Primary tumor location and survival in colorectal cancer: A retrospective cohort study.

BACKGROUND: Primary tumor location is a prognostic factor for metastatic colorectal cancer (mCRC). Post hoc analyses of mCRC clinical trials, including FIRE-3, CALGB/SWOG 80405, suggest that primary tumor location is also predictive of survival benefit with cetuximab or bevacizumab in combination with 5-fluorouracil-based chemotherapy. AIM: Evaluate prognostic/predictive roles of primary tumor location in real-world mCRC patients treated with cetuximab or bevacizumab plus 5-fluorouracil-based chemotherapy. METHODS: This retrospective cohort study selected patients with KRAS wild-type mCRC who initiated first-line therapy with cetuximab or bevacizumab in combination with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) or 5-fluorouracil/ leucovorin/oxaliplatin (FOLFOX) between January 2013 and April 2017 from the Flatiron Health electronic health record-derived database of de-identified patient-level data in the United States. Primary tumor location was abstracted from patients' charts. Left-sided primary tumor location (LPTL) was defined as tumors that originated in the splenic flexure, descending colon, sigmoid colon, or rectum; right-sided primary tumor location (RPTL) was defined as tumors that originated from the appendix, cecum, ascending colon, hepatic flexure, or transverse colon. Propensity score matching was used to balance the baseline demographic and clinical characteristics between patients treated with cetuximab and patients treated with bevacizumab. Kaplan-Meier and Cox regression methods were used for survival analyses. RESULTS: A total of 1312 patients met the selection criteria. Of 248 cetuximab plus FOLFIRI or FOLFOX patients, 164 had LPTL and 84 had RPTL; of 1064 bevacizumab plus FOLFIRI or FOLFOX patients, 679 had LPTL and 385 had RPTL. Cetuximab LPTL and RPTL patients were more likely to receive FOLFIRI vs bevacizumab patients (LPTL: 64.0% vs 24.3%; RPTL: 76.2% vs 24.9%, P < 0.001). Stage at initial diagnosis was different between cetuximab RPTL vs bevacizumab RPTL patients (P < 0.001); cetuximab RPTL patients were more likely to have stage III disease (44.0% vs 22.6%), while bevacizumab RPTL patients were more likely to have stage IV disease (65.7% vs 48.8%). Cetuximab RPTL patients were more likely to have a documented history of adjuvant chemotherapy vs bevacizumab RPTL patients (47.6% vs 22.3%, P < 0.001). In the propensity score-matched sample, median overall survival (OS) was 29.7 mo (95%CI: 26.9-35.2) for LPTL patients vs 18.3 mo (95%CI: 15.8-21.3) for RPTL patients (P < 0.001). Median OS was 29.7 mo (95%CI: 27.4-NA) for cetuximab LPTL patients vs 29.1 mo (95%CI: 26.6-35.6) for bevacizumab LPTL patients (HR = 0.87; 95%CI: 0.63-1.19; P = 0.378) and 17.0 mo (95%CI: 12.0-32.6) for cetuximab RPTL patients vs 18.8 mo (95%CI: 15.8-22.3) for bevacizumab RPTL patients (HR = 1.00; 95%CI: 0.68-1.46; P = 0.996). The interaction of treatment and primary tumor location was not significant in the Cox regression. CONCLUSION: In this real-world mCRC cohort, the prognostic role of primary tumor location was substantiated, but not the predictive role for treatment with cetuximab vs bevacizumab in combination with 5-fluorouracil-based chemotherapy.

Validation of diagnosis codes to identify side of colon in an electronic health record registry.

