Prospective Double Arm Randomized Trial: WBRT Alone and WBRT Plus Silibinin

Study Overview
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Brief Summary
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The occurrence of brain metastases (BMs) is increasing given the availability of a more accurate radiological imaging such as MRI for detecting also small brain lesions and the most effective systemic therapy able to control extracranial disease. Although, the new target therapy and immunotherapy has proven to be effective on brain metastasis too, a subgroup of patients shows prove themselves unresponsive to medical treatment. A further subgroup of patients exhibit diffuse brain disease for the presence of multiple brain lesion (>10 BMs) or leptomeningeal carcinomatosis. Among these patients the most treatment employed is represented by whole brain RT. Since the 1950s, whole-brain radiation therapy (WBRT) has been the most widely used treatment for patients with multiple brain metastases, given its effectiveness in palliation, widespread availability, and ease to delivery. However, the median overall survival recorded is restricted to 3 months, on the average. A better understanding of the molecular and cellular mechanisms underlying brain metastasis might be expected to lead to improvements in the overall survival rate for these patients. Recent studies have revealed complex interactions between metastatic cancer cells and their microenvironment in the brain. Priego et al. describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. Silibinin (or silybin) is a natural polyphenolic flavonoid isolated from seed extracts of the herb milk thistle (Silybum marianum). Silibinin has been shown to impair STAT3 activation. Preclinical studies show that Silibinin has an anticancer effects in vitro and in vivo. Based on this background, the investigators designed a double arm randomized trial evaluating the benefit of Silibinin (in the form of marketed supplement) associated to WBRT respect to WBRT alone.

Official Title
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Prospective Double Arm Randomized Trial for Patients With Multiple Brain Metastasis and/or Leptomeningeal Carcinomatosis: Comparison of WBRT Alone and WBRT Plus Silibinin (Sillbrain)

Conditions
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Brain Metastases, Adult

Intervention / Treatment
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* Other: Silibinin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years Histological or cytological confirmation of solid tumor malignancy Clinical indication for whole brain radiotherapy Karnofsky performance status (KPS) ≥60 Written informed consent Exclusion Criteria: Prior WBRT KPS < 60 Diagnosis of Lymphoproliferative disease Pregnant women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective double arm randomized trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: WBRT + Silibinin<br>Patients undergo WBRT concomitant to Silibinin | Other: Silibinin<br>* WBRT will be concomitant to Silibinin. Silibinin at dose of 500 mg must be administrated twice a day for the first month, after once a day continuously. Total dose and fractionation of WBRT: 30 Gy in 10 fractions.<br>|
| No Intervention: WBRT<br>Patients undergo WBRT alone, total dose of 30 Gy in 10 fractions. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Outcome will be evaluated in months | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity in term of use of corticosteroid therapy | Outcome will be evaluated in term of use or not of corticosteroids | 12 months | 
| Brain Distant Failure (BDF) | Outcome will be evaluated in months | 12 months | 
| Progression Free Survival (PFS) | Outcome will be evaluated in months | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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WBRT, Brain Metastases, Silibinin