Use of quantitative bias analysis to evaluate single-arm trials with real-world data external controls.

PURPOSE: Use of real-world data (RWD) for external controls added to single-arm trials (SAT) is increasingly prevalent in regulatory submissions. Due to inherent differences in the data-generating mechanisms, biases can arise. This paper aims to illustrate how to use quantitative bias analysis (QBA). METHODS: Advanced non-small cell lung cancer (NSCLC) serves as an example, where many small subsets of patients with molecular tumor subtypes exist. First, some sources of bias that may occur in oncology when comparing RWD to SAT are described. Second, using a hypothetical immunotherapy agent, a dataset is simulated based on expert input for survival analysis of advanced NSCLC. Finally, we illustrate the impact of three biases: missing confounder, misclassification of exposure, and outcome evaluation. RESULTS: For each simulated scenario, bias was induced by removing or adding data; hazard ratios (HRs) were estimated applying conventional analyses. Estimating the bias-adjusted treatment effect and uncertainty required carefully selecting the bias model and bias factors. Although the magnitude of each biased and bias-adjusted HR appeared moderate in all three hypothetical scenarios, the direction of bias was variable. CONCLUSION: These findings suggest that QBA can provide an intuitive framework for bias analysis, providing a key means of challenging assumptions about the evidence. However, the accuracy of bias analysis is itself dependent on correct specification of the bias model and bias factors. Ultimately, study design should reduce bias, but QBA allows us to evaluate the impact of unavoidable bias to assess the quality of the evidence.

Receipt of Serial Endoscopy Procedures Prior to Esophageal Adenocarcinoma Diagnosis Is Associated with Better Survival.

BACKGROUND: The poor prognosis of esophageal adenocarcinoma (EAC) has focused efforts on early detection by serial endoscopic surveillance of Barrett's esophagus (BE). Previously, we reported that receipt of endoscopy before EAC diagnosis was associated with improved survival. AIM: We aimed to refine our previous analysis, assessing surveillance as measured by performance of serial endoscopy before EAC diagnosis and evaluating its association with stage and survival. METHODS: A retrospective cohort study was performed using the Surveillance, Epidemiology and End Results-Medicare database. Patients aged ≥ 70 years with EAC diagnosed during 1998-2009 were identified. Diagnosis with BE and receipt of ≥ 2 upper endoscopic procedures within 5 years before cancer diagnosis were identified. We compared a reference group not receiving serial endoscopy to 3 patterns based on ≥ 2 endoscopy dates relative to a timepoint 2 years before cancer diagnosis: "remote," "recent," and "sustained." RESULTS: Among 5532 patients, 28% (n = 1,575) had localized stage. Thirteen percent (n = 703) received ≥ 2 endoscopic procedures before cancer diagnosis: 224, 298, and 181 in the "recent," "remote," and "sustained" groups. Serial endoscopy and prior BE were associated with localized stage ("sustained" group OR 2.95, 95% confidence interval [CI] 2.07, 4.19; prior BE OR 2.68, 95% CI 2.03, 3.56). Serial endoscopy was associated with improved survival even with adjustment for lead time bias ("sustained" group HR 0.45, 95% CI 0.37, 0.55) and length time bias. CONCLUSIONS: Sustained endoscopy was associated with earlier stage and improved survival. These results support the role of sustained surveillance in early detection of EAC.

Cancer preventive services, socioeconomic status, and the Affordable Care Act.

BACKGROUND: Out-of-pocket expenditures are thought to be an important barrier to the receipt of cancer preventive services, especially for those of a lower socioeconomic status (SES). The Affordable Care Act (ACA) eliminated out-of-pocket expenditures for recommended services, including mammography and colonoscopy. The objective of this study was to determine changes in the uptake of mammography and colonoscopy among fee-for-service Medicare beneficiaries before and after ACA implementation. METHODS: Using Medicare claims data, this study identified women who were 70 years old or older and had not undergone mammography in the previous 2 years and men and women who were 70 years old or older, were at increased risk for colorectal cancer, and had not undergone colonoscopy in the past 5 years. The receipt of procedures in the 2-year period before the ACA's implementation (2009-2010) and after its implementation (2011 to September 2012) was also identified. Multivariate generalized estimating equation models were used to determine the independent association and county-level quartile of median income and education with the receipt of testing. RESULTS: For mammography, a lower SES quartile was associated with less uptake, but the post-ACA disparities were smaller than those in the pre-ACA period. In addition, mammography rates increased from the pre-ACA period to the post-ACA period in all SES quartiles. For colonoscopy, in both the pre- and post-ACA periods, there was an association between uptake and educational level and, to some extent, income. However, there were no appreciable changes in colonoscopy and SES after implementation of the ACA. CONCLUSIONS: The removal of out-of-pocket expenditures may overcome a barrier to the receipt of recommended preventive services, but for colonoscopy, other procedural factors may remain as deterrents. Cancer 2017;123:1585-1589. © 2017 American Cancer Society.

