 58) hypoglycemia groups. The cohort was also classified into diabetes (DM, n = 48), stress hyperglycemia (SH, n = 85), and normal glucose (n = 15) groups. RESULTS Hospital- (28% vs. 13%, P = .0199) and 1-year mortality (66% vs. 46%, P = .0185) rates were significantly greater in the high- versus low-risk hyperglycemia groups, respectively. The hypoglycemia rate (<70 mg/dL) was lower among ventilator-liberated patients compared to those who failed to liberate (0.092 vs. 0.130, P<.0001). In the SH group, both hospital mortality (high-risk hyperglycemia 48% and low-risk hyperglycemia 15%, P = .0013) and 1-year mortality (high-risk 74% and low-risk 50%, P = .0482) remained significantly different, while no significant difference in the diabetes group was observed. There were lower hypoglycemia rates with SH compared to diabetes (<70 mg/dL: 0.086 vs. 0.182, P<.0001; <40 mg/dL: 0.012 vs. 0.022, P = .0118, respectively). CONCLUSION Tighter glycemic control was associated with improved outcomes in CCI patients with SH but not in CCI patients with diabetes. Confirmation of these findings may lead to stratified glycemic control protocols in CCI patients based on the presence or absence of diabetes.

The Khorana Score in Predicting Venous Thromboembolism for Patients With Metastatic Urothelial Carcinoma and Variant Histology Treated With Chemotherapy

Background: The Khorana score is a predictive risk model for venous thromboembolism (VTE) in patients with cancer planning to receive chemotherapy. Urothelial carcinoma and variant histologies (UC/VH) were underrepresented in the model. We sought to evaluate whether the Khorana score predicts for VTE in a retrospective multinational data set of patients with metastatic UC/VH. Methods: Patients diagnosed with metastatic UC/VH who received chemotherapy were eligible. Those with incomplete or miscoded data were excluded. Khorana scores were calculated based on the pretreatment data and categorized into high (≥3) or intermediate (1-2) VTE risk. Other patient-, tumor-, and therapy-related factors were also analyzed. The χ2 and logistic regression analyses were used to assess differences in VTE rates based on the clinical characteristics. Subgroup analyses were performed to evaluate the Khorana score and associated variables for early (<3 months) and late (>3 months) VTE. Results: A total of 943 patients were eligible for analysis. The cumulative VTE rate was 9.9%. There was no statistical difference in overall VTE rate between Khorana high- and intermediate-risk groups (P = .16). In the multivariate analysis, nonurothelial histology (odds ratio [OR] = 2.56; P = .002) and the presence of cardiovascular disease (CVD) or CVD risk factors (OR = 2.14; P = .002) were associated with increased VTE risk. In the first 3 months from initiation of chemotherapy, Khorana high risk (OR = 2.08; P = .04) was associated with higher VTE rates. White blood cell (WBC) count (OR = 1.05; P = .04) was the only significant Khorana variable for early VTE. Conclusions: The Khorana score stratifies early but not overall VTE risk in patients with metastatic UC/VH. The WBC count drives the increased early VTE risk seen with the Khorana score.

Venous thromboembolism in metastatic urothelial carcinoma or variant histologies: incidence, associative factors, and effect on survival

Venous thromboembolism (VTE) is common in cancer patients. However, little is known about VTE risk in metastatic urothelial carcinoma or variant histologies (UC/VH). We sought to characterize the incidence, associative factors, including whether various chemotherapy regimens portend different risk, and impact of VTE on survival in metastatic UC/VH patients. Patients diagnosed with metastatic UC/VH from 2000 to 2013 were included in this multicenter retrospective, international study from 29 academic institutions. Cumulative and 6‐month VTE incidence rates were determined. The association of first‐line chemotherapy (divided into six groups) and other baseline characteristics on VTE were analyzed. Each chemotherapy treatment group and statistically significant baseline clinical characteristics were assessed in a multivariate, competing‐risk regression model. VTE patients were matched to non‐VTE patients to determine the impact of VTE on overall survival. In all, 1762 patients were eligible for analysis. There were 144 (8.2%) and 90 (5.1%) events cumulative and within the first 6 months, respectively. VTE rates based on chemotherapy group demonstrated no statistical difference when gemcitabine/cisplatin was used as the comparator. Non‐urotheilal histology (SHR: 2.67; 95% CI: 1.72–4.16, P < 0.001), moderate to severe renal dysfunction (SHR: 2.12; 95% CI: 1.26–3.59, P = 0.005), and cardiovascular disease (CVD) or CVD risk factors (SHR: 2.27; 95% CI: 1.49–3.45, P = 0.001) were associated with increased VTE rates. Overall survival was worse in patients with VTE (median 6.0 m vs. 10.2 m, P < 0.001). Thus, in metastatic UC/VH patients, VTE is common and has a negative impact on survival. We identified multiple associated potential risk factors, although different chemotherapy regimens did not alter risk.

