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Pretreatment ¹⁸F-FAZA PET Predicts Success of Hypoxia-Directed Radiochemotherapy Using Tirapazamine

¹ Clinic for Nuclear Medicine, Technische Universität München, Munich, Germany; ² Clinic for Radiation Oncology, Technische Universität München, Munich, Germany; ³ Department of Nuclear Medicine, Scientific Institute San Raffaele, IBFM-CNR, Milan, Italy; ⁴ Radiopharmazie, PET Zentrum, Universität Tübingen, Tübingen, Germany; and ⁵ Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, Michigan

Correspondence: For correspondence contact: Morand Piert, MD, Division of Nuclear Medicine, Department of Radiology, University of Michigan Health System, University Hospital B1G505C, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0028. E-mail: mpiert{at}umich.edu

We evaluated the predictive value of PET using the hypoxia tracer ¹⁸F-fluoroazomycin arabinoside (¹⁸F-FAZA) for success of radiotherapy in combination with tirapazamine, a specific cytotoxin for hypoxic cells. Methods: Imaging was performed on EMT6 tumor-bearing nude mice before allocating mice into 4 groups: radiochemotherapy (RCT: 8 fractions of 4.5 Gy within 4 d combined with tirapazamine, 14 mg/kg), radiotherapy alone (RT), chemotherapy alone (tirapazamine) (CHT), or control. Treatment success was assessed by several tumor growth assays, including tumor growth time from 70 to 500 µL and absolute growth delay (aGD). The median pretreatment ¹⁸F-FAZA tumor-to-background ratio served as a discriminator between "hypoxic" and "normoxic" tumors. Results: The mean tumor growth was significantly accelerated in hypoxic control tumors (growth time from 70 to 500 µL, 11.0 d) compared with normoxic control tumors (growth time from 70 to 500 µL, 15.6 d). Whereas RT delayed tumor growth regardless of the level of hypoxia, an additive beneficial therapeutic effect of tirapazamine to RT was observed only in hypoxic tumors (aGD, 12.9 d) but not in normoxic tumors (aGD, 6.0 d). Conclusion: This study provides compelling evidence that hypoxia imaging using ¹⁸F-FAZA PET is able to predict the success of RCT of tumor-bearing mice using the hypoxia-activated chemotherapeutic agent tirapazamine. Pretreatment ¹⁸F-FAZA PET, therefore, offers a way for the individualization of tumor treatment involving radiation. The data suggest that by reserving hypoxia-directed therapy to tumors with high ¹⁸F-FAZA uptake, improvement of the therapeutic ratio is possible, as the therapeutic effect of tirapazamine seems to be restricted to hypoxic tumors.

Key Words: tumor hypoxia • tirapazamine • EMT6 • radiochemotherapy • FAZA

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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