Outcomes after endoscopic versus surgical therapy for early esophageal cancers in an older population.

BACKGROUND AND AIMS: Endoscopic treatment of early esophageal cancer provides an alternative to esophagectomy, which older patients may not tolerate. Population-based data regarding short-term outcomes and recurrence after endoscopic treatment for esophageal cancer are limited. We compared short-term outcomes, treated recurrence, and survival after endoscopic versus surgical therapy for early esophageal cancers in an older population. METHODS: We conducted a retrospective cohort study identifying patients aged ≥66 years with Tis or T1a tumors without nodal involvement diagnosed from 1994 to 2011 from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. RESULTS: Of 2193 patients, 41% (n = 893) underwent esophagectomy, and 12% (n = 255) underwent endoscopic treatment within 6 months of diagnosis. Those treated endoscopically were older and more likely to have a Charlson comorbidity score ≥2. A composite endpoint, hospitalization and/or adverse events at 60 days, was higher in surgical patients than in the endoscopic treatment group (30% vs 12%; P < .001). In a Cox model stratified by histology, adjusting for other factors, endoscopic treatment was associated with improved 2-year survival (hazard ratio 0.51; 95% CI, 0.36-0.73). CONCLUSIONS: In this older population, a composite short-term endpoint was worse in the surgical group. Endoscopic treatment was associated with improved survival through 2 years. These results suggest that endoscopic treatment is a reasonable approach for early esophageal cancers in the elderly.

Assessing the impact of propensity score estimation and implementation on covariate balance and confounding control within and across important subgroups in comparative effectiveness research.

PURPOSE: Researchers are often interested in estimating treatment effects in subgroups controlling for confounding based on a propensity score (PS) estimated in the overall study population. OBJECTIVE: To evaluate covariate balance and confounding control in sulfonylurea versus metformin initiators within subgroups defined by cardiovascular disease (CVD) history comparing an overall PS with subgroup-specific PSs implemented by 1:1 matching and stratification. METHODS: We analyzed younger patients from a US insurance claims database and older patients from 2 Medicare (Humana Medicare Advantage, fee-for-service Medicare Parts A, B, and D) datasets. Confounders and risk factors for acute myocardial infarction were included in an overall PS and subgroup PSs with and without CVD. Covariate balance was assessed using the average standardized absolute mean difference (ASAMD). RESULTS: Compared with crude estimates, ASAMD across covariates was improved 70%-94% for stratification for Medicare cohorts and 44%-99% for the younger cohort, with minimal differences between overall and subgroup-specific PSs. With matching, 75%-99% balance improvement was achieved regardless of cohort and PS, but with smaller sample size. Hazard ratios within each CVD subgroup differed minimally among PS and cohorts. CONCLUSIONS: Both overall PSs and CVD subgroup-specific PSs achieved good balance on measured covariates when assessing the relative association of diabetes monotherapy with nonfatal myocardial infarction. PS matching generally led to better balance than stratification, but with smaller sample size. Our study is limited insofar as crude differences were minimal, suggesting that the new user, active comparator design identified patients with some equipoise between treatments.

Recombinant human bone morphogenetic protein-2 and pancreatic cancer: a retrospective cohort study.

PURPOSE: To assess whether use of recombinant human bone morphogenetic protein-2 (rhBMP-2) during lumbar spinal fusion surgery affects subsequent risk of pancreatic cancer. METHODS: Using US Medicare claims data, we performed a retrospective cohort study of patients who underwent lumbar spinal fusion surgery between October 2003 and December 2005. The study population, all >66 years, was identified from procedure codes for lumbar fusion. Claims for a bone morphogenetic protein (BMP) served as a proxy for rhBMP-2 exposure (another BMP product shared the same code). Pancreatic cancer was identified from claims indicating this diagnosis and cancer-specific therapy. We used Cox proportional hazard regression to estimate hazard ratios (HRs) and 95%CIs. RESULTS: Of the 93,654 patients in the study, the mean age was 75 years, and 16.5% had claims for BMP. During a mean 1.4 years of follow-up, 91 patients were diagnosed with pancreatic cancer (eight in the BMP- and 83 in the non-BMP cohort). Consistent with previous research, pancreatic cancer was associated with older age, male gender, black race, and diabetes mellitus. Compared to those who did not receive BMP, patients exposed to BMP were not at increased risk of pancreatic cancer (adjusted HR=0.70, 95%CI: 0.34-1.45). A chart review substudy validated the exposure measure; 52/55 patients with claims for BMP received rhBMP-2. CONCLUSIONS: In this large study of elderly patients who underwent lumbar fusion surgery, exposure to BMP was not associated with an increased risk of pancreatic cancer.

