High-Dose FOLFIRI plus Bevacizumab in the Treatment of Metastatic Colorectal Cancer Patients with Two Different UGT1A1 Genotypes: FFCD 0504 Study.
High-dose FOLFIRI has an acceptable safety profile and promising efficacy. UDP-glucuronosyltransferase: (UGT1A1) polymorphism may be predictive of toxicity and efficacy of irinotecan. This phase II study aimed to evaluate the combination of high-dose FOLFIRI plus bevacizumab in patients with previously untreated metastatic colorectal cancer (MCRC) based on their UGT1A1 genotype. Patients with the UGT1A1 *1/*1 (group 1) or *1/*28 (group 2) genotype received bevacizumab plus high-dose FOLFIRI every 2 weeks. Using the Bryant and Day design with objective response rate and toxicity as the primary endpoints, 54 patients in each group were required with a planned interim analysis after inclusion of 17 patients per group. We planned to stop the trial at the interim analysis if ≤ 7 patients exhibited an objective response (OR) and/or ≥ 3 patients exhibited severe toxicity. At the interim analysis, ORs were higher than the number expected: 52.9% (group 1) and 58.8% (group 2). More than three toxic events occurred in both groups and, according to the interim analysis rule, the trial was closed due to unacceptable toxicity. Recruitment was stopped when 86 patients were included and an analysis on overall population was done for overall survival (OS) and progression-free survival (PFS). The median PFS was 10.7 months (group 1) and 10.4 months (group 2). The median OS was 25.5 months (group 1) and 23.9 months (group 2). This trial does not support the use of the intensive treatment with HD-FOLFIRI plus bevacizumab combination for MCRC in patients with the UGTA1*1/UGT1A1*1 or UGT1A1*1/UGT1A1*28 genotype.
Hepato-Gastroenterology and Digestive Oncology Department, University Hospital Dijon, INSERM U 866, Digestive Cancer Registry of Burgundy, Dijon, France. Fédération Francophone de Cancérologie Digestive, INSERM U866, Dijon, France. sylvain.manfredi@gmail.com.
Sylvain
S
Manfredi
Department of Gastroenterology, CHU Robert Debré, Reims, France.
Olivier
O
Bouché
Assistance Publique Hôpitaux de Paris, Hôpital Européen G Pompidou and Université Paris Descartes, Paris, France.
Philippe
P
Rougier
Department of Gastroenterology, Assistance Publique - Hôpitaux de Marseille, Hôpital la Timone, et Aix-Marseille Université, Marseille, France.
Laetitia
L
Dahan
Assistance Publique Hôpitaux de Paris, Hôpital Européen G Pompidou and Université Paris Descartes, Paris, France.
Marie Anne
MA
Loriot
Department of Gastroenterology and Digestive Oncology, Avicenne Hospital, HUPSSD, APHP and University Paris 13, Bobigny, France.
Thomas
T
Aparicio
Department of Medical Oncology, Clinique Armoricaine de Radiologie, St-Brieuc, France.
Pierre Luc
PL
Etienne
Department of Gastroenterology, Centre Hospitalier, La Roche sur Yon, France.
Jean Pierre
JP
Lafargue
Department of Gastroenterology, Polyclinique Bordeaux Nord Aquitaine, Bordeaux, France.
Cedric
C
Lécaille
Department of Gastroenterology, Centre Hospitalier Régional, Orléans, France.
Jean Louis
JL
Legoux
Fédération Francophone de Cancérologie Digestive, INSERM U866, Dijon, France.
Karine
K
Le Malicot
Fédération Francophone de Cancérologie Digestive, INSERM U866, Dijon, France.
Emilie
E
Maillard
Department of Gastroenterology, CHU de Tours and Université François Rabelais, Chambray les Tours, France.
Thierry
T
Lecomte
Department of Gastroenterology, Centre Hospitalier, Perpignan, France.
Faiza
F
Khemissa
Department of Gastroenterology, Hôpitaux Civils, Colmar, France.
Gilles
G
Breysacher
Department of Gastroenterology, Rouen University Hospital and University of Rouen, Rouen, France.
Pierre
P
Michel
Department of Medical Oncology, Institut Curie, Paris - St. Cloud and Université Versailles St. Quentin, UFR des Sciences de la Santé, Saint Cloud, France.
Emmanuel
E
Mitry
Hepato-Gastroenterology and Digestive Oncology Department, University Hospital Dijon, INSERM U 866, Digestive Cancer Registry of Burgundy, Dijon, France. Fédération Francophone de Cancérologie Digestive, INSERM U866, Dijon, France.
Laurent
L
Bedenne
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068258:Bevacizumab / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D000099148:UGT1A1 Enzyme
D000068258:Bevacizumab; D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D002955:Leucovorin; D000099148:UGT1A1 Enzyme