Pitfalls in the Neuroimaging of Glioblastoma in the Era of Antiangiogenic and Immuno/Targeted Therapy – Detecting Illusive Disease, Defining Response

Abstract

Glioblastoma, the most common malignant primary brain tumor in adults is a devastating diagnosis with an average survival of 14–16 months using the current standard of care treatment. The determination of treatment response and clinical decision making is based on the accuracy of radiographic assessment. Notwithstanding, challenges exist in the neuroimaging evaluation of patients undergoing treatment for malignant glioma. Differentiating treatment response from tumor progression is problematic and currently combines long-term follow-up using standard magnetic resonance imaging (MRI), with clinical status and corticosteroid-dependency assessments. In the clinical trial setting, treatment with gene therapy, vaccines, immunotherapy, and targeted biologicals similarly produces MRI changes mimicking disease progression. A neuroimaging method to clearly distinguish between pseudoprogression and tumor progression has unfortunately not been found to date. With the incorporation of antiangiogenic therapies, a further pitfall in imaging interpretation is pseudoresponse. The Macdonald criteria that correlate tumor burden with contrast-enhanced imaging proved insufficient and misleading in the context of rapid blood–brain barrier normalization following antiangiogenic treatment that is not accompanied by expected survival benefit. Even improved criteria, such as the RANO criteria, which incorporate non-enhancing disease, clinical status, and need for corticosteroid use, fall short of definitively distinguishing tumor progression, pseudoresponse, and pseudoprogression. This review focuses on advanced imaging techniques including perfusion MRI, diffusion MRI, MR spectroscopy, and new positron emission tomography imaging tracers. The relevant image analysis algorithms and interpretation methods of these promising techniques are discussed in the context of determining response and progression during treatment of glioblastoma both in the standard of care and in clinical trial context.

Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape

“…Activation of the immune response during immunotherapy may directly or indirectly result in increased BBB leakiness, resulting in increased contrast enhancement mimicking tumor progression. Specifically, immunotherapies can cause leukocyte infiltration at sites of active tumor resulting in disruption of the BBB and increased contrast enhancement [56,57]. The specific changes or patterns in conventional MRI following immunotherapy, however, are not well characterized due to the limited experience and small study sizes to date.…”

Pediatric Glioblastoma

“…Focal symptoms like neurological deficits, cranial nerve dysfunction, cerebellar symptoms, etc., depend on the location of the lesion. Neurological deficits, when present preoperatively, are known to affect postoperative prognosis negatively (47). Compared to the older children, infants and young children often present with nonspecific complaints, such as failure to thrive, lethargy, nausea/emesis, and macrocephaly, which, at times, can be difficult to diagnose.…”

High-Grade Glioma Management and Response Assessment—Recent Advances and Current Challenges

“…Patients placed on a "drug holiday" from antiangiogenic therapy because of toxicity have in fact demonstrated reversal of the effect and subsequent re-improvement when the drug is restarted 44 . Concern has arisen that antiangiogenic therapy might inadvertently select for a more invasive tumour phenotype that co-opts existing microvasculature rather than relying on neoangiogenesis 51 .…”

“…They also include clinical status as an indirect measure of worsening non-enhancing disease 51 . The lack of an objective imaging parameter for non-enhancing disease is clearly suboptimal; measurement of T2 or fluid attenuation inversion recovery signal abnormality in patients on antiangiogenic therapy has not been helpful in predicting survival 50 .…”