Outcomes of patients with advanced epithelial growth factor receptor mutant lung cancer treated with first-line osimertinib who would not have met the eligibility criteria for the FLAURA clinical trial.

OBJECTIVES: Osimertinib is largely used as first-line therapy for metastatic epithelial growth factor receptor (EGFR) mutant lung cancers based on the FLAURA clinical trial. Real-world patient outcomes often differ from clinical trial outcomes. This study evaluated the efficacy of first-line osimertinib in patients treated in British Columbia (BC), Canada. Furthermore, we compared the outcomes of patients who would and would not have been eligible for the original FLAURA trial. METHODS: Consecutive patients receiving first-line osimertinib for metastatic EGFR exon19 or L858R lung cancer were identified using the BC Cancer Pharmacy Database. Patient eligibility for the FLAURA clinical trial were retrospectively reviewed based on the following criteria: ECOG ≥ 2, symptomatic brain metastases or on steroids, hemoglobin < 90 g/L, platelets < 100x109/L, or a creatinine clearance < 50 mL/min. mOS was assessed for the entire population and compared between patients who would have been eligible and ineligible for FLAURA. RESULTS: From January 2020 to October 2021, 311 patients received first-line osimertinib; 44 % (137/311) were deemed FLAURA ineligible, predominantly due to low ECOG (n = 120). After a median follow-up of 26.5 months, the mOS for the entire cohort was 27.4 months (95 %CI 23.8-30.1). The mOS for ineligible patients was 18 months shorter than eligible patients (15.8 vs 34.2, p < 0.001). Ineligible patients had higher rates of de novo stage IV disease, higher rates of stage IVB disease, and more sites of disease than eligible patients. CONCLUSION: In this real-world population, nearly half of patients would have been ineligible for FLAURA. The mOS was one year shorter than reported in FLAURA. However, patients who would have been eligible for the FLAURA clinical trial had similar OS to patients enrolled in FLAURA. Trial ineligible patients had a higher burden of disease at baseline which may have led to inferior outcomes. Further research is needed to improve outcomes in these patients.

Impact of Antigen Exposure on Outcomes and Treatment Response in Fibrotic Hypersensitivity Pneumonitis.

BACKGROUND: Patients with fibrotic hypersensitivity pneumonitis (fHP) are frequently treated with immunosuppression to slow lung function decline; however, the impact of this treatment has not been studied across different types of antigen exposure. RESEARCH QUESTION: In patients with fHP, do disease outcomes and response to treatment vary by antigen type? STUDY DESIGN AND METHODS: A multicenter interstitial lung disease database (Canadian Registry for Pulmonary Fibrosis) was used to identify patients with fHP. The causative antigen was categorized as avian, mold, unknown, or other. Treatment was defined as mycophenolate ≥ 1,000 mg/d or azathioprine ≥ 75 mg/d for ≥ 30 days. Statistical analysis included t tests, χ2 tests, and one-way analysis of variance. Unadjusted and adjusted competing risks and Cox proportional hazards models were used to assess survival. RESULTS: A total of 344 patients were identified with the following causative antigens: avian (n = 93; 27%), mold (n = 88; 26%), other (n = 15; 4%), and unknown (n = 148; 43%). Patient characteristics and lung function were similar among antigen groups with a mean FVC % predicted of 75 ± 20. The percent of patients treated with immunosuppression was similar between antigens with 58% of patients treated. There was no change in lung function or symptom scores with the initiation of immunosuppression in the full cohort. Immunosuppression was not associated with a change in survival for patients with avian or mold antigen (avian: hazard ratio, 0.41; 95% CI, 0.11-1.59; P = .20; mold: hazard ratio, 1.13; 95% CI, 0.26-4.97; P = .88). For patients with unknown causative antigen, survival was worse when treated with immunosuppression (hazard ratio, 2.65; 95% CI, 1.01-6.92; P = .047). INTERPRETATION: Response to immunosuppression varies by antigen type in patients with fHP. Additional studies are needed to test the role of immunosuppression in fHP, and particularly in those with an unknown antigen.

Vitamin D deficiency in chronic obstructive pulmonary disease.