Surgical approach and the impact of epidural analgesia on survival after esophagectomy for cancer: A population-based retrospective cohort study.

BACKGROUND: Esophagectomy for esophageal cancer carries high morbidity and mortality, particularly in older patients. Transthoracic esophagectomy allows formal lymphadenectomy, but leads to greater perioperative morbidity and pain than transhiatal esophagectomy. Epidural analgesia may attenuate the stress response and be less immunosuppressive than opioids, potentially affecting long-term outcomes. These potential benefits may be more pronounced for transthoracic esophagectomy due to its greater physiologic impact. We evaluated the impact of epidural analgesia on survival and recurrence after transthoracic versus transhiatal esophagectomy. METHODS: A retrospective cohort study was performed using the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database. Patients aged ≥66 years with locoregional esophageal cancer diagnosed 1994-2009 who underwent esophagectomy were identified, with follow-up through December 31, 2013. Epidural receipt and surgical approach were identified from Medicare claims. Survival analyses adjusting for hospital esophagectomy volume, surgical approach, and epidural use were performed. A subgroup analysis restricted to esophageal adenocarcinoma patients was performed. RESULTS: Among 1,921 patients, 38% underwent transhiatal esophagectomy (n = 730) and 62% underwent transthoracic esophagectomy (n = 1,191). 61% (n = 1,169) received epidurals and 39% (n = 752) did not. Epidural analgesia was associated with transthoracic approach and higher volume hospitals. Patients with epidural analgesia had better 90-day survival. Five-year survival was higher with transhiatal esophagectomy (37.2%) than transthoracic esophagectomy (31.0%, p = 0.006). Among transthoracic esophagectomy patients, epidural analgesia was associated with improved 5-year survival (33.5% epidural versus 26.5% non-epidural, p = 0.012; hazard ratio 0.81, 95% confidence interval [0.70, 0.93]). Among the subgroup of esophageal adenocarcinoma patients undergoing transthoracic esophagectomy, epidural analgesia remained associated with improved 5-year survival (hazard ratio 0.81, 95% confidence interval [0.67, 0.96]); this survival benefit persisted in sensitivity analyses adjusting for propensity to receive an epidural. CONCLUSION: Among patients undergoing transthoracic esophagectomy, including a subgroup restricted to esophageal adenocarcinoma, epidural analgesia was associated with improved survival even after adjusting for other factors.

Risk of Cancer Following Lumbar Fusion Surgery With Recombinant Human Bone Morphogenic Protein-2 (rhBMP-2): An Analysis Using a Commercially Insured Patient Population.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is frequently used to promote new bone growth after lumbar fusion surgery. However, because BMP receptors are found on cancer cells, there is concern about potential cancer following treatment with rhBMP-2. Data from clinical trials have reported divergent results and have been limited by small sample sizes and relatively short follow-up. We therefore examined the long-term risk of cancer following treatment with rhBMP-2 after lumbar fusion surgery. METHODS: Using the MarketScan Commercial Claims and Encounters database, we identified all patients <65 years without prior cancer who underwent lumbar fusion surgery between October 2003 and December 2009 and were followed at least 3 years after surgery. Development of any Surveillance Epidemiology and End Results malignancy in follow-up was identified through diagnosis and procedure codes. RESULTS: Among 39 448 eligible patients, 2345 (5.9%) received rhBMP at surgery; the median follow-up in this population was 4.87 years. Cancer in follow-up was observed in 49 BMP-treated patients (0.43/100 person years) and 1072 nontreated patients (0.58/100 person years). Use of rhBMP was associated with a cancer risk similar to that of untreated patients in both univariate (hazard ratio, 0.80; 95%, CI 0.54-1.19) and multivariate proportional hazards analyses (hazard ratio, 0.81; 95% CI, 0.54-1.20). Similar findings were observed in a secondary analysis after adjustment for likelihood of rhBMP administration. CONCLUSIONS: In this retrospective cohort with at least 3 years of follow-up, administration of rhBMP during lumbar fusion surgery was not associated with an increased risk of subsequent cancer. LEVEL OF EVIDENCE: 4.

