Minireview Evaluation of Cancer Therapy Using Diffusion Magnetic Resonance Imaging 1 Brian D. Ross, Bradford A. Moffat, Theodore S. Lawrence, Suresh K. Mukherji, Stephen S. Gebarski, Douglas J. Quint, Timothy D. Johnson, Larry Junck, Patricia L. Robertson, Karin M. Muraszko, Qian Dong, Charles R. Meyer, Peyton H. Bland, Patrick McConville, Hairong Geng, Alnawaz Rehemtulla, and Thomas L. Chenevert 2 University of Michigan Medical School, Ann Arbor, Michigan 48109-0648 Abstract Assessment of the effectiveness of cancer therapy traditionally relies on comparison of tumor images acquired before and after therapeutic intervention by inspection of gross anatomical images to evaluate changes in tumor size. The potential for imaging to provide additional insights related to the therapeutic impact would be enhanced if a specific parameter or combination of parameters could be identified that reflect tissue changes at the cellular or physiological level. This information could also provide a more sensitive and earlier indicator of treatment response in an individual animal or patient. Diffusion magnetic resonance imaging can detect relatively small changes in tissue structure at the cellular level and thus provides an opportunity to quantitatively and serially follow therapeutic-induced changes in solid tumors. This article provides an overview of the use of diffusion magnetic resonance imaging as a surrogate marker for quantitating treatment responsiveness in both preclinical and clinical studies. Introduction Conventional MRI 3 provides an opportunity to noninvasively follow gross tumor morphology and how it evolves over time. Conventional MRI exploits a variety of endogenous tissue properties that allow the investigator the ability to assess gross tumor extent on the resultant MRI contrasts such as T2-weighted and gadolinium-enhanced T1-weighted im- ages. The actual image contrast values are rarely quantified because these are usually arbitrarily scaled and do not have a simple relationship to tissue properties. It is thought that there is significant untapped potential for MRI techniques designed to provide additional functional, structural, or mo- lecular information related to tumor biology and physiology. Such information may be derived from quantitation of tissue properties that reflect, for example, perfusion dynamics, ox- ygenation levels, biochemistry/metabolism, cellularity, and levels of gene expression. Because the spatial information is retained, regional heterogeneity in these tissue properties and their change with therapy are also measurable. Properties of tumor function actively under investigation using MRI include perfusion, oxygenation, and metabolism, however, this article focuses on the application of MRI to provide information related to the microscopic cellular envi- ronment in solid tumors. The use of water diffusion as a surrogate marker to probe tissue cellularity is compelling because this parameter is strongly affected by molecular viscosity and membrane permeability between intra- and extracellular compartments, active transport and flow, and directionality of tissue/cellular structures that impede water mobility. Therefore, diffusion MRI can be used to character- ize highly cellular regions of tumors versus acellular regions, distinguishing cystic regions from solid regions, as well as detection of treatment response, which is manifested as a change in cellularity within the tumor over time. Diffusion MRI pulse sequences incorporate two additional magnetic field gradients that makes the intensity of the MR signal dependent on the mobility of the signal source, i.e., water molecules (1). Conceptually, the first of these two gradient pulses imparts a phase shift to each water molecule proportional to its initial location. The second gradient pulse will totally remove this phase shift if the water molecule remains at its original location. Any molecular movement between first and second pulses, however, leads to incom- plete rephasing. The large number of water molecules and their respective random trajectories produce a net dephasing or signal loss. The amount of signal loss is a direct reflection on water mobility, i.e., the greater signal loss implies greater molecular mobility. If the time interval between gradient pulses is sufficient to allow water molecules to migrate dis- tances comparable with the size of and spacing between cells, then the apparent mobility will be reduced by the impediments of cellular membranes and tortuosity of the extracellular space. Thus, the water mobility within a tumor will increase over time after treatment, and the magnitude of the change will be related to the effectiveness of the therapy, which will result in membrane damage with a subsequent reduction in cell density as shown diagrammatically in Fig. 1. In addition, the directionality of cellular structures can be Received 12/12/02; accepted 1/28/03. 1 This work was supported, in part, by research grants from the Charles A. Dana Foundation and NIH Grants 5R24CA83099, 5P20CA86442, 1PO1CA85878, and 1P50CA93990. 2 To whom requests for reprints should be addressed, at University of Michigan School of Medicine, Department of Radiology, Center for Mo- lecular Imaging, 1500 East Medical Center Drive, University Hospital, Room B2B311, Ann Arbor, MI 48109-0030. Phone: (734) 936-8866; Fax: (734) 764-2412; E-mail: tlchenev@umich.edu. 3 The abbreviations used are: MRI, magnetic resonance imaging; ADC, apparent diffusion coefficient; BCNU, 1,3-bis(2-chloroethyl)-1-nitrosourea; XRT, X-ray therapy. 581 Vol. 2, 581–587, June 2003 Molecular Cancer Therapeutics