PURPOSE OF REVIEW: There is biological and epidemiological evidence supporting a role for vitamin D in the respiratory system, and vitamin D deficiency (VDD) may be associated with poor health outcomes in people with chronic obstructive pulmonary disease (COPD). This review summarizes recent findings relevant to the role of vitamin D in COPD. RECENT FINDINGS: The prevalence of VDD in people with COPD may be underestimated. Treatment of severe VDD [serum 25(OH)D3 < 10 ng/ml] may reduce the risk of COPD exacerbations. Vitamin D supplementation may also improve functional capacity and quality of life in people with COPD. However, there is no strong evidence that vitamin D supplementation slows the decline in lung function. SUMMARY: Although there are many known associations between vitamin D and COPD outcomes, the causal nature of these associations and the precise benefits of vitamin D supplementation remain unclear. High-quality randomized controlled trials are necessary.

Characterizing Regional Variability in Lung Cancer Outcomes across Ontario-A Population-Based Analysis.

Background: Lung cancer (LC) is the leading cause of cancer-related mortality. In Ontario, Canada, there are significant survival differences for patients with newly diagnosed LC across the 14 provincial regions. Methods: A population-based retrospective cohort study using ICES databases from 01/2007-12/2017 identified patients with newly diagnosed LC through the Ontario Cancer Registry and those with LC as the cause of death. Descriptive data included patient, disease, and system characteristics. The primary outcome was 5-year survival by region. Results: 178,202 patient records were identified; 101,263 met inclusion criteria. LC incidence varied by region (5.6-14.6/10,000), as did histologic subtype (adenocarcinoma: 27.3-46.1%). Five-year cancer-specific survival was impacted by age, rurality, pathologic subtype, stage at diagnosis, and income quintile. Timely care was inversely related to survival (fastest quintile: HR 3.22, p < 0.0001). Adjusted 5-year cancer-specific survival varied across regions (24.1%, HR 1.12; 34.0%, HR 0.89, p < 0.001). Conclusions: When adjusting for confounders, differences in survival by health region persisted, suggesting a complex interplay between patient, disease, and system factors. A single approach to improving patient care is likely to be ineffective across different systems. Quality improvement initiatives to improve patient outcomes require different approaches amongst health regions to address local disparities in care.

Management of fibrotic hypersensitivity pneumonitis.

PURPOSE OF REVIEW: Recent guidelines have updated the classification of hypersensitivity pneumonitis, stratifying by the presence or absence of fibrosis as either fibrotic or nonfibrotic hypersensitivity pneumonitis. Fibrotic hypersensitivity pneumonitis represents up to 10% of interstitial lung disease in large cohort studies, and is occasionally even more common in some regions; however, there are many unknown aspects to the diagnosis and management. The goal of this review article is to summarize the management of fibrotic hypersensitivity pneumonitis. RECENT FINDINGS: Historically, the only treatment options for patients with hypersensitivity pneumonitis were antigen avoidance and corticosteroids, although other immunosuppressive therapies are increasingly endorsed by experts in the field. There is accumulating evidence that antifibrotic medications can be useful as a second-line therapy in some patients with fibrotic hypersensitivity pneumonitis who have progression despite immunosuppression. There remains no direct comparison of immunosuppressive vs. antifibrotic medication for the management of fibrotic hypersensitivity pneumonitis, but some clinical, radiological and pathological features may suggest greater likelihood of benefit from one option or the other. SUMMARY: We anticipate that future treatment of fibrotic hypersensitivity pneumonitis will consider a variety of patient features to suggest the most prominent underlying biology that will then be used to guide initial pharmacotherapy; however, additional data are still needed.

Pregnancy Is Not Associated with an Increased Risk of Decompensation, Transplant, or Death in Compensated Cirrhosis.

Background and Aims: Childbirth in women with cirrhosis is increasing and associated with a higher risk of perinatal outcomes compared to the general population. Whether pregnancy influences the risk of liver-related events compared to nonpregnant women with cirrhosis is unclear. This study evaluates the association between pregnancy and liver-related outcomes in women with compensated cirrhosis. Approach and Results. Population-based retrospective matched cohort study in Ontario, Canada, using routinely collected healthcare data. Pregnant women with compensated cirrhosis and without prior history of decompensation between 2000 and 2016 were identified and matched to nonpregnant women with compensated cirrhosis on age, etiology of cirrhosis, and socioeconomic status in a 1 : 2 ratio. The association between pregnancy and the composite outcome of nonmalignant decompensation, liver transplant (LT), and death up to two years after cohort entry was estimated using the multivariate Cox proportional hazard regression adjusting for potential confounders. Overall, 5,403 women with compensated cirrhosis were included (1,801 pregnant; 3,602 nonpregnant; median age 31 years (IQR 27-34); 60% nonalcoholic fatty liver disease, 34% viral hepatitis). After two years of follow-up, only 19 (1.1%) pregnant women had a liver-related event compared to 319 (8.9%) nonpregnant women. Pregnant women with compensated cirrhosis had a lower hazard of a liver-related event compared to nonpregnant women (aHR 0.14, 95% CI 0.09-0.22, P < .001). Conclusions: Pregnancy in women with compensated cirrhosis is not associated with increased liver-related events compared to nonpregnant women. These results can facilitate counselling women with cirrhosis of child-bearing age and suggests that pregnancy may not accelerate liver disease progression.

