title: Phase I trial using the proteasome inhibitor bortezomib and concurrent chemoradiotherapy for head-and-neck malignancies.
abstract: OBJECTIVE
  Advanced head-and-neck cancer (HNC) remains a difficult disease to cure. Proteasome inhibitors such as bortezomib have the potential to improve survival over chemoradiotherapy alone. This Phase I dose-escalation study examined the potential of bortezomib in combination with cisplatin chemotherapy and concurrent radiation in the treatment of locally advanced and recurrent HNC.
  
  
  METHODS
  Eligible patients received cisplatin once weekly at 30 mg/m(2) per week and bortezomib along with concurrent radiation. Bortezomib was given on Days 1, 4, 8, and 11 every 3 weeks, with an initial starting dose of 0.7 mg/m(2) and escalation levels of 1.0 and 1.3 mg/m(2). Dose escalation was performed only after assessment to rule out any dose-limiting toxicity.
  
  
  RESULTS
  We enrolled 27 patients with HNC, including 17 patients with recurrent disease who had received prior irradiation. Patients received bortezomib dose levels of 0.7 mg/m(2) (7 patients), 1.0 mg/m(2) (10 patients), and 1.3 mg/m(2) (10 patients). No Grade 5 toxicities, 3 Grade 4 toxicities (all hematologic and considered dose-limiting toxicities), and 39 Grade 3 toxicities (in 20 patients) were observed. With a median follow-up of 7.4 months, the overall median survival was 24.7 months (48.4 months for advanced HNC patients and 15.4 months for recurrent HNC patients).
  
  
  CONCLUSIONS
  Bortezomib in combination with radiation therapy and cisplatin chemotherapy is safe in the treatment of HNC with a bortezomib maximum tolerated dose of 1.0 mg/m(2) in patients previously treated for HNC and 1.3 mg/m(2) in radiation-naive patients.
authors.affiliation: Department of Radiation Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kubicek
authors.forename: Rita S
authors.initials: RS
authors.lastname: Axelrod
authors.forename: Mitchell
authors.initials: M
authors.lastname: Machtay
authors.forename: Peter H
authors.initials: PH
authors.lastname: Ahn
authors.forename: Pramila R
authors.initials: PR
authors.lastname: Anne
authors.forename: Shannon
authors.initials: S
authors.lastname: Fogh
authors.forename: David
authors.initials: D
authors.lastname: Cognetti
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Myers
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D011879:Radiotherapy Dosage; D013812:Therapeutics
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D002945:Cisplatin