Quantified Tumor T1 Is a Generic Early-Response Imaging Biomarker for Chemotherapy Reflecting Cell Viability

Purpose: Identification of a generic response biomarker by comparison of chemotherapeutics with different action mechanisms on several noninvasive biomarkers in experimental tumor models. Experimental Design: The spin-lattice relaxation time of water protons (T-1) was quantified using an inversion recovery-TrueFISP magnetic resonance imaging method in eight different experimental tumor models before and after treatment at several different time points with five different chemotherapeutics. Effects on T-1 were compared with other minimally invasive biomarkers including vascular parameters, apparent diffusion coefficient, and interstitial fluid pressure, and were correlated with efficacy at the endpoint and histologic parameters. Results: In all cases, successful chemotherapy significantly lowered tumor T-1 compared with vehicle and the fractional change in T-1 (Delta T-1) correlated with the eventual change in tumor size (range: r(2) = 0.21, P < 0.05 to r(2) = 0.73, P < 0.0001), except for models specifically resistant to that drug. In RIF-1 tumors, interstitial fluid pressure was decreased, but apparent diffusion coefficient and permeability increased in response to the microtubule stabilizer patupilone and 5-fluorouracil. Although Delta T-1 was small (maximum of -20%), the variability was very low (5%) compared with other magnetic resonance imaging methods (24-48%). Analyses ex vivo showed unchanged necrosis, increased apoptosis, and decreased %Ki67 and total choline, but only Ki67 and choline correlated with Delta T-1. Correlation of Ki67 and Delta T-1 were observed in other models using patupilone, paclitaxel, a VEGF-R inhibitor, and the mammalian target of rapamycin inhibitor everolimus. Conclusions: These results suggest that a decrease in tumor T-1 reflects hypocellularity and is a generic marker of response. The speed and robustness of the method should facilitate its use in clinical trials. Clin Cancer Res; 16(1); 212-25. (C)2010 AACR.