Designing clinical trials for brain tumors: the next generation

Recent clinical trials have demonstrated improvements in survival in patients with malignant gliomas. Laboratory investigations have uncovered genetic alterations that promote gliomagenesis and defined several critical signaling pathways that affect tumor viability, invasiveness, angiogenesis, and resistance to apoptosis. These advances have stimulated interest in new targeted therapies and clinical trial designs to streamline the determination of efficacy. One such advance is the use of a "progression-free" endpoint, which eliminates the need to demonstrate tumor reduction when there is concurrent treatment-associated tissue necrosis and reflects the cytostatic, not cytotoxic, potential of many new agents. An additional advance is the concept of optimal biologic dose rather than maximum tolerated dose. This concept is being evaluated in laboratory correlative studies through analysis of post-treatment tumor samples. Also, clinical trials are expected to become more efficient through design strategies that permit testing (often simultaneously) of several regimens and facilitate definitive comparisons of the most promising treatment arms. Such designs also require smaller accrual numbers for each study. Finally, investigators have increased interest in determining the impact of treatment on other measures, such as symptom burden, functional status, and quality of life as survival has improved.