BACKGROUND: The use of real-world data to generate evidence requires careful assessment and validation of critical variables before drawing clinical conclusions. Prospective clinical trial data suggest that anatomic origin of colon cancer impacts prognosis and treatment effectiveness. As an initial step in validating this observation in routine clinical settings, we explored the feasibility and accuracy of obtaining information on tumor sidedness from electronic health records (EHR) billing codes. METHODS: Nine thousand four hundred three patients with metastatic colorectal cancer (mCRC) were selected from the Flatiron Health database, which is derived from de-identified EHR data. This study included a random sample of 200 mCRC patients. Tumor site data derived from International Classification of Diseases (ICD) codes were compared with data abstracted from unstructured documents in the EHR (e.g. surgical and pathology notes). Concordance was determined via observed agreement and Cohen's kappa coefficient (κ). Accuracy of ICD codes for each tumor site (left, right, transverse) was determined by calculating the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), and corresponding 95% confidence intervals, using abstracted data as the gold standard. RESULTS: Study patients had similar characteristics and side of colon distribution compared with the full mCRC dataset. The observed agreement between the ICD codes and abstracted data for tumor site for all sampled patients was 0.58 (κ = 0.41). When restricting to the 62% of patients with a side-specific ICD code, the observed agreement was 0.84 (κ = 0.79). The specificity (92-98%) of structured data for tumor location was high, with lower sensitivity (49-63%), PPV (64-92%) and NPV (72-97%). Demographic and clinical characteristics were similar between patients with specific and non-specific side of colon ICD codes. CONCLUSIONS: ICD codes are a highly reliable indicator of tumor location when the specific location code is entered in the EHR. However, non-specific side of colon ICD codes are present for a sizable minority of patients, and structured data alone may not be adequate to support testing of some research hypotheses. Careful assessment of key variables is required before determining the need for clinical abstraction to supplement structured data in generating real-world evidence from EHRs.

Association of Broad-Based Genomic Sequencing With Survival Among Patients With Advanced Non-Small Cell Lung Cancer in the Community Oncology Setting.

Importance: Broad-based genomic sequencing is being used more frequently for patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the association between broad-based genomic sequencing and treatment selection or survival among patients with advanced NSCLC in a community oncology setting. Objective: To compare clinical outcomes between patients with advanced NSCLC who received broad-based genomic sequencing vs a control group of patients who received routine testing for EGFR mutations and/or ALK rearrangements alone. Design, Setting, and Participants: Retrospective cohort study of patients with chart-confirmed advanced NSCLC between January 1, 2011, and July 31, 2016, and who received care at 1 of 191 oncology practices across the United States using the Flatiron Health Database. Patients were diagnosed with stage IIIB/IV or unresectable nonsquamous NSCLC who received at least 1 line of antineoplastic treatment. Exposures: Receipt of either broad-based genomic sequencing or routine testing (EGFR and/or ALK only). Broad-based genomic sequencing included any multigene panel sequencing assay examining more than 30 genes prior to third-line treatment. Main Outcomes and Measures: Primary outcomes were 12-month mortality and overall survival from the start of first-line treatment. Secondary outcomes included frequency of genetic alterations and treatments received. Results: Among 5688 individuals with advanced NSCLC (median age, 67 years [interquartile range, 41-85], 63.6% white, 80% with a history of smoking); 875 (15.4%) received broad-based genomic sequencing and 4813 (84.6%) received routine testing. Among patients who received broad-based genomic sequencing, 4.5% received targeted treatment based on testing results, 9.8% received routine EGFR/ALK targeted treatment, and 85.1% received no targeted treatment. Unadjusted mortality rates at 12 months were 49.2% for patients undergoing broad-based genomic sequencing and 35.9% for patients undergoing routine testing. Using an instrumental variable analysis, there was no significant association between broad-based genomic sequencing and 12-month mortality (predicted probability of death at 12 months, 41.1% for broad-based genomic sequencing vs 44.4% for routine testing; difference -3.6% [95% CI, -18.4% to 11.1%]; P = .63). The results were consistent in the propensity score-matched survival analysis (42.0% vs 45.1%; hazard ratio, 0.92 [95% CI, 0.73 to 1.11]; P = .40) vs unmatched cohort (hazard ratio, 0.69 [95% CI, 0.62 to 0.77]; log-rank P < .001). Conclusions and Relevance: Among patients with advanced non-small cell lung cancer receiving care in the community oncology setting, broad-based genomic sequencing directly informed treatment in a minority of patients and was not independently associated with better survival.

Characteristics of Real-World Metastatic Non-Small Cell Lung Cancer Patients Treated with Nivolumab and Pembrolizumab During the Year Following Approval.

