PracticeUpdate: Neurology - Winter 2018

EXPERT OPINION 12

Cerebral Blood Flow Changes After Radiation Therapy Identifies Pseudoprogression in Diffuse Intrinsic Pontine Gliomas By John Laterra MD Dr. Laterra is a Professor of Neurology, Oncology and Neuroscience and co-Director of the Brain Cancer Program at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland.

B rain MRI serves as a bedrock for monitor- ing patients with brain cancer and evaluating responses to radiation and chemotherapy. MRI is very sensitive but often lacks sufficient specificity when evaluating brain cancer responses to radiation or combination radiation/chemotherapy. This retrospec- tive analysis of multimodality MRI and clinical outcomes in children with diffuse intrinsic pontine gliomas (DIPGs) by Calmon et al 1 highlights this obstacle to evaluat- ing treatment responses, specifically distinguishing true tumor progression from treatment-induced “pseu- doprogression” in brain cancer patients. The ability to make appropriate treatment decisions, prognosti- cate, and effectively evaluate experimental treatments hangs in the balance. This is a critical challenge for adults and children with malignant gliomas. Adult patients most often have hemispheric tumors that allow repeat excisional biopsy or surgical resection to update pathological processes following therapy – options not readily applicable to DIPGs and other deep infiltrating malignancies of childhood. This current study describes changes in arterial spin labeling cerebral blood flow (ASL-CBF) as a potential noninvasive biomarker of early pseudoprogression in patients with aggressive pontine glioma. Strengths of this study are that all patients had biopsies confirming similar aggressive, high-grade, infiltrative glioma before starting treatment; all patients received standard radi- ation therapy, and, while chemotherapies varied to some degree, this apparently did not differ significantly between the pseudoprogression and true tumor pro- gression groups. A key limitation is the absence of any post-treatment pathology (the gold standard for distin- guishing true progression from pseudoprogression) to validate the ASL-CBF biomarker.

Certain unexpected findings warrant pause and further study. The finding that pseudoprogression was asso- ciated with increased ASL-CBF, speculated to result from a vascular normalization mechanism, is somewhat counterintuitive because pseudoprogression following the treatment of supratentorial tumors, a much more extensively studied process, is characterized by vas- cular dysfunction with reductions in cerebral blood volume and cerebral blood flow. One might also expect patients with pseudoprogression to survive longer than those with true tumor progression because the for- mer reflects a more robust anti-tumor response and is often self-limiting. That no differences in survival were observed between the two groups raises ques- tions regarding the clinical/radiographic criteria used to partition patients into the true progression and pseu- doprogression groups. These unexpected findings might very well reflect the very distinct biology of DIPGs, regional differences in cerebrovascular responses to radiation-based thera- pies, and the greater life-threatening consequences of progressive pontine injury whether from true tumor progression or pseudoprogression. The potential utility of ASL-CBF in evaluating treatment responses in DIPG is intriguing and potentially promising. The absence of either histopathology confirmation or clinically distinct biomarker-associated patient outcomes highlights the need to better understand the biological and clinical significance of ASL-CBF in DIPG. Reference 1. R Calmon, S Puget, P Varlet, et al. Cerebral blood flow changes after radiation therapy identifies pseudoprogression in diffuse intrinsic pontine gliomas. Neuro-oncology 2018;20(7):994-1002. www.practiceupdate.com/c/70299

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