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Radiosensitization with carotid intra-arterial bromodeoxyuridine ± 5-fluorouracil biomodulation for malignant gliomas

Departments of Neurology (Drs. Greenberg and Junck, and M.A. Page and D. Crane), Surgery-Section of Neurosurgery (Drs. Greenberg and Chandler), Internal Medicine–Division of Medical Oncology (Dr. Ensminger), Radiation Oncology (Dr. Sandler), Nursing (M.A. Page and D. Crane), Pathology (Dr. McKeever), Pharmacy (R. Tankanow), and Biostatistics (Dr. Bromberg), University of Michigan Medical School, Ann Arbor, MI.

Bromodeoxyuridine (BUdR), a nonhypoxic radiosensitizing drug, is a halogenated pyrimidine analog that is incorporated into the DNA of dividing cells in a competitive process with thymidine. BUdR sensitizes cells to radiation therapy. 5-Fluorouracil (5-FU) inhibits the endogenous synthesis of thymidine, resulting in increased incorporation of the BUdR. Neurons and glial cells have a very low mitotic rate; they will not incorporate BUdR and will not be sensitized. BUdR and 5-FU are best delivered intra-arterially (IA) because of their regional advantage. We infused BUdR ±5-FU over 8 weeks, before and during 59.4-Gy focal conformal external beam radiation therapy, through a permanently implanted pump with a catheter placed retrograde through the external carotid artery to the carotid bifurcation. Sixty-two patients with grades III or IV glioma were entered into one of two trials, with 23 patients receiving BUdR alone and 39 patients receiving BUdR + 5-FU. The maximum tolerated dose (MTD) of BUdR alone was 400 mg/m2/d for 834 weeks. The Kaplan-Meier median survival (KMS) was 20 months. In the BUdR + 5-FU trial, the MTD of BUdR was also 400 mg/m2/d and 5-FU was 5 mg/m2/d with a KMS of 17 months. The KMS of all 62 patients in both trials 1 and 2 was 18 months. Pathologic grading used both the original World Health Organization (WHO) and 1993 modified WHO systems. The KMS of grade IV patients was 13.8 months (48 patients) with the original system and 17 months (58 patients) with the modified system. The 2-year survival rate was 21% with the original and 28% with the modified grading system. The dose-limiting toxicity was a reversible unilateral focal forehead dermatitis, blepharitis, and conjunctivitis. Continuous IA halopyrimidine infusion may enhance the effectiveness of radiation in the treatment of malignant glioma.

Address correspondence and reprint requests to Dr. Harry S. Greenberg, University of Michigan, Department of Neurology, 1500 E. Medical Center Drive, 1914 Taubman Center, Box 0316, Ann Arbor, MI 48109-0316.

Supported by NIH grants RO1CA33768, 1PO1CA42761-01A2, Clinical Research Center grant M01RR00042, University of Michigan Comprehensive Cancer Center grant 5P30CA46592-06, Pfizer Infusaid Company, and the John Masterson Brain Tumor Research Fund.

Received December 20, 1993. Accepted in final form February 23, 1994.