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Pitfalls in the Neuroimaging of Malignant Glioma in the Era of Antiangiogenic and Immuno/Targeted Therapy - Detecting Illusive Disease, Defining Response.

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Glioblastoma is the most common malignant primary brain tumor in adults and most lethal. Average survival with standard treatment (radiotherapy and concomitant chemotherapy with temozolomide followed by adjuvant temozolomide) is 14 months. Challenges exist in the neuroimaging evaluation of patients ...

Glioblastoma is the most common malignant primary brain tumor in adults and most lethal. Average survival with standard treatment (radiotherapy and concomitant chemotherapy with temozolomide followed by adjuvant temozolomide) is 14 months. Challenges exist in the neuroimaging evaluation of patients undergoing treatment for malignant glioma, in the setting of standard care and in the context of new therapies. Accurate interpretation of MRI scans is an important method of measuring treatment response both in the setting of clinical trials and in routine clinical care. The Macdonald Criteria, developed in 1990, provided assessment based on contrast enhanced imaging. As novel treatments have developed, measurement of contrast enhancement has not proven to be a useful method to determine response, but rather a sign of disturbed blood brain barrier. For this reason the RANO (Response Assessment in Neuro-Oncology) criteria were developed, which incorporates assessment of non-enhancing tumor.
The evaluation of disease progression continues to be a difficult task in the face of treatment modality. Radiation injury is a potential complication of radiotherapy, especially focal radiotherapy, and can easily be confused with tumor progression. Differentiating the two entities is problematic and often requires long term follow-up with standard MRI, clinical assessment and use of corticosteroids. The use of PET, MR spectroscopy, and MR perfusion sequences has been helpful, but not specific. In the same manner, pseudoprogression of tumor verses true progression has become a confusing issue in treatment with temozolomide and radiotherapy. This phenomena usually occurs within 3 months post conclusion of radiotherapy, in approximately 40% of patients. In a similar manner treatment with gene therapy, vaccines, and convection-enhanced delivery have been noted to produce changes in MRI which could be interpreted as progression of disease, but fade over time, as patients continue to improve clinically. Treatment decisions need to be made on the basis of MRI, for both patients in clinical trials and those receiving standard care. A neuroimaging method to clearly distinguish between pseudoprogression and tumor recurrence has not been found,
Bevacizumab, an antiangiogenic agent, is approved for treatment of recurrent glioblastoma. Angiogenesis inhibitors as a whole may produce a rapid decrease in contrast enhancement, yet modest effect on overall survival. The early decrease in enhancement may be due to a change in blood brain barrier rather than true tumor reduction. In some cases clinical progression is seen in the context of stable or improved MRI results, provoking the assumption that tumor cell migration, undetectable by current imaging methods, is occurring.
This project will review state of the art imaging in the treatment of malignant glioma, as well as propose new avenues of research to further define response to new treatment modalities. This will include such techniques as dynamic contrast enhanced MRI, dynamic susceptibility MRI, diffusion tensor imaging, arterial spin labeling and new PET tracers ([18F]-fluorodeoxyglucose, [18F]-fluorothymidine, [18F]-DOPA and other amino acid derivatives) as well as relevant image analysis and interpretation methods. Neuro-imaging is key to disease assessment. New techniques to assist in the role of defining response will be presented.


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