INTRAVENOUS PAMIDRONATE IS ASSOCIATED WITH REDUCED MORTALITY IN PATIENTS WITH CHRONIC CRITICAL ILLNESS

OBJECTIVE Chronic critical illness (CCI), characterized by prolonged mechanical ventilation and tracheostomy, commonly manifests with elevated bone resorption, which has previously been shown to abate after treatment with intravenous (IV) bisphosphonates. Our study assessed the impact of pamidronate administration on clinical outcomes in a CCI cohort. METHODS A retrospective case series was performed on 148 patients admitted to The Mount Sinai Hospital Respiratory Care Unit (RCU) from 2009-2010. We identified patients with CCI who did (n = 30) or did not (n = 118) receive IV pamidronate (30 to 90 mg). Both groups included patients with normal and abnormal renal function. Pamidronate was administered for elevated urine or serum N-telopeptide, hypercalciuria, or hypercalcemia. RESULTS RCU and 1-year mortality were significantly lower in the pamidronate group (0 and 20%, respectively) compared to nonreceivers (19 and 56%, respectively) (P = .0077 and P = .0004, respectively). After adjusting for differences in baseline creatinine, estimated glomerular filtration rate, and serum calcium, the association with reduced mortality remained significant at 1 year (P = .0132) and with borderline significance for RCU mortality (P = .0911). Creatinine was significantly lower 7 days following pamidronate administration (P = .0025), with no significant difference at 14 days compared to baseline. Pamidronate receivers showed a greater increase in albumin during the RCU stay (2.49 to 3.23 g/dL), compared to nonreceivers (2.43 to 2.64 g/dL) (P = .0007). Pamidronate administration was associated with a significantly reduced rate of hypoglycemia compared to RCU patients not receiving pamidronate (0.09 versus 0.12; P = .0071). CONCLUSION Pamidronate use in a CCI population is associated with reduced mortality, lower hypoglycemia rates, improved albumin, and stable renal function. ABBREVIATIONS BMI = body mass index CCI = chronic critical illness CI = confidence interval CKD = chronic kidney disease CTx = C-telopeptide eGFR = estimated glomerular filtration rate ICU = intensive care unit IV = intravenous NTx = N-telopeptide PMV = prolonged mechanical ventilation RCU = respiratory care unit.

Hospital Centralization Impacts High-Risk Lung and Bladder Cancer Surgical Patients

ABSTRACT We investigated the effects of hospital centralization on the distribution of the individual surgical patient risk in higher versus lower volume hospitals. Lung (n = 28,471) and bladder (n = 8,160) cancer surgical patients were selected from the New York Statewide Planning and Research Cooperative System database, 1997–2011. Estimated patient risk was consistently lower in the highest compared to the lowest hospital volume-quartiles for lung and bladder cancer mortality, complications, and long length of stay. Although centralization has improved outcomes, lower volume hospitals continue to perform surgery on higher surgical risk patients compared to higher volume hospitals.

Anti-Obesity Agents and the US Food and Drug Administration

Despite the growing market for obesity care, the US Food and Drug Administration (FDA) has approved only two new pharmaceutical agents—lorcaserin and combination phentermine/topiramate—for weight reduction since 2000, while removing three agents from the market in the same time period. This article explores the FDA’s history and role in the approval of anti-obesity medications within the context of a public health model of obesity. Through the review of obesity literature and FDA approval documents, we identified two major barriers preventing fair evaluation of anti-obesity agents including: (1) methodological pitfalls in clinical trials and (2) misaligned values in the assessment of anti-obesity agents. Specific recommendations include the use of adaptive (Bayesian) design protocols, value-based analyses of risks and benefits, and regulatory guidance based on a comprehensive, multi-platform obesity disease model. Positively addressing barriers in the FDA approval process of anti-obesity agents may have many beneficial effects within an obesity disease model.