Nathalie Baize1, Isabelle Monnet2, Laurent Greillier3, Margaux Geier4, Hervé Lena5, Henri Janicot6, Alain Vergnenegre7, Jacky Crequit8, Regine Lamy9, Jean-Bernard Auliac2, Jacques Letreut10, Hervé Le Caer11, Radj Gervais12, Eric Dansin13, Anne Madroszyk14, Patrick-Aldo Renault15, Gwenaëlle Le Garff11, Lionel Falchero16, Henri Berard17, Roland Schott18, Patrick Saulnier19, Christos Chouaid20. 1. Service de Cancérologie, Centre Hospitalier Universitaire d'Angers, Angers, France. 2. Service de Pneumologie, CHI Créteil, Créteil, France. 3. Aix-Marseille University, Marseille, France; Department of Multidisciplinary Oncology and Therapeutic Innovations, APHM, Hôpital Nord, Marseille, France; Department of Multidisciplinary Oncology and Therapeutic Innovations, Hôpital Nord, Marseille, France. 4. Service de Pneumologie, CHU Brest, Brest, France. 5. Service de Pneumologie, CHU Rennes, Rennes, France. 6. Service de Pneumologie, CHU Clermont-Ferrand, Clermont Ferrand, France. 7. Service de Pneumologie, CHU Limoges, Limoges, France. 8. Service de Pneumologie, Centre Hospitalier de Beauvais, Beauvais, France. 9. Service de Pneumologie, CH Bretagne Sud, Lorient, France. 10. Service de Pneumologie, Hôpital Européen, Marseille, France. 11. Service de Pneumologie, Centre Hospitalier de Saint Brieuc, Saint-Brieuc, France. 12. Service d'Oncologie, Centre François Baclesse, Caen, France. 13. Service d'Oncologie, Centre Oscar Lambret, Lille, France. 14. Service d'Oncologie, Institut Paoli-Calmettes, Marseille, France. 15. Service de Pneumologie, Centre Hospitalier de Pau, Pau, France. 16. Service de Pneumologie, Centre Hospitalier de Villefranche de Rouergue, Villefranche, France. 17. Service de Pneumologie, Hôpital d'instruction des armées Sainte-Anne, Toulon, France. 18. Service d'Oncologie, Centre Paul Strauss, Strasbourg, France. 19. Département de Biostatistiques et Méthodologie, Centre Hospitalier Universitaire d'Angers, Angers, France. 20. Service de Pneumologie, CHI Créteil, Créteil, France; Institut Mondor de Recherche Biomédicale, U955 Inserm-Université Paris Est Créteil, Créteil, France. Electronic address: christos.chouaid@chicreteil.fr.
Abstract
BACKGROUND:Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer. METHODS: In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0-2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m2 from day 1 to day 3]) or oral topotecan (2·3 mg/m2 from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02738346. FINDINGS:Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0-37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9-5·5 vs 2·7 months, 2·3-3·2; stratified hazard ratio 0·57, 90% CI 0·41-0·73; p=0·0041). The most frequent grade 3-4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group. INTERPRETATION: Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer. FUNDING: Amgen and the French Lung Cancer Group (Groupe Français de Pneumo-Cancérologie).
RCT Entities:
BACKGROUND:Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer. METHODS: In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0-2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m2 from day 1 to day 3]) or oral topotecan (2·3 mg/m2 from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02738346. FINDINGS: Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0-37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9-5·5 vs 2·7 months, 2·3-3·2; stratified hazard ratio 0·57, 90% CI 0·41-0·73; p=0·0041). The most frequent grade 3-4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group. INTERPRETATION: Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer. FUNDING: Amgen and the French Lung Cancer Group (Groupe Français de Pneumo-Cancérologie).
Authors: Xuetian Gao; Ling Peng; Li Zhang; Kai Huang; Cuihua Yi; Bei Li; Xue Meng; Jisheng Li Journal: J Cancer Res Clin Oncol Date: 2021-11-08 Impact factor: 4.322
Authors: A-M C Dingemans; M Früh; A Ardizzoni; B Besse; C Faivre-Finn; L E Hendriks; S Lantuejoul; S Peters; N Reguart; C M Rudin; D De Ruysscher; P E Van Schil; J Vansteenkiste; M Reck Journal: Ann Oncol Date: 2021-04-20 Impact factor: 51.769