The Role of Chemotherapy in Metastatic Brain Tumors

Introduction

Brain metastases pose a major treatment challenge and typically confer a poor prognosis for patients diagnosed with these secondary tumors. While surgical resection and various forms of radiation therapy play important roles in the multidisciplinary therapy of brain metastases, the role of chemotherapy is less clear. In this chapter we will examine the evidence for and against the use of chemotherapy for brain metastases.

The American Cancer Society Registry data show that ≈1.4 million Americans are diagnosed with cancer every year; 40% of these will develop brain metastases ( ). However, the exact incidence of brain metastases is often underestimated due to the way information is gathered from epidemiological studies. For example, most epidemiological studies use death certificates, tumor registries, and hospital records to gather information regarding the incidence of brain metastases. These are often incomplete as patients with brain metastases are usually coded under their primary tumor, leaving the brain metastases uncoded. A study ( ) looked at the incidence of brain metastases found at autopsy and estimated the incidence of brain metastases to be more than double the incidence of primary brain tumors. This is as compared to epidemiologic studies which put the incidence of brain metastases to be equal to or no more than double that of primary brain tumors. Another study ( ) looked at the rate that brain metastases occurred in a given group of patients diagnosed with cancer and estimated that of 1 497 926 patients diagnosed with cancer in 2007, 70 000, or 4.6% would develop brain metastases over their lifetime. This is approximately three times the incidence of primary brain tumors per year. Even this was regarded as an underestimate by the authors of the study.

There is a tremendous amount of research being done on therapy for brain metastases as well as for primary brain tumors. Most cancers, when found early, can be treated with a combination of surgical resection, chemotherapy and/or radiation. However, by the time a patient develops a metastatic brain tumor, the prognosis is generally poor. The recently published evidence-based guidelines for the treatment of patients with metastatic brain tumors ( ) provide an excellent resource as an analysis of the current literature to aid the modern day physician in determining which of several multidisciplinary and multimodality treatment options to use.

Standard of Care for Brain Metastases

Despite the poor prognosis and burden of disease, studies show that patients with brain metastases are surviving longer ( ). This is primarily due to advances in treatment options as well as more aggressive care. With the advent of computerized tomography in the 1970s, radiation therapy for brain metastases was initially the mainstay of treatment. Outcomes, however, remained poor. A landmark study ( ) randomized patients with single brain metastases to either surgical resection followed by radiation or needle biopsy followed by radiation and concluded that patients with single brain metastases who receive both surgical resection and radiation had a longer length of survival and longer functionality compared to treatment with radiation alone. In addition, a follow-up study by the same authors compared outcomes after whole brain radiotherapy with surgical resection to surgical resection alone. Although length of survival and functionality were not statistically significant, patients who received whole brain radiotherapy and surgical resection were less likely to die of neurologic causes. Thus, surgical resection followed by radiation has since been the standard of care for single brain metastatic lesions; more recently, stereotactic radiosurgery has also become an important treatment option.

Therapeutic modalities for most primary cancers and for many metastatic cancers involve chemotherapy. However, cancer that is metastatic to the brain poses a significant challenge due to the presence of the blood–brain barrier. The blood–brain barrier is a specialized layering of cells that effectively separates the systemic circulating blood from the brain, providing a microenvironment that is distinct from the rest of the body. Many substances are therefore excluded from the brain unless they can be actively transported across the blood–brain barrier ( ). In addition to the blood–brain barrier, astrocytes provide a second barrier to the movement of foreign substances into the brain – they may absorb and break down certain substances. As such, there is a trend for chemotherapeutic agents to be selected based on their potential to permeate the blood–brain barrier, regardless of whether or not they are effective against brain metastases in treatment. For instance, temozolomide is an alkylating agent that has relatively good central nervous system penetration ( ). As such, it has been studied for treatment of metastatic breast cancer to the brain. However, it has limited efficacy in treating breast cancer. On the other hand, capecitabine, which has good efficacy in treating breast cancer, has limited penetration into the blood–brain barrier ( ). Experimental models show that when a metastatic brain tumor grows more than 1–2 mm, there is structural and functional damage to the blood–brain barrier ( ). Thus, some chemotherapeutic drugs may potentially be able to permeate a disrupted blood–brain barrier, eventually reaching metastases.