Article: article from journal or magazin.
An EORTC phase I itudy of bortezomib in combination with oxaliplatin, leucovorin and 5-fluorouracil in patients with advanced colorectal cancer.
European Journal of Cancer
The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m(2), which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m(2) (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified.
Adenocarcinoma/drug therapy, Adenocarcinoma/genetics, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Apoptosis/genetics, Boronic Acids/administration & dosage, Colorectal Neoplasms/drug therapy, Colorectal Neoplasms/genetics, DNA Repair/genetics, Disease-Free Survival, Drug Administration Schedule, Drug Resistance, Neoplasm/genetics, Female, Fluorouracil/administration & dosage, Humans, Kaplan-Meiers Estimate, Leucovorin/administration & dosage, Male, Maximum Tolerated Dose, Middle Aged, Organoplatinum Compounds/administration & dosage, Polymorphism, Genetic, Pyrazines/administration & dosage, Survival Rate
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