DELAYED CONTRAST MRI FOR DIFFERENTIATING TUMOR FROM TREATMENT EFFECTS IN CONVENTIONAL AND ANTI-ANGIOGENIC TREATMENTS

Conventional MRI is unable to differentiate progression from treatment effects (TEs) in brain tumor (BT) patients. We have applied a novel technique, based on MR images acquired with a delay of >1 hour, enabling high resolution complete separation between tumor (contrast clearance at the delayed time point) and TEs (contrast accumulation) with no overlap. 496 maps were calculated for 151 patients with primary/metastatic BTs recruited/followed on study. The maps were validated by comparing pre-surgical maps of 51 resected patients with histology, resulting in 100% sensitivity and 93% specificity to active tumor regions (ATRs). Following initial validation, the maps were used for making 232 clinical decisions. In 67 cases the decision was to continue follow-up and in 165 to change treatment (surgery, chemoradiation, radiation treatments, switch to Avastin, etc). The incidence of decisions to change treatment was significantly higher in primary BTs (83%) than in metastatic BTs (54%). The application to Avastin was studied in 20 recurrent GBM patients and 2 patients with breast cancer brain metastases scanned pre/during Avastin. 90% of the GBM patients demonstrated significant reduction in TEs 1 month (58 ± 16% of original volume, p 5 months post treatment. This data suggests that Avastin may induce antineoplastic effects (mostly short term), and not only reduction in TEs/edema, as previously suggested. In 10 GBM patients who reached progression, the change in ATRs 1 month post treatment was found to correlate significantly with patients' PFS. The correlation calculated from the maps (r2 = 0.9, p < 0.0001) was significantly higher than those calculated from T1-Gd (r2= 0.65, p < 0.009) and FLAIR (r2 = 0.55, p < 0.02), suggesting the maps provide additional information regarding response to Avastin. A subgroup of 6 patients underwent re-irradiation during Avastin. All showed significant radiological response in the maps (ATRs decreased to 62 ± 10% of original volume while TEs increased to 296 ± 72%), in agreement with clinical stabilization, while conventional MRI showed radiological deterioration (T1-Gd/FLAIR showed stable/increased enhancing volumes reaching 92 ± 21%/155 ± 18% of original volumes). 2 patients with 4 breast cancer metastases showed significant response as well (ATRs decreased to 10 ± 3% of original volumes). In summary, our high resolution, easy to interpret, model-independent maps provide clear differentiation between tumor/non-tumor tissues in BT patients undergoing conventional treatments. Initial experience with Avastin suggests that the maps may also be valuable in assessing response to antiangiogenic treatments.