BACKGROUND: Evidence from cancer clinical trials can be difficult to generalize to real-world patient populations, but can be complemented by real-world evidence to optimize personalization of care. Further, real-world usage patterns of programmed cell death protein 1 (PD-1) inhibitors following approval can inform future studies of subpopulations underrepresented in clinical trials. MATERIALS AND METHODS: We performed a multicenter analysis using electronic health record data collected during routine care of patients treated in community cancer care clinics in the Flatiron Health network. Real-world metastatic non-small cell lung cancer (NSCLC) patients who received nivolumab or pembrolizumab in the metastatic setting (n = 1,344) were selected from a starting random sample of 55,969 NSCLC patients with two or more documented visits from January 1, 2011, through March 31, 2016. The primary study outcome measurement was demographic and treatment characteristics of the cohort. RESULTS: Median age at PD-1 inhibitor initiation was 69 years (interquartile range 61-75). Patients were 56% male, 88% smokers, 65% nonsquamous histology, and 64% diagnosed at stage IV. Of 1,344 patients, 112 (8%) were tested for programmed death-ligand 1 expression. Overall, 50% received nivolumab or pembrolizumab in the second line, with a substantial proportion of third and later line use that began to decline in Q4 2015. CONCLUSION: During the year following U.S. regulatory approval of PD-1 inhibitors for treatment of NSCLC, real-world patients receiving nivolumab or pembrolizumab were older at treatment initiation and more had smoking history relative to clinical trial cohorts. Studies of outcomes in underrepresented subgroups are needed to inform real-world treatment decisions. IMPLICATIONS FOR PRACTICE: Evidence gathered in conventional clinical trials used to assess safety and efficacy of new therapies is not necessarily generalizable to real-world patients receiving these drugs following regulatory approval. Real-world evidence derived from electronic health record data can yield complementary evidence to enable optimal clinical decisions. Examined here is a cohort of programmed cell death protein 1 inhibitor-treated metastatic non-small cell lung cancer patients in the first year following regulatory approval of these therapies in this indication. The analysis revealed how the real-world cohort differed from the clinical trial cohorts, which will inform which patients are underrepresented and warrant additional studies.

Real-world first-line treatment and overall survival in non-small cell lung cancer without known EGFR mutations or ALK rearrangements in US community oncology setting.

PURPOSE: To establish a baseline for care and overall survival (OS) based upon contemporary first-line treatments prescribed in the era before the introduction of immune checkpoint inhibitors, for people with metastatic non-small cell lung cancer (NSCLC) without common actionable mutations. METHODS: Using a nationally representative electronic health record data from the Flatiron dataset which included 162 practices from different regions in US, we identified patients (≥18 years old) newly diagnosed with stage IV NSCLC initiating first-line anticancer therapy (November 2012- January 2015, with follow-up through July 2015). Patients with documented epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) translocation were excluded. Anti-cancer drug therapy and overall survival were described overall, and by histology. RESULTS: A total of 2,014 patients with stage IV NSCLC without known EGFR or ALK genomic tumor aberrations initiated systemic anticancer therapy, 22% with squamous and 78% with nonsquamous histology. Their mean (SD) age was 67 (10) years, 55% were male, and 87% had a smoking history. In nonsquamous NSCLC, carboplatin plus pemetrexed either without (25.7%) or with bevacizumab (16%) were the most common regimens; 26.6% of nonsquamous patients receiving induction therapy also received continuation maintenance therapy. In squamous NSCLC, carboplatin plus paclitaxel (37.6%) or nab-paclitaxel (21.1%) were the most commonly used regimens. Overall median OS was 9.7 months (95% CI: 9.1, 10.3), 8.5 months (95% CI: 7.4, 10.0) for squamous, and 10.0 months (95% CI: 9.4, 10.8) for nonsquamous NSCLC. CONCLUSION: The results provide context for evaluating the effect of shifting treatment patterns of NSCLC treatments on patient outcomes, and for community oncology benchmarking initiatives.

The prevalence and economic impact of prescription opioid-related side effects among patients with chronic noncancer pain.

OBJECTIVES: To estimate the prevalence of opioid-related side effects among patients with chronic noncancer pain (CNCP) who initiated opioids and compare healthcare costs of patients with and without side effects using patient survey, medical charts, and claims data. PATIENTS, PARTICIPANTS: Patients initiating opioids, who were aged ≥18 years, had ≥1 pain diagnosis, and did not have cancer, were identified through claims data and medical records from a Central Massachusetts medical group practice and mailed surveys between October 2010 and July 2012. MAIN OUTCOMES MEASURES: Prevalence of opioid-related side effects was estimated from patient surveys, charts, and claims data within 90 days after opioid initiation (study period). Study period healthcare costs were compared between patients with and without side effects (self-reported problematic side effects or side effects recorded in medical charts or claims). RESULTS: Among patients with CNCP who initiated opioids and completed the survey (N = 167), the average age was 53 years, and 62.9 percent were women. Based on the survey, charts, and claims, 91.6 percent, 15.0 percent, and 19.2 percent of patients, respectively, had ≥1 opioid-related side effect. Overall, 59.3 percent of patients reported having ≥1 problematic side effect or side effect recorded in charts or claims. In the analysis that controlled for baseline characteristics and resource use, patients with versus without side effects had higher mean study period healthcare costs ($3,347 vs $2,521, p = 0.049). CONCLUSIONS: Prevalence of opioid-related side effects among patients with CNCP who initiated opioids was substantially higher based on patient survey than from charts or claims. Opioid-related side effects were associated with significantly higher healthcare costs.

