title: Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study.
abstract: OBJECTIVE
  Skin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data.
  
  
  METHODS
  After 21 days of standard-dose cetuximab (400 mg/m(2) initial dose, then 250 mg/m(2) per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m(2) per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C).
  
  
  RESULTS
  The intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 mg/m(2) were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups. Dose escalation (n = 44) was associated with an increase in skin reactions ≥ grade 2 compared with standard (n = 45) dosing (59% v 38%, respectively). Dose escalation, compared with standard dosing, showed some evidence for improved response rate (30% v 16%, respectively) and disease control rate (70% v 58%, respectively) but no indication of benefit in relation to overall survival. In an exploratory analysis, dose escalation seemed to increase response rate compared with standard dosing in patients with KRAS wild-type but not KRAS mutant tumors.
  
  
  CONCLUSIONS
  Cetuximab serum concentrations increased predictably with dose. Higher dose levels were well tolerated. The possible indication for improved efficacy in the dose-escalation group warrants further investigation.
authors: University Hospital Gasthuisberg, Leuven, Belgium. eric.vancutsem@uz.kuleuven.ac.be
authors: Eric
authors: E
authors: Van Cutsem
authors: Sabine
authors: S
authors: Tejpar
authors: Dirk
authors: D
authors: Vanbeckevoort
authors: Marc
authors: M
authors: Peeters
authors: Yves
authors: Y
authors: Humblet
authors: Hans
authors: H
authors: Gelderblom
authors: Jan B
authors: JB
authors: Vermorken
authors: Frederic
authors: F
authors: Viret
authors: Bengt
authors: B
authors: Glimelius
authors: Elisa
authors: E
authors: Gallerani
authors: Alain
authors: A
authors: Hendlisz
authors: Annemieke
authors: A
authors: Cats
authors: Markus
authors: M
authors: Moehler
authors: Xavier
authors: X
authors: Sagaert
authors: Soetkin
authors: S
authors: Vlassak
authors: Michael
authors: M
authors: Schlichting
authors: Fortunato
authors: F
authors: Ciardiello
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000556:secondary; D004305:Dose-Response Relationship, Drug; D003875:Drug Eruptions / Q000145:classification* / Q000209:etiology; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077146:Irinotecan; D000068818:Cetuximab; D002166:Camptothecin