Eligibility of patients with brain metastases for phase I trials: time for a rethink?

Since the inception of phase I clinical trials in cancer, patients with symptomatic brain metastases have commonly been excluded from participation because of a poor outlook. However, patients with asymptomatic brain metastases pose an increasingly frequent challenge for clinicians: more sensitive brain imaging can identify clinically silent brain metastases; frequency of detection might have increased because of changes in the natural history of many tumour types as a result of more effective systemic treatment; and routine brain imaging as a screening procedure before entry into a clinical trial can show lesions which are of questionable clinical importance, but which frequently preclude trial enrolment. Evidence suggests that delaying whole-brain radiotherapy until symptomatic progression has no adverse effect on prognosis. Safety and efficacy data are accumulating for targeted agents to treat brain metastases. We think that a subset of patients with asymptomatic brain metastases might be appropriately entered into phase I trials, and we present our approach for their stratification. As a consequence, patients might have increased access to experimental treatments and thus effective interventions for brain metastases might be developed more promptly.