Pergamon Int. I. Radiation Oncology Biol. Phys., Vol. 33, No. 4, 855-859, 1995 pp. Copyright 0 1995 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/95 $9.50 + ,013 0360-3016(95)00072-O l Biology Original Contribution NONINVASIVE MONITORING OF CARBOGEN-INDUCED CHANGES IN TUMOR BLOOD FLOW AND OXYGENATION BY FUNCTIONAL MAGNETIC RESONANCE IMAGING SIMON P. ROBINSON, B.Sc., FRANKLYN A. HOWE, B.A., D&IL. AND JOHN R. GRIFFITHS, M.B.B.S., DPHIL CRC Biomedical Magnetic Resonance Research Group, Division of Biochemistry, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK Purpose: The response of tumors to radiotherapy can be enhanced if carbogen (95% 0,, 5% COz) is breathed. The timing of carbogen administration is critical, and a noninvasive method of monitoring the response of individual tumors would have obvious utility. Functional gradient recalled echo (GRR) magnetic resonance imaging (MRI) techniques are sensitive to changes in the concentrations of deoxyhemoglobin, which, thus, acts as an endogenons contrast agent for oxygenation status and blood flow. Methods and Materials: Subcutaneous GH3 prolactinomas in three rats were imaged at 4.7 Tesla with a GRE ‘II sequence [echo time (TR) = 20 ms, repetition time (TR) = 80 ms, flip angle = 45”, 1 mm slice, 256 phase encode steps, 4 cm field of view, in-plane resolution 0.08 x 0.08 mm, acquisition time = 4 mitt]. The rats breathed air or carbogen for four periods of 20 mitt; three control rats breathed only air. Results: Carbogen breathing caused increases of up to 100% in the GRE image intensity of the tumors. Reversion to air breathing causedthe image intensity to fail; essentially the same response was observed with the second cycle of carbogen and air breathing. Control rat tumors showed no sign&ant change. Conclusions: The response of tumors to carbogencan be monitored noninvasively by GRR MRI. In principle, tbis could be due to an increase in oxygen content of the blood, a decrease in tumor cell oxygen consumption, or an increasein tumor blood flow. Tbe very large changes in signal intensity suggest that a blood flow increase is the most probable explanation. If tbis technique can be successfully applied in man, it should be possible to optimize carbogentreatment for individual radiotherapy patients, and perhapsalso to enhance tumor uptake of chemotherapeutic agents. Radiotherapy, Carbogen, Oxygenation, Blood flow, Functional MRI. INTRODUCTION Tumor blood flow, and the related parameter tumor oxy- genation, are of fundamental importance to most forms of cancer therapy. Poorly perfused regions of tumors are hypoxic and, hence, radioresistant, and anticancer drugs of all kinds gain access to tumor cells through the vascula- ture. The principal area of interest at present is radioresis- tance caused by hypoxia, which is thought to develop by two mechanisms: diffusion-limited or chronic hypoxia, due to reduced oxygen diffusion to regions distant from the tumor blood vessels (30), and acute hypoxia due to transient occlusion of vessels (3). Many approaches have focussed on modifying tumor blood flow to improve oxy- genation (2, 12, 29). It has been shown that carbogen (95% OZr 5% COz) breathing enhances the radiosensitivity of rodent tumors, particularly targetting chronically hyp- oxic regions (4, 17,28). Furthermore, carbogen, in combi- nation with nicotinamide, is currently undergoing clinical trials as a radiosensitizer (25). A noninvasive method of assessing tumor blood flow and oxygenation during carbogen breathing would, thus, be of great clinical value. Recently, the development of functional magnetic reso- nance imaging (fMRI) techniques has allowed observa- tion of changes in cerebral oxygenation and/or blood flow in response to an external stimulus in both animals (22) and humans (21, 23, 31). When used in the brain, these methods have been described as functional or physiologi- cal imaging, depending on the type of information sought. The basis of fMRI is that paramagnetic deoxyhemoglobin Reprint requests to: Simon Robinson. E-mail: sgbclO0 @sghms.ac.uk Acknowledgements- This work wassupported by me Cancer Research Campaign,grant SP 1971/0402.We thank Loreta Rodrigues for maintenance of the tumor line and Rick Skilton and his staff for care of the animals. S.P.R. is a CRC/CRCT/ ZENECA student. Acceptedfor publication 10 February 1995. 855