Outcomes of Pregnant Women With Cirrhosis and Their Infants in a Population-Based Study.

BACKGROUND & AIMS: The incidence of cirrhosis is increasing among women of childbearing age. Contemporary outcomes of pregnant women with cirrhosis and their infants, as well as liver-related complications, have not been described in North America, to our knowledge. We investigated the association between cirrhosis and perinatal outcomes and evaluated perinatal liver-related events. METHODS: We performed a retrospective cohort study using population-based administrative health care data from Ontario, Canada (2000-2017). We identified pregnant women with compensated cirrhosis (n = 2022) using validated case definitions and routine mother-infant linkage; the women were matched to 10,110 pregnant women in the general population (1:5) based on birth year and socioeconomic status. Maternal and infant outcomes up to 6 weeks postpartum and liver-related complications up to 1 year postpartum were evaluated by using multivariate log-binomial regression. RESULTS: After we adjusted for demographic and metabolic risk factors, cirrhosis was independently associated with intrahepatic cholestasis of pregnancy (relative risk [RR], 10.64; 95% confidence interval [CI], 7.49-15.12), induction of labor (RR, 1.15; 95% CI, 1.03-1.28), puerperal infections (RR, 1.32; 95% CI, 1.02-1.70), preterm birth (RR, 1.60; 95% CI, 1.35-1.89), infants who were large for gestational age (RR, 1.24; 95% CI, 1.05-1.46), and neonatal respiratory distress (RR, 1.20; 95% CI, 1.02-1.42). Fewer than 2% of pregnant women with cirrhosis had liver-related complications, but these occurred in a significantly higher proportion of women with a history of hepatic decompensation (13%) than women with compensated cirrhosis (1.2%) (P < .001). CONCLUSIONS: In a population-based study, we found that cirrhosis is an independent risk factor for adverse perinatal outcomes. However, liver-related complications are rare. Multidisciplinary teams are needed to coordinate care for pregnant women with cirrhosis during pregnancy and postpartum to optimize outcomes.

Improving Timeliness of Lung Cancer Diagnosis and Staging Investigations Through Implementation of Standardized Triage Pathways.

PURPOSE: Timely care for patients with lung cancer (LC) is associated with improved clinical outcomes. In Southeastern Ontario, Canada, we identified delays in the diagnostic process for patients undergoing evaluation for suspected LC through a rapid assessment clinic. We developed improvement initiatives with an aim of reducing the time from referral to diagnosis. METHODS: A Standardized Triage Process (STP) was implemented for patients referred with suspected LC, including routine interdisciplinary triage, standardized pathways with preordered staging tests, and a new Small Nodule Clinic. We retrospectively analyzed all patients referred pre-STP (January to April 2018) and prospectively for improvement (May 2018 to March 2019). Process measures included STP compliance and time to completion of staging investigations (positron emission tomography [PET] and computed tomography/magnetic resonance imaging of brain). Data are reported as means; significance was determined by special-cause variation using Statistical Process Control charts; unpaired t tests were compared between groups. RESULTS: We reviewed 833 referrals (207 baseline and 626 post-STP). STP compliance improved monthly to 99.4%. Post-STP, time from referral to PET decreased (from 38.5 to 15.7 days), time from referral to brain imaging decreased (from 33.4 to 13.1 days), and time from referral to diagnosis decreased (from 38.0 to 22.7 days), all demonstrating special-cause variation. Patients completing preordered staging tests experienced significantly faster care than those without preordered tests, including time to PET (23.0 v 35.9 days), computed tomography/magnetic resonance imaging of brain (16.2 v 29.9 days), and diagnosis (39.9 v 28.1 days), all P < .001. CONCLUSION: An STP significantly improved timeliness of diagnosis and staging for patients with suspected LC undergoing evaluation in a rapid assessment clinic.