© 1992 by Oxford University Press
Journal of the National Cancer Institute, Vol. 84, No. 4, 235-241,
February 19, 1992
© 1992 Oxford University Press
13-cis-Retinoic Acid and Interferon 
-2a: Effective Combination. Therapy for Advanced Squamous Cell Carcinoma of the Skin
Department of Medical Oncology, The University of Texas M. D. Anderson Cancer Center Houston
Department of Clinical Immunology, The University of Texas M. D. Anderson Cancer Center Houston
Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center Houston
Department of General Surgery, The University of Texas M. D. Anderson Cancer Center Houston
Department of Plastic Surgery, The University of Texas M. D. Anderson Cancer Center Houston
Department of Clinical Development, Hoffmann-La Roche Nutley, N. J.
*Correspendence to: Scott M. Lippman, M.D., Department of Medical Oncology, Box 80, The University to Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030
Background: Retinoids (vitamin A derivatives) and interferon-
(IFN- ) are potent regulators of malignant cell differentiation and proliferation, and both have immunomodulatory and antiangiogenesis activity. A large body of preclinical and clinical data supports the use of combination therapy with 13-cis-retinoic acid (13-cRA) and IFN- in patients with squamous cell car–cinoma of the skin. This carcinoma is an extremely common and frequently severely disfiguring cancer, for which about 10% of patients remain uncured following standard local therapy. Pur–pose: Our purpose was to test whether a 20% or greater complete response rate could be achieved using a com–bination of these two agents in patients with advanced squamous cell carcinoma of the skin in whom local therapy had failed or was unfeasible or who had regional and/or distant metastases. Methods: Thirty-two patients with heavily pretreated, advanced inoperable cutaneous squamous cell carcinoma of the skin were given a combination of oral 13-cRA (1 mg/ kg per day) and subcutaneous recombinant human IFN 2a (3 million units per day) for at least 2 months, un–less disease progressed earlier, in a phase II trial. Results: Nineteen (68%) of the 28 assessable patients responded, seven (25%) of whom had complete responses. Response rates were 93% (13 of 14) in patients with advanced local disease (six complete responses), 67% (four of six) in patients with regional disease (no complete respon–ses), and 25% (two of eight) in patients with distant metastases (one complete response). The relationship between decreased response rate and increased extent of disease was highly statistically significant (P<. 005, chi-square test). The median response duration was greater than 5 months. No life-threatening toxic effects occurred in assessable patients treated with this combination, although dose reductions were required in 18 patients. The major limiting side effect in this elderly patient population (median age, 67 years) was cumulative fatigue. Con–clusion: These results indicate that combined systemic therapy with 13-cRA and IFN -2a is highly effective in patients with advanced squamous cell carcinoma of the skin. [J Natl Cancer Inst 84:235– 241, 1992]
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|
|
|
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|
|
|
|
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|
|
|
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|
|
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|
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|
|
|
|
 |
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|
|