Inclusion of Patients with Brain Metastases in Phase I Trials: An Unmet Need

Abstract

Patients with brain metastases are increasing in number; however, these patients are often excluded in phase I/II trials due to perceived poor prognosis, risk of hemorrhage, inefficient drug delivery, and confounding toxicities. Tsimberidou and colleagues demonstrate that selected patients can be appropriately enrolled in phase I trials and have outcomes representative of the general cancer population. Clin Cancer Res; 17(12); 3855-7. Ó2011 AACR.In this issue of Clinical Cancer Research, Tsimberidou and colleagues (1) report their single-institution experience of patients with brain metastases treated in various phase I clinical trials. This series reports on a neglected topic in experimental oncology and follows on the heels of an abstract detailing the Royal Marsden Hospital experience (2) and an excellent editorial (3). More than 170,000 patients with brain metastases are identified annually, and treatment of such patients poses a significant clinical challenge due to the confined anatomic location of the tumors, the blood-brain barrier (BBB), and variant tumor biology (4).The goal of phase I studies is to establish the safety, dose, toxicity, and pharmacokinetics of a new drug or regimen (5). In identifying appropriate patients, clinicians must weigh on one hand the scientific and clinical benefits, and on the other hand the risk of delay from unrelated toxicity and early patient drop-out. A metaanalysis of phase I trials showed overall response rates, stable disease, and toxicity-related deaths of approximately 10%, 34%, and 0.5%, respectively (6). Although these are surrogate endpoints, in selected patients (e.g., those with EGFR mut non-small cell lung cancer) this can be used to predict a survival benefit. Eligibility criteria serve as objective guidelines to identify low-risk, appropriate patients, and typically exclude patients with poor performance status, organ dysfunction, a life expectancy of <12 weeks, concomitant medications that interfere with metabolism, and comorbidities (e.g., brain metastases). Brain Metastases and Clinical TrialsPatients with brain metastases represent a heterogeneous population with a wide range of outcomes. Gaspar and colleagues (7) retrospectively analyzed 1,200 patients with brain metastases who presented with neurological symptoms and were enrolled in Radiation Therapy Oncology Group randomized trials from 1979 to 1993. The authors evaluated various radiation doses, schedules, and radiosensitizers, and on the basis of a recursive partitioning analysis proposed 3 prognostic classes. Class I patients had a Karnofsky performance status (KPS) greater than 70, age under 65 years, controlled primary disease with brain-only metastatic site, and a median overall survival of 7.1 months. Class III patients had a KPS less than 70 and survival of 2.1 months. Class II patients had a survival of 4.5 months and were neither class I nor class III. To further refine the model, other investigators have used prognostic indices incorporating age, control of primary disease, response to st...

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“…Perhaps the greatest impediment to the development of improved treatments for patients with brain metastases has been the common practice of excluding these patients from clinical trials (Gounder & Spriggs, 2011). The recent impressive results in patients with brain metastases in the phase I trial of dabrafanib, and reports that demonstrate similar outcomes to patients without CNS involvement in early-stage clinical trials, have brought attention to and challenged this practice (Gounder & Spriggs, 2011;Long, et al, 2010;Tsimberidou et al, 2011).…”