Cost-effectiveness of denosumab compared with zoledronic acid in patients with breast cancer and bone metastases.

BACKGROUND: Results from a phase III clinical trial showed that denosumab significantly reduced the risk of first on-study and subsequent skeletal-related events (SREs) compared with zoledronic acid. This study aims to assess the cost-effectiveness of denosumab vs. zoledronic acid in the prevention of SREs in patients with advanced breast cancer and bone metastases. MATERIALS AND METHODS: A Markov model was developed with 4-week model cycles and a 1-year time horizon. The health states were defined by SRE status (no SRE, first on-study SRE, subsequent SRE, no SRE but history of SRE) and SRE type (pathologic fracture, radiation to the bone, surgery to the bone, spinal cord compression). Costs (in 2011 US dollars) included drug, SRE treatment, and adverse event (AE) costs and were assessed from a third-party payer perspective. The primary outcome was incremental total cost per SRE avoided; the secondary outcome was incremental total cost per pathologic fracture avoided. One-way and probabilistic sensitivity analyses were used to assess the robustness of the model. RESULTS: During the 1-year treatment period, denosumab incurred $7522 higher costs ($30,033 for denosumab and $23,511 for zoledronic acid), 0.06 fewer SREs, and 0.02 fewer pathologic fractures per patient, which led to an incremental total cost per SRE and pathologic fracture avoided of $114,628 and $290,136, respectively, compared with zoledronic acid. Results were robust to 1-way and probabilistic sensitivity analyses. CONCLUSION: Although denosumab demonstrated superiority in preventing SREs in the phase III trial, it may not be cost-effective compared with zoledronic acid because of its high cost.

Direct and indirect costs associated with Dupuytren's contracture.

OBJECTIVE: To compare direct (medical and drug) and indirect (work loss) costs between privately insured US employees with Dupuytren's contracture (DC) and demographically matched controls without DC. METHODS: Employees aged 18-64 with ≥ 1 DC diagnosis (ICD-9-CM: 728.6, 718.44) with service dates 1/1/2000-3/31/2009 were selected from a de-identified, privately insured claims database (n∼3,000,000). The index date was defined as the most recent DC diagnosis with continuous eligibility for 6 months prior (baseline period) and 1 year after (study period) diagnosis. Employees with DC were matched 1:1 on age, region, gender, and index date to controls without DC, Peyronie's, or Ledderhose disease diagnoses in their claims histories. Descriptive analyses compared demographic characteristics, comorbidities, resource utilization, direct costs, and indirect costs inflated to 2009 dollars. RESULTS: DC employees (n=1406, mean age 49 years) with matched controls met the inclusion criteria. DC employees compared with controls had significantly (all p<0.05) higher baseline comorbidities, including hyperlipidemia (21.1% vs 15.6%), hypothyroidism (3.5% vs 2.0%), cancer (3.1% vs 1.5%), and diabetes (8.1% vs 3.6%). During the study period, DC employees had significantly (all p<0.01) higher rates of inpatient stays (7.7% vs 5.3%), emergency department visits (19.8% vs 13.9%), outpatient visits (100.0% vs 78.4%), physical therapy visits (30.2% vs 7.2%), and any prescription use (85.0% vs 69.2%), as well as higher mean work loss days (14.2 vs 7.3). DC employees had on average significantly (all p<0.01) higher annual direct costs ($5974 vs $3175), indirect costs ($2737 vs $1309), and total costs ($8712 vs $4485) compared with controls during the study period. LIMITATIONS: Findings did not account for lost productivity at work and were based on a privately insured, employed population, which may not be generalizable to all DC patients. CONCLUSIONS: Employees with DC had substantially higher comorbidity rates, utilization, and direct and indirect costs compared with demographically matched controls.