Sodium and proton diffusion MRI as biomarkers for early therapeutic response in subcutaneous tumors

Abstract

The ability to quantitate early effects of tumor therapeutic response using noninvasive imaging would have a major impact in clinical oncology. One area of active research interest is the ability to use MR techniques to detect subtle changes in tumor cellular density. In this study, sodium and proton diffusion MRI were compared for their ability to detect early cellular changes in tumors treated with a cytotoxic chemotherapy. Subcutaneous 9L gliosarcomas were treated with a single dose of 1,3-bis(2-chloroethyl)-1-nitrosourea. Both sodium and diffusion imaging modalities were able to detect changes in tumor cellularity as early as 2 days after treatment, which continued to evolve as increased signal intensities reached a maximum approximately 8 days posttreatment. Early changes in tumor sodium and apparent diffusion coefficient values were predictive of subsequent tumor shrinkage, which occurred approximately 10 days later. Overall, therapeutical induced changes in sodium and diffusion values were found to have similar dynamic and spatial changes. These findings suggest that these imaging modalities detected similar early cellular changes after treatment. The results of this study support the continued clinical testing of diffusion MRI for evaluation of early tumor treatment response and demonstrate the complementary insights of sodium MRI for oncology applications.

Fig. 1

Quantitative proton ADC maps (A) and corresponding coregistered sodium images (B) of a representative untreated tumor on Days 13 and 18 after tumor implantation. Tumor growth shown on the images (see right flank) does not produce any change in tumor diffusion. At the same time, tumor sodium concentration slightly increased, demonstrating the ability of Na to detect subtle changes in tumors.

Fig. 2

Quantitative proton ADC maps (A) and corresponding coregistered sodium MR images (B) of treated tumors on Days 0, 8 and 17 after a single dose of BCNU. Heterogeneous tumor ADC increases along with intensive sodium uptake can be seen on Day 8 posttreatment. On Day 17, tumor ADC values and sodium concentration are returning to their pretreatment values. Repopulation of the tumor mass can be seen on Day 17 as a gray (low diffusion) region of the tumor on the ADC map (A), which corresponds to the low Na concentration in the sodium image (B).

Fig. 3

The time course of 9L tumor growth in BCNU-treated (●) and BCNU-untreated rodents (◯). Tumor volumes were normalized to 1 at the time of treatment, denoted by the downward pointing arrow on Day 0.

Fig. 4

The time course of subcutaneous tumor ADCs in BCNU-treated (●) and BCNU-untreated rodents (◯). Time 0 corresponds to administration of BCNU 13 days after tumor implantation. Note the large increase in tumor ADC values observed for the treated group relative to the untreated group of tumors.

Fig. 5

The time course of tumor sodium concentration in BCNU- treated (●) and BCNU-untreated rodents (◯). Time 0 corresponds to the time of BCNU injection (13 days after tumor implantation). Tumor sodium concentration in untreated animals slowly increases at the later stages of tumor growth.

Fig. 6

A plot of the average tumor sodium concentration versus average tumor ADC values obtained after tumor treatment (y =−19.9+65.1×10³×ADC; R =.97).