Extra-cerebral metastases are the most common malignancy affecting the brain. There are an estimated 100,000 to 170,000 new patients with brain metastases in the United States each year [Johnson 1996]. As systemic therapy for malignancy improves, brain metastases will become an increasingly frequent management problem due to the impaired ability of chemotherapy to pass the blood-brain barrier. Survival for untreated patients with brain metastases is generally less than seven weeks. Standard palliative treatment, including glucocorticoids and whole brain radiation therapy (WBRT), extends median survival to three to six months by preventing or delaying neurologic progression [Posner 1992]. Radiation Therapy Oncology Group (RTOG) trials conducted during the 1970's demonstrated no difference in survival, or time to neurologic progression, among a wide range of WBRT regimens: 20 Gray (Gy) in 5 fractions, 30 Gy in 10 fractions, 30 Gy in 15 fractions, 40 Gy in 15 fractions, or 40 Gy in 20 fractions [Borgelt 1980]. About 40% of the patients in each treatment arm suffered neurologic progression. A follow-up RTOG trial found that favorable patients with controlled primary tumors fared no better with an escalated WBRT dose (50 Gy in 20 fractions) versus a dose of 30 Gy in 10 fractions. On that basis, 30 Gy in 10 fractions became the de facto regimen in the United States. Patients who received WBRT usually experienced mild acute toxicity, such as alopecia, skin reaction, and headache. More importantly, in long-term survivors, there are neurocognitive sequelae that may take months to years to manifest. A long-term study from the Memorial Sloan Kettering Cancer Center found a 11% risk of dementia in patients at one year following treatment with 3.0 Gy fraction sizes or greater [DeAngelis 1989]. Therefore, many institutions have adopted the 2.5 Gy fraction size as the standard protocol for patients with a good prognosis.

Although most patients with brain metastases succumb to systemic cancer progression, there is aselect subgroup of patients with good performance status and limited systemic disease who are likely to die of neurological progression if treated by WBRT alone. Aggressive surgical resection provides better local control of brain metastases in these patients and can markedly prolong survival. Patchell et al. demonstrated, in a randomized trial of patients with a single brain metastasis, that surgery and WBRT resulted in survival of 40 weeks versus 15 weeks with WBRT alone [Patchell 1990]. Vecht et al. reported similar results [Vecht 1993]. The necessity of administering WBRT following surgical resection of metastases is controversial. After complete surgical resection of a single metastasis (confirmed by post-operative magnetic resonance imaging (MRI)), Patchell et al. demonstrated in a second prospective randomized trial that the addition of WBRT markedly decreased the incidence of local recurrence (46% versus 10%), distant brain recurrence (37% versus 14%), and death from a neurologic cause (44% versus 14%) [Patchell 1998]. There was no effect on overall survival or duration of functional independence, presumably due to successful salvage measures in the surgery alone group (delayed WBRT), or detrimental neurocognitive effects from WBRT. Surgery cannot be offered to all patients because many are poor medical candidates or have lesions in locations not amenable to resection. In addition, patients with multiple lesions have rarely been offered surgery because the morbidity was felt to be excessive [Kondziolka 1999].

Stereotactic radiosurgery (SRS) is less invasive than conventional surgery and has become an increasingly accepted method of treating brain metastases due to the high rate of local control.SRS delivers high-dose radiation in a single session, to a stereotactically defined target volume, and minimizes the dose to surrounding normal tissue. Brain metastases are ideal targets for SRS because most lesions are small, pseudo-spherical and well demarcated from the surrounding brain tissue. Rates of local control in large series have averaged 80% to 90% [Flickinger 1994]. Although there are no randomized trials directly comparing SRS to surgery, the preponderance of retrospective data supports the equivalence of the modalities for small, single lesions. For instance, a retrospective, matched comparison analysis of 108 patients concluded that survival for patients with a single metastasis was similar whether they received SRS alone or surgery and WBRT [Muacevic 1999]. A subgroup of patients who have multiple metastases may benefit from the addition of SRS to WBRT. A randomized trial from the University of Pittsburgh, of patients with two to four metastases, found a non-significant survival advantage for patients who received SRS + WBRT (11 months) versus for patients who received WBRT alone (7.5 months). Local control at one year was 100% for patients who received SRS + WBRT versus 8% for those who received WBRT alone [Kondziolka 1999]. The results of the RTOG 9508 trial have been presented in abstract form. In the study, patients with one to three brain metastases were randomized to WBRT + SRS boost or to WBRT alone. A statistically significant survival advantage was demonstrated for the patients in the WBRT + SRS arm that had a solitary brain metastasis, RPA class I, age <50 years, or non-small cell lung cancer or any squamous cell cancer [Sperduto 2002]. At one year, local control was significantly better for the WBRT + SRS boost arm. As with excisional surgery, SRS is a focused treatment that would not be expected to address the risk of distant brain progression. Based on Patchell's randomized data, WBRT would be expected to decrease the risk of distant brain progression [Patchell 1990]. Nevertheless, the rolE of WBRT + SRS remains undefined. Retrospective data from the University of California atSan Francisco and the Memorial Sloan Kettering Cancer Center have demonstrated that freedom from progression of brain metastases was significantly worse for patients who received SRS alone versus those who received SRS + WBRT, (28% vs. 69% at 1 year). However, overall survival was similar due to successful salvage measures [Sneed 1999]. Similar data have been reported from the University of Pittsburgh [Flickinger 1994] and from the Karolinska Institute in Stockholm [Kihlstrom 1991]. These studies are subject to retrospective biases, such asdifferences in selection criteria for WBRT and type of salvage treatment given. At the current time, it is unclear whether the addition of conventional WBRT results in either survival advantage or decreased risk of neurological death. Even if there is no survival advantage quality of life may be improved and treatment may be cost effective, due to avoiding thepsychological distress of brain recurrence and the future need for subsequent salvage therapy. On the other hand, the potential side effects of WBRT, including fatigue, alopecia, cognitive decline, and diminished hearing, may result in a decreased quality of life for the patient.