Kinematic modeling and its implication in longitudinal chemotherapy study of tumor physiology: ovarian xenograft mouse model and contrast-enhanced dynamic CT (Honorable Mention Poster Award)

Abstract

The purpose of this study is to demonstrate that dynamic CT provides the necessary sensitivity to quantify tumor physiology and differences in chemotherapeutic response. A compartmental mouse model utilizing measured contrast-enhanced dynamic CT scans is used to simulate systematic and statistical errors associated with tumor physiology: perfusion, permeability (PS), fractional plasma volume (fp), and fractional interstitial volume. The solute utilized is a small molecular weight radio-opaque contrast agent (isovue). For such an intravascular-interstitial medium, the kinematics simplifies to a two compartmental diffusive dominated set of coupled differential equations. Each combination of physiological parameters is repeatedly simulated fifteen times from which statistical errors calculated. The fractional change relative to the true value (systematic error) and standard deviation (statistical error) are plotted as a function of PS, fp, scanner temporal resolution and noise, and contrast media injection rates. By extrapolating from experimental data found in literature, a relative change in PS and fp of approximately 40% is required. Thus, the longitudinal response of two chemotherapeutic drugs under investigation - proteasome and IMPDH inhibitors - are hypothesized to induce different physiological responses. The first set of simulations varies PS from 0.05 to 0.40 mL/min/mL and fp from 0.01 to 0.07 mL/mL while holding all other physiological parameters constant. Errors in PS remain below 3% while statistical errors for fp increase significantly as the volume decreases toward 1-2%: errors remain less than 6% for fp>0.03 while increasing to above 15% for fp<0.02. The second set of simulations are performed quantifying the relationship between scanner temporal resolution and contrast media injection rate for various tumor permeabilities. For the majority of cases, the errors remain below 5%. As PS approaches perfusion, a total error less than 6% can be maintained for a temporal resolution less than or equal to 3 seconds, and an error less than 9% up to 5-7 seconds. As the injection rate decreases from 2 mL/min down to 0.25 mL/min, inadequate sampling of the contrast dynamics necessary to decouple the physiological parameters is lost increasing both systematic and statistical errors from 10% when sampling at 5 seconds in excess of 20-25% at a 9 second sampling rate. In each case, dynamic CT provides the necessary sensitivity to distinguish between the differing therapeutic reponses of proteasome and IMPDH inhibitors.