Although gross increase in volume, associated with progressive destruction of normal bone, usually is indicative of poor response, other changes such as changes in host reaction (periosteal reaction, calcification) or changes within the tumor itself (calcification, ossification, fracture, hemorrhage) do not correlate with histologic grading of response (Fig. 56.3). In Ewing’s sarcoma, a marked reduction of the soft tissue tumor component in association with solidification of periosteal new bone, reconstitution of the cortical shaft, and reappearance of intramedullary trabeculations is commonly observed. However, this also does not correlate with histologic grading [12, 13].

Morphologic MRI criteria have been proven to be inaccurate in assessing response to chemotherapy. Only an increase in tumor volume not caused by massive hemorrhage within the tumor correlates with a poor histologic response. An unchanged or decreasing tumor volume is not predictive for a good response. In Ewing’s sarcoma the presence of a decreased but still present residual soft tissue mass after chemotherapy is correlated with poor histologic response. Only complete disappearance of tumor is indicative of good response and improved survival. The increase of signal intensity on T2-weighted images, basically reflecting liquefaction, may indicate a favorable histologic response. Increase of peritumoral (outside the low-signal-intensity pseudocapsule) edema has been correlated with poor histologic response. Decrease of peritumoral edema is a common finding that is not correlated with a favorable histologic response [14, 15].

The recently updated Response Evaluation Criteria in Solid Tumors (RECIST 1.1) only uses morphology, in particular changes in volume [16].

Static Gd-chelate-enhanced images taken minutes after intravenous administration reflect morphology. Enhancement is a function not only of perfusion but also of diffusion. Therefore, identification of viable tumor is inaccurate [17]. In dynamic Gd-chelate-enhanced imaging (DCE), we image the small molecular contrast agent as it passes from the intravascular space into the interstitium at a rate determined by the permeability of the capillaries (tumor vessels lack a muscular wall and contain large endothelial gaps), total vascular cross-sectional area, interstitial pressure, volume of extracellular space, contrast agent injection rate, and cardiac output. Although the impact of these factors can be manipulated by the type and especially the size of contrast agents used, the commonly used extracellular-interstitial Gd chelates reflect all these functions.

Serial images with high temporal resolution are taken before, during, and after an intravenous bolus injection of Gd chelates such as Gd-DTPA to evaluate the initial distribution of the contrast agent in the capillaries and interstitial space. Directly after MRI data acquisition is started, a bolus injection of Gd chelate with a concentration of 0.2 mL/kg at an injection rate of 4 mL/s is intravenously administered. An imaging frequency (temporal resolution) of at least one image per 3 s is initially needed to produce at least two data points in the first part of the enhancement curve, with its potentially rapid rise of concentration of the contrast agent in the tumor. In addition to obtaining information on the initial enhancement, information on distribution of the contrast agent is obtained by sampling for approximately 5 min with a temporal resolution that can be lower than the initial one.

Enhancement on T1-weighted DCE-MRI can be assessed in two ways: by the analysis of signal intensity changes (semiquantitative) and/or by quantifying contrast agent concentration change using pharmacokinetic modeling techniques. Signal enhancement can be visually evaluated with the use of subtraction techniques and by using the region of interest (ROI) method. Subtraction images are created by subtraction of precontrast MRI images from the gadolinium-chelate-enhanced MRI images. On these subtraction images, small areas within the tumor that enhance fast relative to enhancement of nearby arteries can be identified. ROIs are placed on these early enhancing areas that are identified on subtraction images. The signal intensity within these ROIs is plotted against time in time-intensity curves (Fig. 56.4). Semiquantitative parameters can be derived from these time-intensity curves. These parameters include curve shape, onset time (time from arrival of contrast agent in an artery relative to arrival of contrast agent in the tissue of interest), slope of enhancement curves, time to maximum enhancement, maximum enhancement, and washout. Commercial software is currently becoming available that generates standardized quantitative data. This requires T1 mapping prior to contrast agent administration. Validation of these quantitative parameters is still an issue.

A two-compartment model relating the change of tissue tracer concentration to the difference between arterial plasma and interstitial fluid concentrations is most often used. A detailed discussion on pharmacokinetic modeling techniques can be found elsewhere [18]. A transfer constant K ^trans (s⁻¹) describes the transendothelial transport of the small molecular contrast agent from the vascular to the interstitial space. Three major factors determine the behavior of the contrast agent in tissues during the first few minutes after injection: blood perfusion, transport of contrast agent across vessel walls, and diffusion of contrast medium in the interstitial space. Changes in the semiquantitative parameters can be used to assess changes in microcirculation during chemotherapy.

DCE-MRI has been reported to be a valuable technique for the identification and localization of residual viable tumor after chemotherapy and improves differentiation between good and poor response in bone and soft tissue sarcomas. DCE-MRI targets parameters that define angiogenesis. Under therapy, changes in capillary permeability (time-intensity curve shape and slope) and vascular density (maximum enhancement) are often observed before changes in tumor volume. Direct visual inspection of the (subtraction) images before and after chemotherapy allows easy detection of highly vascular and/or highly perfused viable tumor tissue. When more than 10 % of the total tumor volume enhances early (defined as enhancement within 6 s after arterial enhancement), a poor response with more than 10 % of tumor tissue remaining viable should be suspected. Areas of early and rapidly progressive enhancement (steep slopes) confirmed by type III, IV, or V time-intensity curves (Fig. 56.4) correspond with more rapid uptake of the contrast agent, owing to increased vascularization and perfusion associated with presence of viable tumor. Areas within the tumor demonstrating late and gradual or absence of enhancement confirmed by type I or II time-intensity curves reflect the presence of nonviable tumor tissue (Figs. 56.3, 56.5, 56.6, and 56.7; Table 56.1).