Radiosurgery, Radiotherapy, or Resection?
Object. Multiple brain metastases are a common health problem, frequently found in patients with cancer. The prognosis, even after treatment with whole-brain radiation therapy (WBRT), is poor, with an average expected survival time of less than 6 months. Investigators at numerous centers have evaluated the role of stereotactic radiosurgery in retrospective case series of patients harboring solitary or multiple tumors. Tumor resection is used mainly for patients with large tumors that cause acute neurological syndromes. The authors conducted a randomized trial in which they compared radiosurgery combined with WBRT with WBRT alone.
Methods. Twenty-seven patients were randomized (14 to recieve WBRT alone and 13 to receive WBRT combined with radiosurgery). The rate of local failure at 1 year was 100% after WBRT alone but only 8% in patients in whom boost radiosurgery was performed. The median time to local failure was 6 months after WBRT alone (95% confidence interval (CI) 3.5-8.5) in comparison to 36 months (95% CI 15.6-57) after WBRT and radiosurgery (p = 0.0005). The median time to the development of any brain failure was improved in the combined modality group (p = 0.002). Survival was shown to be related to the extent of extracranial disease (p = 0.02).
Conclusions. Combined WBRT and radiosurgery for the treatment of patients with two to four brain metastases significantly improves control of brain disease. Whole-brain radiation therapy alone does not provide lasting and effective care when treating most patients. Surgical resection remains important for patients with large symptomatic tumors and in whom limited extracranial disease has been demonstrated.

Brain metastases develop in up to 50% of all patients with cancer. In most series, the use of fractionated WBRT extends a patient's survival by 3 to 5 months. Although more patients harbor multiple rather than solitary brain metastases at presentation (over 100,000 patients with solitary tumors are diagnosed in the United States each year), few gains have been made in the treatment of this disease. For patients with a single brain metastasis, the authors of two randomized trials found a survival benefit after surgical resection combined with WBRT as compared with WBRT alone, although a third trial that included more patients with active systemic disease, did not. Because many patients have metastases in brain locations not amenable to surgical resection, the potential benefit of resection cannot be offered to all patients. In addition, if the patient is in poor medical condition, craniotomy and resection may be precluded.

Most physicians expect a poor outcome in a patient with multiple brain metastases. Treatment regimens are often palliative in nature. Traditionally, surgical resection has been offered rarely to patients with multiple metastases, because the resection-related morbidity in multiple brain locations was believed to be excessive, and the risk for developing additional tumors was perceived to be high. Stereotactic radiosurgery, a method to deliver a single, high-dose fraction of ionizing radiation to a small, precisely defined target volume, potentially provides answers to both problems (Fig. 1). First, radiosurgery can be performed in any location in the brain, regardless of regional brain function. Second, radiosurgery can be used to treat multiple brain lesions in one setting, irrespective of tumor's histological type or configuration. However, because radiosurgery, like conventional surgery, is still a focused treatment, it potentially is limited by the risk of the development of additional tumors outside the initial irradiated regions.



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Figure 1. Contrast-enhanced axial MR images obtained in a patient with multiple brain metastases from renal cell carcinoma (arrows). The patient refused WBRT and was one of the first patients with multiple metastases to be treated at our center. He lived 14 months and continued to practice medicine for almost 1 year after undergoing radiosurgery.





In the 1980s and early 1990s, it was the practice at most institutions to limit the use of radiosurgery to the management of patients with solitary tumors. This approach was more often used in patients with multiple metastases because of the high incidence of concurrent, active systemic disease. However, there was a subset of patients with multiple tumors in whom, because of the tumors' small sizes, good neurological function was maintained and who had treated or controlled systemic disease. These patients usually received fractionated WBRT, up to a dose of approximately 30 Gy. In years past, if multiple brain tumors were found after prior WBRT had been administered, then either no treatment or a smaller, fractionated whole-brain irradiation boost (10-20 Gy) was administered.

Approximately 10 years ago, we began to explore the role of radiosurgery for the treatment of patients with multiple (two to four) brain metastases (Fig. 2). Our hypothesis was that stereotactic radiosurgery in addition to WBRT would provide improved local brain tumor control and progression-free survival in patients with multiple tumors.



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Figure 2. Axial MR images obtained in a male patient with lung cancer metastatic to brain. He had completed WBRT following a craniotomy and tumor resection 1 year prior. Upper: Four new tumors (arrows) were identified on routine follow-up MR imaging. Lower: One year later, his brain disease remained stable, with three tumors reduced in size. He died 3 years after radiosurgery of a gastrointestinal hemorrhage.