Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer

Introduction Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0–3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2–16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2–18.8) for CPE and 10.3 months (95% CI 7.1–15.5; hazard ratio (HR) 0.62, 95% CI 0.25–1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07–0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8–61.9 months) for CPE compared to 17.2 months (95% CI 11.5–45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22–1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity

Airway inflammation and mannitol challenge test in COPD

Abstract Background Eosinophilic airway inflammation has successfully been used to tailor anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). Airway hyperresponsiveness (AHR) by indirect challenges is associated with airway inflammation. We hypothesized that AHR to inhaled mannitol captures eosinophilia in induced sputum in COPD. Methods Twenty-eight patients (age 58 ± 7.8 yr, packyears 40 ± 15.5, post-bronchodilator FEV1 77 ± 14.0%predicted, no inhaled steroids ≥4 wks) with mild-moderate COPD (GOLD I-II) completed two randomized visits with hypertonic saline-induced sputum and mannitol challenge (including sputum collection). AHR to mannitol was expressed as response-dose-ratio (RDR) and related to cell counts, ECP, MPO and IL-8 levels in sputum. Results There was a positive correlation between RDR to mannitol and eosinophil numbers (r = 0.47, p = 0.03) and level of IL-8 (r = 0.46, p = 0.04) in hypertonic saline-induced sputum. Furthermore, significant correlations were found between RDR and eosinophil numbers (r = 0.71, p = 0.001), level of ECP (r = 0.72, p = 0.001), IL-8 (r = 0.57, p = 0.015) and MPO (r = 0.64, p = 0.007) in sputum collected after mannitol challenge. ROC-curves showed 60% sensitivity and 100% specificity of RDR for >2.5% eosinophils in mannitol-induced sputum. Conclusions In mild-moderate COPD mannitol hyperresponsiveness is associated with biomarkers of airway inflammation. The high specificity of mannitol challenge suggests that the test is particularly suitable to exclude eosinophilic airways inflammation, which may facilitate individualized treatment in COPD. Trial registration Netherlands Trial Register (NTR): NTR1283</p

Doxycycline for outpatient-treated acute exacerbations of COPD: a randomised double-blind placebo-controlled trial

Background Antibiotics do not reduce mortality or short-term treatment non-response in patients receiving treatment for acute exacerbations of COPD in an outpatient setting. However, the long-term effects of antibiotics are unknown. The aim of this study was to investigate if the antibiotic doxycycline added to the oral corticosteroid prednisolone prolongs time to next exacerbation in patients with COPD receiving treatment for an exacerbation in the outpatient setting. Methods In this randomised double-blind placebo-controlled trial, we recruited a cohort of patients with COPD from outpatient clinics of nine teaching hospitals and three primary care centres in the Netherlands. Inclusion criteria were an age of at least 45 years, a smoking history of at least 10 pack-years, mild-to-severe COPD (Global Initiative of Chronic Obstructive Lung Disease [GOLD] stage 1–3), and at least one exacerbation during the past 3 years. Exclusion criteria were poor mastery of the Dutch language, poor cognitive functioning, known allergy to doxycycline, pregnancy, and a life expectancy of shorter than 1 month. If a participant had an exacerbation, we randomly assigned them (1:1; with permuted blocks of variable sizes [ranging from two to ten]; stratified by GOLD stage 1–2 vs 3) to a 7 day course of oral doxycycline 100 mg daily (200 mg on the first day) or placebo. Exclusion criteria for randomisation were fever, admission to hospital, and current use of antibiotics or use within the previous 3 weeks. Patients in both groups received a 10 day course of 30 mg oral prednisolone daily. Patients, investigators, and those assessing outcomes were masked to treatment assignment. The primary outcome was time to next exacerbation in all randomly allocated patients except for those incorrectly randomly allocated who did not meet the inclusion criteria or met the exclusion criteria. This trial is registered with the Netherlands Trial Register, number NTR2499. Findings Between Dec 22, 2010, and Aug 6, 2013, we randomly allocated 305 (34%) patients from the cohort of 887 patients to doxycycline (152 [50%]) or placebo (153 [50%]), excluding four (1%) patients (two [1%] from each group) who were incorrectly randomly allocated from the analysis. 257 (85%) of 301 patients had a next exacerbation (131 [87%] of 150 in the doxycycline group vs 126 [83%] of 151 in the placebo group). Median time to next exacerbation was 148 days (95% CI 95–200) in the doxycycline group compared with 161 days (118–211) in the placebo group (hazard ratio 1·01 [95% CI 0·79–1·31]; p=0·91). We did not note any significant differences between groups in the frequency of adverse events during the first 2 weeks after randomisation (47 [31%] of 150 in the doxycycline group vs 53 [35%] of 151 in the placebo group; p=0·54) or in serious adverse events during the 2 years of follow-up (42 [28%] vs 43 [29%]; p=1). Interpretation In patients with mild-to-severe COPD receiving treatment for an exacerbation in an outpatient setting, the antibiotic doxycycline added to the oral corticosteroid prednisolone did not prolong time to next exacerbation compared with prednisolone alone. These findings do not support prescription of antibiotics for COPD exacerbations in an outpatient setting. Funding Netherlands Organization for Health Research and Development

Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study

Objective To compare the effectiveness of discontinuing treatment with amoxicillin after three days or eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days' treatment. Design Randomised, double blind, placebo controlled non-inferiority trial. Setting Nine secondary and tertiary care hospitals in the Netherlands. Participants Adults with mild to moderate-severe community acquired pneumonia (pneumonia severity index score ≤ 110). Interventions Patients who had substantially improved after three days' treatment with intravenous amoxicillin were randomly assigned to oral amoxicillin (n = 63) or placebo (n = 56) three times daily for five days. Main outcome measures The primary outcome measure was the clinical success rate at day 10. Secondary outcome measures were the clinical success rate at day 28, symptom resolution, radiological success rates at days 10 and 28, and adverse events. Results Baseline characteristics were comparable, with the exception of symptom severity, which was worse in the three day treatment group. In the three day and eight day treatment groups the clinical success rate at day 10 was 93% for both (difference 0.1%, 95% confidence interval - 9% to 10%) and at day 28 was 90% compared with 88% (difference 2.0%, - 9% to 15%). Both groups had similar resolution of symptoms. Radiological success rates were 86% compared with 83% at day 10 (difference 3%, - 10% to 16%) and 86% compared with 79% at day 28 (difference 6%, - 7% to 20%). Six patients (11%) in the placebo group and 13 patients (21%) in the active treatment group reported adverse events (P = 0.1). Conclusions Discontinuing amoxicillin treatment after three days is not inferior to discontinuing it after eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days' treatment

Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis:A retrospective cohort analysis

Objectives: Development of leptomeningeal metastasis (LM) in non-small cell lung cancer (NSCLC)patients is associated with a poor prognosis. It has been suggested that LM-patients with epidermal growth factor receptor mutated (EGER+) NSCLC have a superior prognosis compared to EGFR-wild type NSCLC. Studies in EGFR+ NSCLC-patients with LM are scarce. We retrospectively evaluated a multiinstitutional cohort of EGER+ NSCLC-patients for LM to assess clinical outcome in relation to patient characteristics and treatment modalities. Material and methods: Medical records of advanced-stage EGFR+ NSCLC-patients (diagnosed between August 2000 and June 2014) from 11 Dutch hospitals were evaluated for LM as diagnosed by MRI and/or cytopathological liquor analysis. Data on patient characteristics, treatment and outcome were collected. Results: Thirty-two of 356 (9.0%) advanced-stage EGFR+ NSCLC-patients (median follow-up 21.0 months), were diagnosed with LM between 2006 and 2014. LM was diagnosed by MM (59.4%), liquor analysis (9.4%) or by both MRI and liquor analysis (31.3%). Median survival after LM-diagnosis was 3.1 months (95% Cl: 0.0-7.3). Six- and 12-month survival rates were 43.8% and 18.8%, respectively. Patients with performance status (PS) 0-1 at time of diagnosis of LM had a significantly higher chance to be alive after 6 months and had a significantly longer survival after diagnosis of LM compared to patients with PS >= 2. Age, treatment with high-dose EGFR-TKI, radiotherapy and whether LM was the only site of progressive disease did not influence survival after LM-diagnosis. Conclusion: Although median survival after LM-diagnosis in EGFR-mutated NSCLC-patients was poor, a substantial part of the patients had a prolonged survival of more than 6 months. PS of 0-1 at time of diagnosis of LM was associated with prolonged survival. No other patient- or treatment-related characteristics were identified. Further research is warranted to identify treatment strategies that improve survival in EGFR+ NSCLC-patients with LM. (C) 2015 Elsevier Ireland Ltd. All rights reserved