Case for including patients with brain metastases in clinical trials

A need for subgroup analyses where patients with brain metastases are analysed separately from those with systemic extracranial disease only

The presence of brain metastases should not preclude patients from being entered into clinical trials, delegates heard in the Molecular Neuro-Oncology Special Symposium (29 September 2012). However, Professor Michael Brada, from the Royal Marsden Hospital, London, UK, told the audience that there was a need for subgroup analyses where patients with brain metastases are analysed separately from those with systemic extracranial disease only.

Professor Brada advised that this will be especially important in clinical trials testing new anti- metastatic agents, otherwise it will be impossible to provide proof-of-principal for the therapeutic efficacy of these agents in the brain.

Traditionally, investigators have shied away from recruiting patients with brain metastases into clinical trials since chemotherapy agents are of limited efficacy due to their inability to cross the blood brain barrier. However, tumour vasculature tends to be relatively permeable, as evidenced by enhancement of lesions with contrast agents. Therefore, many chemotherapeutic agents, although unable to penetrate the blood-brain barrier, may still achieve therapeutic levels where brain metastases have disrupted the blood brain barrier.

Professor Brada stressed that future clinical trials exploring agents in brain metastases should focus on patients in whom brain metastases are likely to be the main determinants of outcome and who have inactive system disease. The issue has been that many previous trials treating patients with solitary brain metastases with chemotherapy have not influenced survival, suggesting that brain disease is not the principal determinant of life expectancy when patients have disseminated disease.
Professor Brada concluded that for future studies to have any chance of success, appropriate patient selection using enrichment with predictive biomarkers will also be needed.