title: Combined interferon-alfa, 13-cis-retinoic acid, and alpha-tocopherol in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase II trial.
abstract: OBJECTIVE
  Retinoids and interferons (IFNs) have single-agent and synergistic combined effects in modulating cell proliferation, differentiation, and apoptosis in vitro and clinical activity in vivo in the head and neck and other sites. Alpha-tocopherol has chemopreventive activity in the head and neck and may decrease 13-cis-retinoic acid (13-cRA) toxicity. We designed the present phase II adjuvant trial to prevent recurrence or second primary tumors (SPTs) using 13-cRA, IFN-alpha, and alpha-tocopherol in locally advanced-stage head and neck cancer.
  
  
  METHODS
  After definitive local treatment with surgery, radiotherapy, or both, patients with locally advanced SCCHN were treated with 13-cRA (50 mg/m(2)/d, orally, daily), IFN-alpha (3 x 10(6) IU/m(2), subcutaneous injection, three times a week), and alpha-tocopherol (1,200 IU/d, orally, daily) for 12 months, with a dose modification. Screening for recurrence or SPTs was performed every 3 months.
  
  
  RESULTS
  Tumors of 11 (24%) of the 45 treated patients were stage III, and 34 (76%) were stage IV. Thirty-eight (86%) of 44 patients completed the full 12-month treatment (doses modified as needed). Toxicity generally was consistent with previous IFN and 13-cRA reports and included mild to moderate mucocutaneous and flu-like symptoms; occasional significant fatigue (grade 3 in 7% of patients), mild to moderate hypertriglyceridemia in 30% of patients who continued treatment along with antilipid therapy, and mild hematologic side effects. Six patients did not complete the planned treatment because of intolerable toxicity or social problems. At a median 24-months of follow-up, our clinical end point rates were 9% for local/regional recurrence (four patients), 5% for local/regional recurrence and distant metastases (two patients), and 2% for SPT (one patient), which was acute promyelocytic leukemia (ie, not of the upper aerodigestive tract). Median 1- and 2-year rates of overall survival were 98% and 91%, respectively, and of disease-free survival were 91% and 84%, respectively.
  
  
  CONCLUSIONS
  The novel biologic agent combination of IFN-alpha, 13-cRA, and alpha-tocopherol was generally well tolerated and promising as adjuvant therapy for locally advanced squamous cell carcinoma of the head and neck. We are currently conducting a phase III randomized study of this combination (v no treatment) to confirm these phase II study results.
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology, Diagnostic Imaging, Head and Neck Surgery, Biostatistics, Radiation Oncology, and Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. shindm@msx.upmc.edu
authors.forename: D M
authors.initials: DM
authors.lastname: Shin
authors.forename: F R
authors.initials: FR
authors.lastname: Khuri
authors.forename: B
authors.initials: B
authors.lastname: Murphy
authors.forename: A S
authors.initials: AS
authors.lastname: Garden
authors.forename: G
authors.initials: G
authors.lastname: Clayman
authors.forename: M
authors.initials: M
authors.lastname: Francisco
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.forename: B S
authors.initials: BS
authors.lastname: Glisson
authors.forename: L
authors.initials: L
authors.lastname: Ginsberg
authors.forename: V
authors.initials: V
authors.lastname: Papadimitrakopoulou
authors.forename: J
authors.initials: J
authors.lastname: Myers
authors.forename: W
authors.initials: W
authors.lastname: Morrison
authors.forename: A
authors.initials: A
authors.lastname: Gillenwater
authors.forename: K K
authors.initials: KK
authors.lastname: Ang
authors.forename: S M
authors.initials: SM
authors.lastname: Lippman
authors.forename: H
authors.initials: H
authors.lastname: Goepfert
authors.forename: W K
authors.initials: WK
authors.lastname: Hong
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D004357:Drug Synergism; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics; D015474:Isotretinoin / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D016609:Neoplasms, Second Primary / Q000517:prevention & control; D016019:Survival Analysis; D015996:Survival Rate; D014810:Vitamin E / Q000008:administration & dosage
chemical_list: D016898:Interferon-alpha; D014810:Vitamin E; D015474:Isotretinoin