Systemic Chemotherapy for Metastatic Tumors of the Central Nervous System

The incidence of brain metastases exceeds 100,000 per year in the United States (21), thus making tumor metastasis to the central nervous system (CNS) a significant challenge in the management of patients with solid tumors. To put this into perspective, brain metastases occur at almost one order of magnitude greater than primary malignant brain tumors. Metastatic tumors to the brain and spine also arise in approx 10 to 15% of patients with systemic cancers. This incidence rises to approx 24% when results from autopsy studies are factored in. Patients with intracranial and intraspinal metastases comprise approx 5% of all cancer patients (4). Despite this preponderance of metastatic tumors to the CNS vs primary malignancies of the nervous system, the amount of research effort directed at the two sources of CNS disease is disparate. This is evidenced by the low number of scientific publications, a little more than 300 on brain metastases published between 1998 and 2000. However, during the same period more than 5000 publications were devoted to primary brain neoplasms. This disparity in attention to metastatic tumors of the CNS may be explained, at least in part, by the clinical complexity inherent in treating metastatic cancer. The diversity of the tumor histologies that metastasize to the brain and spinal cord combined with the absence of good clinical studies of the effectiveness of various forms of therapies, e.g., systemic chemotherapy vs radiation therapy, has hampered progress in developing efficacious therapies. Most clinical trials that have attempted to study the value of systemic chemotherapy for this group of patients have included “all comers” representing patients with multiple histologies. Metastatic tumors to the CNS arise most frequently in patients who have primary lung cancer (35–50%), particularly in patients who have small cell lung cancer (SCLC) (18). Metastases from solid tumors of the breast account for approx 10–30% of metastatic disease, followed by malignant melanoma with a 30–40% frequency of occurrence, and approx 5% for renal and colorectal cancer. The remaining other metastases to the brain (15%) are from systemic neoplasms, including nonsolid tumors, such as leukemia and lymphoma. By the time these diseases are discovered, they have frequently resulted in multiple brain metastases. In contrast to malignant melanoma, lung and breast carcinomas, which frequently have multiple brain metasta-ses, patients who have colorectal and renal cell carcinoma typically have a single brain metastasis at the time of diagnosis (10,34). The challenge of treating patients with tumors metastatic to the CNS is compounded by the fact that these space-occupying lesions are within the closed, confined cranial vault. Patients typically demonstrate a slow decline in their physical, cognitive, and emotional functions as a consequence of the growing metastatic foci. Other patients, however, may have a focus of disease in a relatively silent area of the brain. Few symptoms are obvious in these patients until the brain is overwhelmed and a sudden decompensation and a decreased level of consciousness ensues. Typically, patients with metastatic tumors to the CNS have symptoms that include headache, change in mental status, somnolence, cranial nerve palsies, dysphasia, visual field defects, hemiparesis, and focal or generalized seizures (34). Because many patients with systemic cancers are living longer, there is an increased likelihood that metastatic disease will occur in the CNS. Furthermore, the incidence of cancers such as malignant melanoma and lung cancer is increasing. The successful management of late-stage metastatic disease has thus become a clinical imperative. Although surgical resection of symptomatic lesions and whole-brain cranial radiotherapy have improved survival, more effective treatments for metastatic disease will ultimately reside in as yet undiscovered treatment strategies (53). These will undoubtedly include innovative, novel chemotherapy regimens.