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

Abstract

We evaluated the predictive value of PET using the hypoxia tracer (18)F-fluoroazomycin arabinoside ((18)F-FAZA) for success of radiotherapy in combination with tirapazamine, a specific cytotoxin for hypoxic cells. 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 microL and absolute growth delay (aGD). The median pretreatment (18)F-FAZA tumor-to-background ratio served as a discriminator between "hypoxic" and "normoxic" tumors. The mean tumor growth was significantly accelerated in hypoxic control tumors (growth time from 70 to 500 microL, 11.0 d) compared with normoxic control tumors (growth time from 70 to 500 microL, 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). This study provides compelling evidence that hypoxia imaging using (18)F-FAZA PET is able to predict the success of RCT of tumor-bearing mice using the hypoxia-activated chemotherapeutic agent tirapazamine. Pretreatment (18)F-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 (18)F-FAZA uptake, improvement of the therapeutic ratio is possible, as the therapeutic effect of tirapazamine seems to be restricted to hypoxic tumors.