Treatment of Locally Advanced Cancer of the Head and Neck With 5′-Iododeoxyuridine and Hyperfractionated Radiation Therapy: Measurement of Cell Labeling and Thymidine Replacement

• Published in: JNCI : Journal of the National Cancer Institute 1994-12, Vol.86 (23), p.1775-1780
• Main Authors: Epstein, Alan H., Lebovics, Robert S., Goffman, Thomas, Teague, Diane, Fuetsch, Elizabeth S., Glatstein, Eli, Okunieff, Paul, Cook, John A.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biological and medical sciences; Cancer; Chromatography, High Pressure Liquid; Combined Modality Therapy; Diseases of the upper aerodigestive tract; Ent and stomatology; Female; Flow Cytometry; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - pathology; Head and Neck Neoplasms - radiotherapy; Humans; Idoxuridine - administration & dosage; Idoxuridine - therapeutic use; Infusions, Intravenous; Male; Medical research; Medical sciences; Middle Aged; Pilot Projects; Radiation; Radiotherapy - methods; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Therapy; Time Factors
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/86.23.1775

Background: The halogenated pyrimidines 5'-iododeoxyuridine (IdUrd) and 5'-bromodeoxyuridine (BrdUrd) are under active study as radiation sensitizers for a variety of malignancies. Head and neck neoplasms may also be suitable for halogenated pyrimidine-mediated sensitization; previous regimens using intra-arterial BrdUrd delivery, however, were poorly tolerated. Purpose: A pilot study was undertaken with the use of intravenous IdUrd with hyperfractionated radiotherapy to assess tolerance. In addition, serial tumor biopsy specimens were obtained to determine the kinetics of IdUrd labeling and incorporation. Methods: Twelve patients with squa-mous cell carcinomas of the head and neck (one patient had stage II cancer, one had stage III, and 10 had stage IV) were treated with hyperfractionated radiation therapy at a dose of 1.2 or 1.5 Gy twice a day, to a total dose in the range of 70–76 Gy. IdUrd (1000 mg/m2 per day) was infused for a maximum of 14 days at the beginning and then again during the middle of the radiotherapy. A tumor biopsy specimen was obtained from 11 patients following initiation of treatment with IdUrd. Eight patients consented to serial biopsy to allow the study of IdUrd-labeling indices and thymidine replacement over time. Incorporation of IdUrd into tumor DNA was determined by high-performance liquid chromatography, and cell labeling was determined with the use of an anti-BrdUrd/IdUrd monoclonal antibody in conjunction with flow cytometry. Patients continue to be followed to assess local control. Results: A plot of corrected IdUrd replacement as a function of infusion time suggests the possibility of a plateau after 5–7 days of infusion at 7.5%–8%. The average rate of replacement from days 1 to 5 was 1.3% per day and was determined by linear regression analysis. Acute toxic effects, especially mucositis, were severe enough to require delays in the radiation therapy. Eleven of 12 patients treated had complete clinical remissions. Seven of these patients remain clinically free of local disease at the time of death or most recent follow-up. Conclusions: The level of IdUrd incorporation and cell labeling should be adequate to produce sensitization. However, the treatment as prescribed in this study (two 14-day infusions of IdUrd during radical radiotherapy with only one planned split) was not completed in a single patient because of either dose-limiting hematologic toxicity or severe mucositis necessitating treatment break. Since this particu