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Brain Trauma Neuro-oncology
How the North American Brain Tumor Consortium Shaped
Clinical Research in Neuro-oncology
a report by
Susan Chang, MD
Professor and Lai Wan Kan Chair of Neurological Surgery, Neuro-oncology Service, Department of Neurological Surgery, University of California, San Francisco
The North American Brain Tumor Consortium (NABTC) is one of three challenging patient population. Bolstered by public awareness regarding
multi-institutional consortia initially funded by the National Cancer Institute the need for clinical research devoted to brain tumors and an increase in
(NCI) in 1994 with the primary purpose of efficiently evaluating novel patient advocacy groups, a significant effort began to better understand
treatments in adults with central nervous system (CNS) tumors. Its current the disease and find effective therapies.
counterpart is New Approaches to Brain Tumor Therapy (NABTT) and
although the consortia share common goals, they have thus far had Under the leadership of Michael Prados, MD, the NABTC invited 10
separate identities and infrastructures. As a new era begins in which these institutions to participate in the consortium. All principal investigators (PIs)
two consortia will merge to form the Adult Brain Tumor Consortium and representatives from each site met twice a year to review the progress
(ABTC), it is important to reflect on and learn from past successes and of the consortium with respect to patient accrual, data management and
failures. Therefore, I am happy to have been asked to write this editorial regulatory compliance, and proposals for new protocols, and to discuss
describing the lessons learned at the NABTC and how the organization has priorities for the group. Monthly conference calls also facilitated
influenced neuro-oncology clinical research. communication among the members and were critical for discussion of
toxicity assessments and plans for dose escalation in phase I studies.
The NCI’s decision to prioritize early clinical trials in this orphan disease Because all PIs had equal responsibility and authority in the decision-making
was a critical step in forming the consortia. The recognition of the process, new initiatives could be implemented expeditiously and without
significant morbidity and high mortality associated with CNS tumors, the impediments posed by a large, bureaucratic infrastructure. Individual
despite the relatively low incidence compared with other solid tumors, sites were held accountable for meeting the expectations outlined in the
and the dedication of basic science and clinical researchers to improving grant written for each study and were assessed for intellectual contribution
the outcome of patients were important factors in the success of the to the research agenda, patient accrual, and regulatory compliance. A
consortia. By 1994, the field of neuro-oncology had grown enough to central data management center, dedicated biostatistical support, and a
sustain the clinical research effort proposed by the NCI. Prior to this effort, pharmacokinetic core were key initial components of the consortium. Many
most therapeutic agents were inherited from phase I experience in solid members of the NABTC relied on National Institutes of Health (NIH)-funded
cancers and subsequently tested in neuro-oncology patients. One reason general clinical research centers to assist with the administration of the
for this was the reluctance of pharmaceutical companies to invest in early agents and the acquisition of multiple blood samples for pharmacokinetic
clinical development of their product in such a small-volume disease. analyses. To date, more than 1,000 patients, primarily with recurrent
There were also concerns that agents would not be safely tolerated by malignant glioma, have been accrued.
patients with a CNS disease that carried such a poor prognosis. A major
advantage of forming the NABTC was that it established the credibility To improve the scientific rigor of the studies, protocol templates were
needed to generate funding for research and to gain access to new agents developed to standardize key elements of clinical trial design. These
for early testing in brain tumor patients. One important objective of the included eligibility criteria, end-point assessment, and biostatistical
consortia, therefore, was to demonstrate the ability to complete well- considerations. This also allowed for the generation of a robust database to
designed and -conducted multi-institutional phase I/II trials in this test hypotheses for future studies. In addition, the mandate that all phase I
studies have accompanying pharmacokinetic end-points was critical to
achieving a better understanding of the influence of concomitant
Susan Chang, MD, is Director of the Division of Neuro-
oncology at the University of California, San Francisco, and
medications typically used in brain tumor patients. One of the NABTC’s early
President of the Society of Neuro-oncology. In addition to findings was that hepatic enzyme-inducing anti-epileptic drugs (EIAEDs)
developing novel and effective therapeutic strategies for adult
could alter the pharmacokinetic parameters and toxicity profiles of
patients with primary brain tumors, Dr Chang’s research goals
include the evaluation of novel imaging techniques that may
therapeutic agents. This was shown for cytotoxic and molecularly targeted
influence treatment selection for patients and assess response agents.
1,2
Trial designs in neuro-oncology have since evolved to test the
to therapy. Dr Chang also trains students in the conduct of
agent in patients not taking EIAEDs first to determine efficacy. Only if there
clinical trials and in the analysis and interpretation of clinical-
trial data. Her training includes a residency in internal medicine and fellowships in medical
is evidence of efficacy in this patient population is there a reason to perform
oncology and neuro-oncology. phase I testing in patients on EIAEDs to establish the appropriate dose for
phase II evaluation. This strategy optimizes both patient and financial
E: changs@neurosurg.ucsf.edu
resources and expedites the assessment of an agent’s clinical utility.
40 © TOUCH BRIEFINGS 2008
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