Rosell R.,Catalan Institute of Nanoscience and Nanotechnology |
Rosell R.,University of Barcelona |
Carcereny E.,Catalan Institute of Nanoscience and Nanotechnology |
Gervais R.,Center Francois Baclesse |
And 54 more authors.
The Lancet Oncology | Year: 2012
Background: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. Methods: We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (>18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m 2 on day 1 plus docetaxel (75 mg/m 2 on day 1) or gemcitabine (1250 mg/m 2 on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m 2 or AUC 5 with gemcitabine 1000 mg/m 2) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. Findings: Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p<0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. Interpretation: Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. Funding: Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer. © 2012 Elsevier Ltd.
Herin F.,University Paul Sabatier |
Boutet-Robinet E.,University Paul Sabatier |
Levant A.,Limoges University Hospital Center |
Dulaurent S.,Limoges University Hospital Center |
And 5 more authors.
Thyroid | Year: 2011
Background: Fipronil represents a chemical class of insecticides acting at the γ-aminobutyric acid receptor in pets. Fipronil has been associated with a significant increase in the incidence of thyroid gland tumors concomitant with prolonged exposure to thyroid-stimulating hormone (TSH) in rats. An association between human TSH concentration and thyroid cancer has been also reported. The primary objective of this study was to test the hypothesis that chronic occupational fipronil exposure may be associated with abnormal thyroid function tests. Methods: In 2008, 159 workers of a factory manufacturing fipronil-containing veterinary drugs were assessed. Serum concentrations of TSH, total thyroxine, free thyroxine, fipronil, and fipronil sulfone were measured. Results: A positive and significant correlation was observed between serum fipronil or fipronil sulfone levels and duration of fipronil exposure. Serum fipronil sulfone concentration was negatively correlated with TSH concentration in fipronil-exposed workers, but with no significant increase in thyroid function test abnormalities. Conclusion: This study did not show that chronic fipronil exposure was associated with an increase of thyroid function test abnormalities. But, despite the fact that fipronil exposure in rats has been associated with increased serum TSH, fipronil sulfone concentrations were negatively correlated with serum TSH concentrations in fipronil-exposed workers, raising the possibility that fipronil has a central inhibitory effect on TSH secretion in humans. Close occupational medical surveillance, therefore, appears to be required in factory workers manufacturing fipronil-containing veterinary drugs. Larger epidemiological studies as well as investigations on possible thyroid-disrupting mechanisms of fipronil are also required. © 2011 Mary Ann Liebert, Inc.