P16.07.b prospective double arm phase 2 randomized trial for patients with multiple brain metastasis and/or leptomeningeal carcinomatosis: comparison of whole brain radiation therapy (wbrt) alone and wbrt plus silibinin

Abstract BACKGROUND Occurrence of brain metastases (BMs) is increasing given availability of Magnetic Resonance Imaging (MRI) able to detect also small brain lesions, and most effective systemic therapy able to better control extra-cranial disease. Estimated 20% of patients with cancer will develop BMs. In case of limited brain metastases, radiosurgery or hypofractionated radiosurgery is treatment of choice. A subgroup of patients characterized by extensive brain disease and/or leptomeningeal carcinomatosis can require whole brain radiotherapy (WBRT). Since the 1950s, WBRT has been the most treatment used for patients with multiple BMs, given its effectiveness in palliation, widespread availability, and ease to deliver. However, the median overall survival (OS) recorded is restricted to 3 months, on the average. A better understanding of molecular and cellular mechanisms underlying brain metastasis might be expected to lead of improvements in overall survival. Recent studies demonstrated that active signal transducer and activator of transcription 3 (STAT3) in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis, even at advanced stages of colonization. Silibinin is a natural polyphenolic flavonoid isolated from seed extracts of herb milk thistle. It has been shown to impair STAT3 activation, and in preclinical studies, show an anticancer effects in vitro and in vivo. Based on this background, we designed a double arm phase 2 randomized trial evaluating the benefit of Silibinin associated to WBRT respect to WBRT alone. Primary endpoint is OS, secondary endpoints are toxicity in term of corticosteroid therapy use, brain failure (BF) and progression free survival (PFS). MATERIAL AND METHODS Forty-four patients will be enrolled in two years. Patients with histological or cytological confirmation of solid tumor malignancy, clinical indication for WBRT and Karnofsky performance status (KPS) ≥60 will be enrolled. In arm A experimental, WBRT is concomitant to Silibinin, in arm B control, WBRT alone will be administered. In both arms, total dose of radiotherapy is 30 Gy in 10 fractions. Quality of life and use of corticosteroids will be evaluated first, last day of RT, and during follow-up. Outcome will be evaluated by MRI or CT at 2 months after RT, and every 3 months thereafter. RESULTS From March 2023, 6 patients were enrolled, 2 patients in Arm A and 4 in arm B. Primary histology was breast cancer in 3 patients and non small cell lung cancer in 3. In arm A, 1 patients dismissed RT for worsening of general conditions related to rapid lung progression. CONCLUSION WBRT with or without Silibinin was well tolerated, no acute toxicities or increase of corticosteroids were observed.