Abstract
BackgroundLittle is known about tumor-associated vasogenic edema in brain metastasis, yet it causes significant morbidity and mortality. Our purpose was to characterize edema in patients treated with anti-PD-1 and to study potential causes of vessel leakage in humans and in pre-clinical models.MethodsWe analyzed tumor and edema volume in 18 non-small cell lung (NSCLC) and 18 melanoma patients with untreated brain metastases treated with pembrolizumab on a phase II clinical trial. Melanoma brain metastases were stained with anti-CD34 to assess vessel density and its association with edema. We employed an in vitro model of the blood-brain barrier using short-term cultures from melanoma brain and extracranial metastases to determine tight junction resistance as a measure of vessel leakiness.ResultsEdema volumes are similar in NSCLC and melanoma brain metastases. While larger tumors tended to have more edema, the correlation was weak (R2 = 0.30). Patients responding to pembrolizumab had concurrent shrinkage of edema volume and vice versa (R2 = 0.81). Vessel density was independent of the degree of edema (R2 = 0.037). Melanoma brain metastasis cells in culture caused loss of tight junction resistance in an in vitro blood-brain barrier model system in some cases, whereas extracerebral cell cultures did not.ConclusionsEdema itself should not preclude using anti-PD-1 with caution, as sensitive tumors have resultant decreases in edema, and anti-PD-1 itself does not exacerbate edema in sensitive tumors. Additional factors aside from tumor mass effect and vessel density cause perilesional edema. Melanoma cells themselves can cause decline in tight junction resistance in a system void of immune cells, suggesting they secrete factors that cause leakiness, which might be harnessed for pharmacologic targeting in patients with significant perilesional edema.
Highlights
Little is known about tumor-associated vasogenic edema in brain metastasis, yet it causes significant morbidity and mortality
Tumor and edema volumes in non-small cell lung cancer (NSCLC) or melanoma patients are weakly correlated Based on clinical observations that Brain metastases (BMs) of similar size can induce variable edema volumes, we used 3D modeling to quantitate tumor and edema volumes
Response to anti-PD-1 was independent of baseline edema As there was no difference in edema volumes between melanoma and NSCLC patients when correcting for tumor size, we combined the cohorts for subsequent analyses
Summary
Little is known about tumor-associated vasogenic edema in brain metastasis, yet it causes significant morbidity and mortality. Immune checkpoint inhibitors (CPIs) have provided significant benefit in treating advanced melanoma. Neurologic symptoms from BMs are often caused by edema rather than from the tumor itself, as edema volume can be several-fold greater than tumor volume. While progress has been made towards understanding activity of contemporary drugs in BMs, research is still needed to determine how best to treat patients with neurological symptoms, patients requiring corticosteroids, and patients with significant perilesional edema. CPI effects on edema are understudied, as edema is often not recorded or quantitated in clinical trials. Little is known about the relationship between tumor-associated vasogenic edema and tumor volume or survival [9]
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