MRI-based treatment response assessment maps (TRAMs) for differentiating active tumor from treatment-induced effects in patients with brain tumors

Introduction: Previous studies suggest that 14-30% of glioblastoma multiforme (GBM) patients experience treatment-effects in the first few months after treatment. Similarly, 5-24% of patients with brain metastases experience treatment-effects at various durations following radiation-based therapies. These treatment-induced changes, often termed pseudoprogression/radiation-necrosis, are depicted as increasing volumes of contrast-enhancing lesions on MRI, mimicking progression. Treatment decisions, such as whether to operate on a patient with radiographic deterioration, continue current treatment or change treatment is a daily struggle involving interdisciplinary teams of neurosurgeons, neuro-oncologists and neuro-radiologists which are often unable to reach unanimous interpretation of the patient`s status. We have applied delayed contrast MRI for calculating high resolution treatment response assessment maps (TRAMs) clearly differentiating tumor/non-tumoral tissues.

Material and Method: Over 400 patients in Israel and 150 patients in USA, Europe and Russia were recruited and followed as part of our ongoing studies. The patients were scanned by standard 3D-T1 MRI 5 min and >1 hour after contrast injection and the TRAMs were calculated by subtracting the early 3D-T1 from the late 3D-T1. The TRAMs were validated histologically in 54 resected patients by comparing the pre-surgical TRAMs of patients with primary and metastatic tumors undergoing surgery during the study with histology.

Results and Discussion: Histological validation confirmed that blue regions in the TRAMs (efficient clearance of the contrast agent >1hr post contrast injection) represent morphologically active tumor while red regions (contrast accumulation) represent non-tumor tissues. Sensitivity and PPV to morphologically active tumor was found to be 100% and 93%, respectively. Significant correlation was found between tumor burden in the TRAMs and histology in a subgroup of lesions resected en-block (r²=0.90, p<0.0001). The feasibility of applying the TRAMs for differentiating progression from treatment-effects, depicting tumor within hemorrhages and detecting residual tumor post-surgery was demonstrated.

Conclusions: Delayed MRI enables near complete separation between tumor (negative signal) and treatment effects (positive signal) with no overlap. In addition it enables using robust MR sequences resulting in high resolution maps clearly depicting tumor/non-tumor tissues. Since 2014 the TRAMs are being used for routine neuro-oncological clinical decisions in Israel (~40 patients/month scanned routinely), and recently also in various hospitals in Europe, Australia and America. Extending the TRAMs approach to additional types of cancer and additional imaging modalities is ongoing.