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Combined Interferon-Alfa, 13-cis-Retinoic Acid, and Alpha-Tocopherol in Locally Advanced Head and Neck Squamous Cell Carcinoma: Novel Bioadjuvant Phase II Trial

From the 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; Division of Medical Oncology, Vanderbilt University, Nashville, TN; and Head and Neck Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA.

Address reprint requests to Dong M. Shin, MD, Head and Neck Cancer Program, University of Pittsburgh Cancer Institute, 200 Lothrop St, MUH N-755, Pittsburgh, PA 15213-2582; email: shindm{at}msx.upmc.edu

PURPOSE: 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-, and -tocopherol in locally advanced-stage head and neck cancer.

PATIENTS AND METHODS: After definitive local treatment with surgery, radiotherapy, or both, patients with locally advanced SCCHN were treated with 13-cRA (50 mg/m²/d, orally, daily), IFN- (3 x 10⁶ IU/m², subcutaneous injection, three times a week), and -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.

CONCLUSION: The novel biologic agent combination of IFN-, 13-cRA, and -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.

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