Neuro-oncology clinical trials: promise and pitfalls.

The treatment of malignant neoplasms involving the central nervous system, from either primary or metastatic cancer, remains inadequate. Despite intensive efforts in laboratory and clinical investigations, the prognosis for patients with involvement of the central nervous system remains grim. For example, patients with glioblastoma multiforme have a median survival of less than one year, similar to that reported in 1980 [1]. Similarly, patients with metastatic lesions from systemic cancer continue to do poorly unless the lesions are few in number (3 or less) and are amenable to both local (surgical removal or radiosurgery) and whole brain radiotherapy [2]. Clearly, significant advances are needed in the treatment of malignant brain tumors. There has been great interest in developing chemotherapy-based treatment strategies for brain tumors, focusing mainly on primary glial neoplasms (i.e., anaplastic astrocytoma and glioblastoma multiforme). Early investigations into the biology of these tumors recognized that the lesions are extremely heterogeneous. These tumors form a solid distinct mass that is easily visible using current imaging modalities. However, pathologic evaluations reveal significant infiltration of the surrounding brain parenchyma by tumor cells, detectable only by microscopic examination [3]. Imaging studies of this area, often referred to a 'brain-around-tumor' (BAT), show either edema or normal appearing parenchyma. Conversely, brain metastases usually exhibit clear delineation between tumor and surrounding normal brain. Malignant brain tumors, both primary and metastatic, are typically enhancing on imaging studies, indicating blood-brain barrier dysfunction in the region. The enhancing region encompasses the entire metastases, but glial neoplasms have a non-enhancing, infiltrating component present in the surrounding brain parenchyma, in which the blood-brain barrier remains functional. Therefore, despite pathologic differences in regional infiltration of tumor, patients with infiltrating glial malignancies, and those with multiple brain metastases, have a common need for a treatment that encompasses a large portion of the brain. For this reason, external beam radiotherapy is the standard treatment for both types of central nervous system cancers. Although proven to be efficacious, radiation therapy is not curative and recurrent tumor is a frequent occurrence, which has elicited great interest in developing chemotherapy strategies for recurrent cancers. Three manuscripts in this journal describe studies using the chemotherapy agent, temozolomide, for recurrent malignant gliomas and recurrent brain metastases [4-6]. This enthusiasm stems from several factors: temozolomide is an oral agent; has a low incidence of side-effects, non-cumulative myelotoxicity; and crosses the blood-brain barrier [7]. Additionally, pharmacokinetic studies indicate that the metabolism of temozolomide is not altered by concurrently administered drugs that modify the hepatic cytochrome p450 system, including many of the anticonvulsants, a problem encountered with other chemotherapy agents in brain tumor trials [8, 9]. (. The two articles in this issue evaluating treatment of recurrent malignant glioma illustrate several of the controversial issues facing the field of neuro-oncology. The first is the importance of establishing the specific prognostic factors that affect the outcomes in a clinical trial, particularly a phase II trial. The study by Brandes et al. includes patients with glioblastoma, anaplastic astrocytoma and anaplastic oligodendroglioma. Each pathologic diagnosis has a distinct prognosis that may be modified by other prognostic factors, as demonstrated by the recursive partioning analysis by Curran et al. [10]. Because of the varied tumor histologies included in this trial, their findings are not directly comparable to other phase II studies. The study by Brada evaluates the efficacy of temozolomide in patients only with recurrent glioblastoma; therefore, it is more comparable with similar phase II trials for this disease. The second major issue facing the interpretation of brain tumor clinical trials is the definition of response. The widely accepted response criteria, established by MacDonald et al. [11], evaluate the cross-sectional area of tumor on imaging studies have provided standardization of response. The patient must be on a stable or decreasing dose of corticosteroids to be suitable for response assessment. However, even with standardization of assessment criteria, response rates remain low for most glioma treatments and controversy remains regarding the significance of the 'stable disease' designation. Comparing the papers by Brandes et al. and Brada et al. illustrates this controversy. Brandes et al. use the established criteria and report a response rate of 22%, combining partial response with stable disease. In contrast, the manuscript by Brada reports only six month progression-free survival and does not use response as a measure of treatment efficacy. Brada et al. reflect the recent trend in neuro-oncology, comparing treatments by the absence of progression, setting aside issues related to defining response. This is understandable, given that the disease process is mired with complex images and determination of response is complicated by prior therapies such as radiation, radiosurgery and implantation of chemotherapy into the tumor bed. Criteria based on progression-free survival are slowly being established