SADA-20 ROLE OF NEOADJUVANT LOSARTAN IN 5-ALA FLUORESCENCE-GUIDED RESECTION IN CNS METASTASES

Abstract

Surgical resection is the primary management of metastasis to CNS in patients with large, symptomatic metastatic tumors. Complete resections are necessary, as subtotal resection can lead to a significant local tumor recurrence up to 57% at 12 months in some studies. To maximize GTR, 5-Aminolevulinic Acid (5-ALA) fluorescence guided surgery may be useful in cerebral metastases from epithelial in origin primary tumors such as lung, breast, colon, bladder, and melanoma. The use of 5-ALA guided surgery tends to improve the rate of complete resection (GTR) compared to white-light surgery alone as fluorescence can help detect infiltrative cells in the perilesional zone, potentially improving survival rates and quality of life. Despite the benefits, false negative margins are frequently attributed to tumor fluorescence heterogeneity which is due to solid stress generated by the extracellular matrix of the tumor, mainly collagen and hyaluronan. Which leads to collapse of abnormal vasculature of the tumor leading to impaired delivery of 5-ALA and subsequent hypoxia limiting the metabolic conversion to fluorescent Protoporphyrin IX (PpIX). Neoadjuvant therapy with Losartan, an angiotensin II receptor blocker with potent anti-desmoplastic properties, by inhibiting TGF-β signaling and depleting collagen can decompress the tumor matrix and promote vascular normalization. This restoration of perfusion would not only enhance the delivery of 5-ALA to the infiltrative margins but also alleviate the hypoxia, which enables the aerobic conversion to Protoporphyrin IX. Hence, short-course neoadjuvant Losartan regimen could significantly homogenize intra-operative fluorescence, enabling maximal resection intra-operatively. Major limitations are 5-ALA-induced fluorescence is also seen in areas of edema surrounding metastatic tumors and therefore must be used with caution in cases with significant pre-lesional edema as it can lead to neurological defects and this cannot be used in areas of necrosis. Clinical trials are warranted to validate the safety and efficacy.