Prediction and Early Detection of Response by NMR Spectroscopy and Imaging

The authors’ laboratory was the first to demonstrate that 31P NMR spectroscopy was able to detect early metabolic changes in subcutaneous tumors in mice in response to chemotherapy, radiation therapy, and hyperthermia.1 In addition, the authors and others2,3 showed that nuclear magnetic resonance (NMR) detectable changes during untreated growth reflected changes in tumor perfusion, energetics, and pH, which could serve as sensitive predictors of therapeutic response. These seminal observations were subsequently translated into the clinic and led to the initiation of a National Institutes of Health supported multi-institutional program to evaluate the potential utility of 31P magnetic resonance spectroscopy (MRS) for the prediction and early detection of therapeutic response. This program was initially headed by Dr Truman Brown at the Fox Chase Cancer Center and included Memorial Sloan-Kettering, Wayne State University, Duke, University of California in San Francisco (UCSF), Johns Hopkins, and The Royal Marsden and St George’s Hospitals in London. Initially the study included 4 malignancies rgR exhibited approximately a 50:50 response rate—non-Hodgkin lymphoma (NHL), squamous cell carcinoma of the head and neck (HNSCC), soft tissue sarcomas (STS), and locally advanced breast cancer (LABC). Because of limited accrual, HNSCC, STS, and LABC were dropped from the study, and Wayne State, Duke, and UCSF left the study. However, the Radboud University Nijmegen Medical Center in the Netherlands joined the study. The participants call themselves Cooperative Group for NMR Spectroscopy of Cancer. While the participants in this program have continued to work together for over a decade, some have changed institutions. Dr Brown moved from Fox Chase to Columbia Presbyterian Medical Center and more recently to the Medical College of South Carolina, but a new principal investigator (PI), Dr Fernando Arias-Mendoza, has remained at Columbia. The Johns Hopkins Group under Dr Glickson moved to the University of University of Pennsylvania in 1996, and St George’s group under Dr Griffiths recently transferred to Cambridge University in the United Kingdom. Despite changes of institutions among some of the participants, and the use of different commercial imaging systems (General Electric, Siemens, and Philips), a uniform protocol has been developed for acquisition and analysis of MRS data,4 with statistical evaluation being performed at the PI institution (Columbia). Both the Columbia and University of Pennsylvania programs are participating in this report. Until now, all the 31P studies were performed on 1.5 T instruments, although future plans are to continue the studies at 3 T. Because of the limited sensitivity of 31P MRS, studies have been limited to large (≥3 × 3 × 3 cm3) mostly superficial lesions in the axial, inginal, or head and neck lymph nodes. Data were generally analyzed from a single voxel, although data acquisition was performed by 2-dimensional chemical shift imaging followed by voxel shifting to optimally localize the tumor in one voxel (Fig. 1). Visualization of the tumor was achieved by T2-weighted 1H magnetic resonance imaging (MRI). Recently, a number of institutions have initiated 1H MRS (lactate [Lac]) or (total choline [tCho]) and MRI (diffusion-weighted imaging [DWI]), which can accommodate substantially smaller lesions (approximately 1 cm3 for Lac and tCho and smaller for DWI).