title: Phase I trial of dose-escalated cisplatin with concomitant cetuximab and hyperfractionated-accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck.
abstract: BACKGROUND
  Cetuximab is active in the treatment of squamous cell carcinoma of the head and neck (SCCHN), enhancing both radiotherapy and chemotherapy effects. This phase I study was designed to investigate the safety and tolerability of combining weekly cisplatin treatment with cetuximab and hyperfractionated-accelerated radiotherapy (HART) for locally advanced SCCHN.
  
  
  METHODS
  Patients with unresectable stage III or IVA/B SCCHN were treated with cetuximab, 400 mg/m² initial dose on day -7 of HART, followed by 250 mg/m² weekly during the administration of HART, which started with 2.0 Gy/day (5 days/week) for 3 weeks followed by 1.4 Gy/twice-daily (Monday to Friday) for another 3 weeks, resulting in a total dose of 70.6 Gy. Cisplatin was administered weekly starting on the first day of radiotherapy until week 6. Cisplatin was dose escalated of four dose levels from 20 to 40 mg/m² using a classical 3 + 3 dose escalation algorithm.
  
  
  RESULTS
  Eighteen patients were enrolled. Sixteen patients were eligible for toxicity, and 15 for response. No maximum tolerated dose was reached for cisplatin. One of six patients of dose level 4 had grade 4 neutropenia. This patient died 1 week after the end of the study treatment. The most common types of grade 3+ adverse events were mucositis (9 of 16 patients), in-field dermatitis (6 of 16 patients) and neutropenia (4 of 16 patients). Cetuximab-related hypersensitivity was observed in 1 out of 18 patients. Six weeks after the end of the study treatment, 5 complete responses, 8 partial responses and 1 progressive disease (at distant sites) were documented in a total of 15 patients (objective response rate 87%).
  
  
  CONCLUSIONS
  The combination of cisplatin with cetuximab and HART is active, well tolerated and merits additional investigation. The recommended weekly dose of cisplatin for phase II studies is 40 mg/m².
authors.affiliation: Department of Radiation Oncology, University of Rostock, Rostock. Electronic address: thomas.kuhnt@uni-rostock.de.
authors.forename: T
authors.initials: T
authors.lastname: Kuhnt
authors.affiliation: Department of Head and Neck Surgery, Martin-Luther-University, Halle-Wittenberg.
authors.forename: A
authors.initials: A
authors.lastname: Sandner
authors.affiliation: Department of Radiation Oncology, Friedrich-Schiller-University, Jena.
authors.forename: T
authors.initials: T
authors.lastname: Wendt
authors.affiliation: Department of Radiation Oncology, Phillips-University, Marburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Engenhart-Cabillic
authors.affiliation: Department of Radiation Oncology (Maastro Clinic), Maastricht, The Netherlands; Department of Radiation Therapy and Radiation Oncology, University of Düsseldorf, Düsseldorf.
authors.forename: G
authors.initials: G
authors.lastname: Lammering
authors.affiliation: Department of Radiation Oncology, University of Würzburg, Würzburg.
authors.forename: M
authors.initials: M
authors.lastname: Flentje
authors.affiliation: Department of Radiation Oncology, Hospital Coburg, Coburg.
authors.forename: G
authors.initials: G
authors.lastname: Grabenbauer
authors.affiliation: Department of Radiation Oncology, Hospital Dresden-Friedrichstadt, Friedrichstadt.
authors.forename: A
authors.initials: A
authors.lastname: Schreiber
authors.affiliation: Department of Radiation Oncology, University of Rostock, Rostock.
authors.forename: A
authors.initials: A
authors.lastname: Pirnasch
authors.affiliation: Department of Radiation Oncology, University of Schleswig-Holstein, Campus Lübeck, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Dunst
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D000068818:Cetuximab; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011446:Prospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D002945:Cisplatin