Pharmacogenetic clinical randomised phase II trial to evaluate the efficacy and safety of FOLFIRI with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients according to their UGT1A 1 genotype
Mené sur 82 patients atteints d'un cancer colorectal de stade métastatique, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse globale, et la toxicité d'une chimiothérapie de type FOLFIRI avec de hautes doses d'irinotécan, en fonction du génotype UGT1A1
Background : Patients harbouring the UGT1A1*28/*28 genotype are at risk of severe toxicity with the standard irinotecan dose. However, this dose is considerably lower than the dose that can be tolerated by UGT1A1*1/*1 and *1/*28 patients. This randomised phase II trial evaluated the efficacy and safety of the FOLFIRI regimen with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients. Methods : Eighty-two patients with the UGT1A1*1/*1 or the *1/*28 genotype were randomised to receive HD-FOLFIRI versus FOLFIRI. Patients with the UGT1A1*28/*28 genotype were excluded. In the experimental group, the irinotecan dose was 300 mg/m2 for UGT1A1*1/*1 and 260 mg/m2 for *1/*28 patients. In the control group, the dose was 180 mg/m2. We analysed the overall response rate (ORR), toxicity, and survival. Results : The ORR was significantly higher in the HD-FOLFIRI group (67.5 versus 43.6%; p = 0.001 OR: 1.73 [95% CI:1.03–2.93]). Neutropenia (17.7%), diarrhoea (5.1%), and asthenia (5.1%) were the most common grade 3–4 toxicity. No differences were observed in severe toxicity (22.5% versus 20.5%), dose reduction (22.5% versus 28.2%), or prophylactic G-CSF (17.5% versus 12.8%). No difference in survival was found. Conclusions : Patients with the UGT1A1*1/*1 and *1/*28 genotypes can receive high doses of irinotecan to achieve a more favourable ORR without significant adverse events.