RESUMEN
BACKGROUND: Tolerability to irinotecan may be explained by pharmacogenomic polymorphisms. The purpose of this pharmacogenetic trial was to study the relevance of thymidylate synthase (TS) genotyping and of the isoform 1A1 of uridine diphosphate glucuronosyltransferase (UGT1A1) in order to tailor a combination chemotherapy regimen of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) in metastatic colorectal cancer. PATIENTS AND METHODS: Patients with favourable TS and UGT1A1 profiles received high-dose (HD) FOLFIRI. Patients with TS-3R/3R could not receive HD-FOLFIRI, and those with UGT1A1-7/7 received standard FOLFIRI. The endpoints were overall response rate and safety. RESULTS: Sixty-nine patients were enrolled in the study. Sixty-five patients received chemotherapy. Twenty patients (30.8%) achieved a partial response. The haematological toxicity was less in the HD-FOLFIRI subgroup. Patients having received HD-FOLFIRI did not experience increased levels of nausea-vomiting, asthenia or alopecia. Diarrhoea was more frequent with HD-FOLFIRI. CONCLUSION: The genotypic assessment allowed a safer use of HD-FOLFIRI. Further investigations may target patients who benefit from intensification.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Glucuronosiltransferasa/genética , Farmacogenética , Timidilato Sintasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Neoplasias Colorrectales/patología , ADN de Neoplasias/genética , Femenino , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Genotipo , Humanos , Leucovorina/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Metástasis Linfática , Masculino , Persona de Mediana Edad , Mutación/genética , Estadificación de Neoplasias , Proyectos Piloto , Reacción en Cadena de la Polimerasa , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
UNLABELLED: The antitumor efficacy of irinotecan may be dose dependent. This study aimed to determine the safety and efficacy of high-dose (HD) irinotecan combined with LV5FU2 or simplified LV5FU (LV5FUs) in first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Patients with unresectable and measurable metastatic colorectal cancer, not pretreated for metastatic disease, were given irinotecan 260 mg/m(2) combined with LV5FU2 in the first 25 patients, then with LV5FUs (HD-FOLFIRI) in 35 patients. G-CSF was given in case of febrile neutropenia, grade 4 neutropenia >7 days or neutropenia grade >1 at day 15. RESULTS: The response rate was 57% (95% confidence interval 43-69%). Second surgery with curative intent was performed in 28% of patients, leading to 20% radiological complete response. Median response duration, time to progression and overall survival were 11, 9 and 22 months, respectively. The median dose intensity of irinotecan was 117 mg/m(2)/week. G-CSF was given to 45% of patients over 33% of cycles. Usual toxicity of irinotecan and 5-FU were observed without major increased frequency, except hematological toxicity. Tolerance was similar with LV5FU2 and LV5FUs, though more asymptomatic grade 3-4 neutropenia was observed with LV5FU2. CONCLUSION: HD-irinotecan plus LV5FU2 or HD-FOLFIRI is feasible and achieved a high response rate and postsurgery complete response rate.