title: The use of high dose d,l-leucovorin in first-line bevacizumab+mFOLFIRI treatment of patients with metastatic colorectal cancer may enhance the antiangiogenic effect of bevacizumab.
abstract: The role of d,l-leucovorin (d,l-LV) dose on efficacy and toxicity of first-line bevacizumab+mFOLFIRI or mFOLFIRI treatment has never been investigated in patients with metastatic colorectal cancer. This study was an investigator initiated retrospective observational investigation performed on 450 consecutive patients. The mFOLFIRI regimen consisted of irinotecan (180 mg/m(2)), d,l-LV low (200 mg/m(2)) or high (400 mg/m(2)) dose and bolus 5-fluorouracil (5-FU) (400 mg/m(2)), followed by a 46-h infusion of 5-FU (2400 mg/m(2)). The bevacizumab+mFOLFIRI regimen consisted of bevacizumab (5 mg/kg)+mFOLFIRI. The efficacy (objective response [OR], progression-free [PFS] and overall survival [OS]) and toxicity was evaluated and compared. The use of high versus low dose d,l-LV in bevacizumab+mFOLFIRI regimen improved the OR rate (63 and 38 %, respectively; P = 0.00015), median PFS (13 and 9 months, respectively; P = 0.000005) and median OS (26 and 21 months, respectively; P = 0.0058). The efficacy of mFOLFIRI and the toxicity pattern of both bevacizumab+mFOLFIRI and mFOLFIRI regimens were independent of d,l-LV dose. Beside the d,l-LV dose the bevacizumab-related hypertension was an independent marker of longer survival. The use of high d,l-LV dose in bevacizumab+mFOLFIRI regimen would enhance the antiangiogenic effect of bevacizumab and subsequently the efficacy of treatment without increasing the number of adverse events. These findings need to be further confirmed in a randomized controlled prospective trial.
authors.affiliation: National Institute of Oncology, Budapest, Hungary. budai@oncol.hu
authors.forename: B
authors.initials: B
authors.lastname: Budai
authors.forename: T
authors.initials: T
authors.lastname: Nagy
authors.forename: I
authors.initials: I
authors.lastname: Láng
authors.forename: E
authors.initials: E
authors.lastname: Hitre
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin