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Brain metastases (BMs) develop in up to 30% of patients (pts) with cancer. Survival of BMs pts is extremely variable and remarkably poor in absence of active treatment. The use of stereotactic radiosurgery (SRS) for the treatment of BMs has increased in recent years providing excellent local control rates even though radiological assessment of the response to treatment can often be challenging. Preclinical studies showed that silibinin - a natural polyphenolic flavonoid isolated from seed extracts of the herb milk thistle - demonstrates anticancer effects in vitro and in vivo. The use of a silibinin-based nutraceutical resulted in significant clinical and radiological improvement of BMs in non-small cell lung cancer (NSCLC) pts that progressed after whole brain radiotherapy and chemotherapy. Thus, the aim of the present explorative study (SUSTAIN trial) is to evaluate whether the use of silibinin-based nutraceuticals (SILLBRAIN®) can significantly reduce distant brain failure (DBF) rate at 6 months in pts with first diagnosis of BMs treated with SRS with or without surgery. Here a preliminary analysis on the first 18 pts enrolled is reported.

SUSTAIN is a prospective, single arm, phase II study planning to recruit a total of 80 pts with up to 10 BMs from all primary tumors (except small cell lung cancer), aged 18 or older, amenable for treatment with SRS or surgery followed by SRS to cavity. Pts received 2 capsules (cps) of SILLBRAIN® per day for the first month after SRS and 1 cp per day thereafter. The 6-month DBF rate is assessed according to RANO criteria for brain metastases (RANO-BM). Contrast-enhanced magnetic resonance (MRI) of the brain is performed at baseline and every 12 weeks after SRS as per clinical practice. EORTC QLQ-C30 and BN20 questionnaires are administered at baseline and every 12 weeks after SRS to evaluate health-related quality of life (HRQoL).

At the time of this first analysis 18 pts have been enrolled. The prevalent primary tumors were NSCLC and breast cancer, with 9 and 4 pts respectively. Ten pts had metachronous BMs onset, and 8 pts synchronous. Nine pts received at least 1 line of systemic therapy and 17 pts reported a controlled extracranial disease at BMs diagnosis. The overall number of BMs was 55. All BMs were treated with SRS, with a median prescription dose and median prescription isodose of 24Gy and 80%, respectively. According to RANO-BM criteria, 1 pt reported distant intracranial failure with 3 months of DBF. The median OS was 8 months. Only 1 pt discontinued SILLBRAIN® assumption due to the onset of grade 1 nausea (CTCAE v5.0). No other adverse events were reported.

The addition of silibinin-based nutraceuticals after SRS administration might improve intracranial disease control in BMs pts, with a good safety profile. Final results from SUSTAIN trial are awaited to confirm these encouraging findings.