Cancer is the second most common cause of mortality in the United States, accounting for approximately one-quarter of all deaths. Although primary central nervous system (CNS) cancers are relatively rare, the annual estimated incidence of brain metastases in the United States exceeds 100,000 cases. The vast majority of patients with metastatic brain cancer die within a few months of diagnosis, making this one of the most common immediate causes of death in the United States.
The most frequent primary cause of brain metastases is lung cancer, which is responsible for almost half of all secondary tumors of the brain. Other major primary tumors that contribute significantly to the occurrence of brain metastases include breast cancer, melanoma, and colorectal cancer. Less commonly, primary tumors of the kidney, other gastrointestinal neoplasms, lymphomas, sarcomas, gynecologic tumors, and, rarely, prostate cancer also metastasize to the brain.
Recent therapeutic advances have led to longer disease-free survival for patients with several types of cancer, thereby increasing the overall population of cancer survivors. Unfortunately, these patients are not truly cured, and their longer disease-free interval places them at higher risk of developing metastatic disease at sanctuary sites, such as the brain, where penetration of traditional cytotoxic therapeutic agents is impaired by the blood-brain barrier. These clinical observations, combined with enhanced utilization of cranial imaging, explain the apparent perception of an increase in the overall incidence of brain metastases.
In 1954, Chao et al first reported on the value of external-beam radiation in the treatment of brain metastases. Because of its simplicity and ease of delivery as an outpatient modality, with little morbidity, low cost, and minimal disruption of quality of life, external-beam radiation rapidly became the most commonly used strategy in the management of patients with brain metastases.
The Radiation Therapy Oncology Group (RTOG) has conducted several sequential studies exploring a variety of different fractionation schedules.[3,4] Four major conclusions were drawn from these studies: (1) Median survival improves to 15 to 21 weeks, a slight improvement over steroids only. (2) A radiation dose of 30 Gy in 10 fractions is as efficacious as more prolonged regimens or higher doses. (3) No significant survival advantage is afforded by prolonged fractionation or higher doses (up to 50 Gy), implying the lack of a dose-response relationship in this range. (4) Prognostic criteria that predict for slightly improved survival include age < 60 years, Karnofsky performance score (KPS) > 70, control of the primary tumor, and the brain as the sole site of metastasis. Subsequent reanalysis of these data by Swift et al showed the presence of three or fewer lesions to be an additional favorable prognostic factor.
Based on the RTOG trials, the standard treatment for most patients with brain metastases for the last 2 decades has been conventional external-beam radiation (30 Gy in 10 fractions) delivered to the whole brain. The fact that this is, indeed, the most widely practiced community standard was confirmed in the Patterns of Care palliation survey conducted in the 1980s.
Accelerated Hyperfrationated Schedules
In the older RTOG studies, one-third to one-half of the patients died from neurologic deterioration. One might logically assume that if such deterioration could be controlled, survival might be enhanced. In order to test this hypothesis, a recent RTOG study evaluated the role of dose-escalation using accelerated hyperfractionation (1.6 Gy twice daily to total doses ranging from 48 to70.4 Gy). This study demonstrated that higher doses significantly improve survival and neurologic function, suggesting that control of intracranial disease may be related to dose and that such control may translate into a neurologic improvement and survival advantage.
Although this phase I/II RTOG report suggested a potential benefit from an altered fractionation regimen in patients with limited metastatic disease and good KPS or neurologic function, a randomized trial failed to conclusively demonstrate any improvement in survival with accelerated hyperfractionated radiotherapy (1.6 Gy twice daily to a total dose of 54.4 Gy), as compared to a conventional regimen of 30 Gy in 10 fractions. The results of this phase III trial notwithstanding, the fact remains that relatively low doses, on the order of 30 Gy, cannot successfully diminish tumor growth or control it for a sustained period. The need for a higher dose to improve tumor control is one of the central reasons for considering radiosurgical boost.
The role of surgery in the treatment of brain metastasis remains controversial. Clear indications for resection include craniotomy or stereotactic biopsy to establish the diagnosis, when it is in doubt, and removal of the tumor mass when such therapy is likely to provide immediate palliation. Such indications lead to a very high level of selectivity in surgical series. It is common practice in some institutions to select patients with a single brain metastasis who are otherwise clinically stable for surgical resection.
Resection Plus Whole-Brain Radiation
Retrospective data suggest that, in patients undergoing craniotomy without external-beam radiation, the relapse rate approaches 85%. In a recent prospective, randomized trial, the addition of whole-brain radiation therapy to surgical resection improved intracranial progression-free survival. Several retrospective series suggest that, in highly selected patients, surgical resection followed by whole-brain radiotherapy may prolong survival from a median of 16 to 26 months.
To establish whether improved intracranial control would reduce morbidity, improve quality of life, prolong survival, and alter mortality patterns, three, small, randomized trials have compared surgery plus whole-brain external-beam radiotherapy to radiotherapy alone in patients with single brain metastases. Two of the trials showed an improvement in median survival, to 43 and 40 weeks, respectively, with the addition of surgery.[12,13] These two trials also demonstrated that functional independence, as defined by maintenance of KPS at or above a level of 70 following therapy, was sustained for a longer duration in patients undergoing surgery. These findings therefore established resection as a new standard for selected patients with single brain metastases.
These results lend credence to the notion that aggressive management strategies directed at improving local control are beneficial for selected patients with brain metastases. However, a more recent and slightly larger randomized trial addressing this issue failed to identify a survival benefit from the addition of surgery: Median survival was 6.3 months in the radiation-alone group, as compared with 5.6 months in the resection group.