Risk of cancer after lumbar fusion surgery with recombinant human bone morphogenic protein-2 (rh-BMP-2).

STUDY DESIGN: Retrospective cohort study among Medicare beneficiaries with lumbar spinal fusion surgery. OBJECTIVE: To determine the risk of subsequent cancer among patients who received recombinant human bone morphogenic protein (rhBMP) at surgery compared with those who did not. SUMMARY OF BACKGROUND DATA: rhBMP is commonly used to promote bone union after spinal surgery. BMP receptors are present on multiple cancer types, but the risk of cancer after receiving rhBMP has not been well studied. METHODS: We identified 146,278 subjects aged 67 years and older who underwent surgery in 2003 to 2008 and were followed through 2010 for a new diagnosis of 1 of 26 cancers. Proportional hazards models were used to determine cancer risk associated with rhBMP use. RESULTS: rhBMP was administered in 15.1% of the cohort. After an overall average follow-up of 4.7 years, 15.4% of rhBMP-treated and 17.0% of untreated patients had a new cancer diagnosis, with most commonly recorded types as prostate, breast, lung, and colorectal. In a multivariate proportional hazards model, there was no association of rhBMP with cancer risk (hazard ratio: 0.99, 95% confidence interval: 0.95-1.02). There was also no association of rhBMP with the risk of any individual cancer types. The results were consistent in analyses using 2 secondary definitions of incident cancer. CONCLUSION: In this large population-based analysis of Medicare beneficiaries, we found no evidence that administration of rhBMP at the time of lumbar fusion surgery was associated with cancer risk. LEVEL OF EVIDENCE: 4.

Glycemic response and attainment of A1C goals following newly initiated insulin therapy for type 2 diabetes.

OBJECTIVE: To identify the characteristics associated with glycemic response to newly initiated insulin therapy. RESEARCH DESIGN AND METHODS: We identified 1,139 type 2 diabetic patients who initiated insulin therapy between 1 January 2009 and 30 June 2010. Outcomes of interest were the proportion of patients achieving A1C <7% and mean change in A1C within 3-9 months. RESULTS: Mean A1C at insulin initiation was 8.2 vs. 9.2% among those who did and did not attain A1C <7% (P < 0.001). Within a mean of 5 months, 464 (40.7%) patients attained A1C <7%. In multivariable analyses controlling for insulin regimen, dose, and oral agent use, preinsulin A1C was responsible for nearly all the explained variance in A1C change. Each one percentage point of preinsulin A1C reduced the probability of attaining <7% by 26% (odds ratio 0.74 [95% CI 0.68-0.80]). CONCLUSIONS: Insulin initiation at lower levels of A1C improves goal attainment and independently increases glycemic response.

Receipt of guideline-recommended follow-up in older colorectal cancer survivors : a population-based analysis.

BACKGROUND: After curative resection for colorectal cancer, routine follow-up with office visits, carcinoembryonic antigen (CEA), and colonoscopy is recommended. The actual adherence to these guidelines as well as the potential overuse of testing in routine practice has not been well studied. METHODS: The authors identified 9426 eligible patients aged > or = 66 years in a linked tumor registry-claims database who were diagnosed with adenocarcinoma of the colon or rectum from 2000 to 2001. Patients were observed to 3 years after diagnosis. Receipt of > or = 2 office visits per year, > or = 2 CEA tests per year (years 1 and 2), and > or = 1 colonoscopy within 3 years constituted guideline fulfillment. RESULTS: Guidelines for office visits, colonoscopy, and CEA testing were met in 92.3%, 73.6%, and 46.7% of patients, respectively. In addition, receipt of 2 nonrecommended procedures, abdominal/pelvic computed tomography scans and positron emission tomography scans, was documented in 47.7% and 6.8%, respectively. Overall, 60.2% received testing below recommended levels, 17.1% at recommended frequency, and 22.7% above guideline recommendations. In a multivariate analysis, factors associated with meeting guidelines included younger age group, white race, regional stage cancers, and poorly differentiated tumors. Considerable geographic variation in meeting guidelines was also observed. CONCLUSIONS: Many older colorectal cancer survivors in this population-based cohort underwent testing below a minimum frequency specified by clinical practice guidelines, especially with regard to CEA. Further studies should ascertain the reasons for poor compliance and the effect on patient outcome.