Brain metastases develop in approximately 10% to 20% of cancer patients each year in the United States (~500,000 patients). With insufficient brain imaging to detect the number and location of the metastases, clinicians previously had no option other than empiric whole-brain radiation therapy (WBRT).[1,2] The development of better systemic targeted cancer therapies coupled with the recognition of the long-term deleterious effects of WBRT has spurred rapid expansion of the use of stereotactic radiosurgery (SRS).
Although current level I evidence supports the use of SRS in patients with up to four brain metastases, specialists are already treating patients with many more than four brain metastases. Outcomes after Gamma Knife surgery (GKS) for multiple brain metastases have been defined in a number of retrospective studies over the past 2 decades. Routinely, patients harboring as many as 20 or more metastases are successfully treated in a single, minimally invasive, outpatient procedure. In most retrospective series, a higher number of metastatic lesions has not been shown to change survival for patients with more than five brain metastases if all are treated. The total cumulative volume of brain metastases, Karnofsky performance score (KPS), older age, and control of systemic disease are much more important factors that affect survival.
In a retrospective study by Bhatnagar et al, median overall survival (OS) in patients with four or more brain metastases was 8 months after treatment with SRS, and higher intracranial burden (but not the number of brain metastases) predicted poorer outcomes. Grandhi et al studied 61 patients with 10 or more brain metastases (a total of 806 tumors [mean, 13.2 lesions]) who underwent SRS. The median survival for a patient with fewer than 14 brain metastases, nonmelanomatous primary tumor, and controlled systemic disease was 21 months. Sustained local tumor control was achieved in 81% of patients. Mohammadi et al retrospectively evaluated OS and factors predicting outcome in 170 patients with more than five brain metastases treated with GKS. Median OS after GKS was 6.7 months. Lower KPS, patient age younger than 60 years, multiple extracranial metastases, and greater intracranial burden of disease (volume) were prognostic factors for poor outcome. These studies suggest that the number of brain metastases (1–4 vs > 5) do not affect the outcome, but rather it is the total tumor burden that may impact local tumor control and patient survival. The tumor burden depends upon the size, not the number, of brain metastases. For example, the total volume of a single spherical brain metastasis with a 3-cm diameter is approximately 14 mL, while total volume of 10 brain tumors each measuring 1 cm in maximum diameter has only 5 mL total volume.
In a study of 26 patients with 10 or more brain metastases each, Kim et al observed a median OS of 34 weeks after SRS. The tumor control rate was 86.9% and 79.5% at 3 and 6 months, respectively, following treatment. On univariate analysis, synchronous time of discovering brain metastases, a higher KPS, and controlled primary disease were positive prognostic factors. The use of upfront WBRT, tumor volume, number of metastases, and tumor margin dose had no significant effect on survival. In a retrospective study, Serizawa et al compared the outcomes after GKS and WBRT for the treatment of up to 10 brain metastases from non–small-cell lung cancer in 96 patients. The tumor control rate was 94.8% 1 year after therapy. Both the estimated OS and estimated intervals free from neurologic death were significantly higher in the GKS group (mean survival time, 377 days vs 199 days). Univariate analysis revealed that systemic control, treatment method, and pathologic composition were prognostic for survival, whereas multivariate analyses confirmed that systemic control and treatment method, as well as KPS, were positively prognostic. These studies again highlight the fact that although some physicians may consider the number of brain metastases as an indicator of their prognosis, this has not been substantiated in long-term studies; they also suggest that systemic disease burden, patients’ functional status, and the type of treatment offered may be more important for overall prognosis than the number of brain metastases.
Serizawa et al evaluated the results of patients with 1 to 10 brain metastases receiving GKS alone. Seven hundred seventy-eight consecutive cases met inclusion criteria. On multivariate analysis, adverse prognostic factors for OS were active systemic disease, poor (< 70) initial KPS, and male gender. The mean survival for these patients was 7 months. Neurologic survival and qualitative survival rates at 1 year were 92.7% and 88.2%, respectively. New lesion–free survival at 6 months and 1 year were 69.8% and 43.8%, respectively. Yamamoto et al enrolled 1,194 patients with brain metastases in an observational multi-institutional study. Median OS after SRS in all patients was 12 months, with no difference in median OS for patients with 2 to 4 tumors and 5 or more tumors. These data supported the hypothesis that the volume, and not the number, of metastases may be the driver in determining the outcomes of patients with brain metastases.
SRS achieves high rates of local progression-free survival for patients with treated lesions, and its efficacy may be less influenced by histology or radiosensitivity vs WBRT. Only a minority of patients experience adverse effects after SRS.
Collectively, the outcomes reported in retrospective and prospective studies, as well as the ability to salvage intracranial relapses with further application of SRS, have recently led to the use of SRS alone for patients with multiple brain metastases. During follow-up surveillance imaging (done every 3 months for the first year), newly recognized brain metastases can be effectively treated by repeat SRS. The current role of WBRT is reserved for patients who develop miliary brain disease or carcinomatous meningitis. This approach enhances neurocognitive outcomes and virtually eliminates the development of brain leukodystrophy, which can occur in patients who undergo WBRT.[11,12]
The aggressive management of brain metastases with SRS has supplanted radiation therapy in an effort to maintain patient quality of life in an era of advancing systemic cancer options. Death from brain progression is now rare. SRS for patients with one or many brain metastases provides a high rate of tumor control, a low risk of adverse effects, and does not delay systemic cancer management. SRS is now the standard of care for patients with newly diagnosed brain metastases.
Financial Disclosure: Dr. Niranjan has served as a consultant for the International Gamma Knife Research Consortium. Dr. Lunsford is a consultant and stockholder with AB Elekta; he is also a member of Insightec DSMB.
1. Delattre JY, Krol G, Thaler HT, Posner JB. Distribution of brain metastases. Arch Neurol. 1988;45:741-4.
2. Nussbaum ES, Djalilian HR, Cho KH, Hall WA. Brain metastases. Histology, multiplicity, surgery, and survival. Cancer. 1996;78:1781-8.
3. Bhatnagar AK, Flickinger JC, Kondziolka D, Lunsford LD. Stereotactic radiosurgery for four or more intracranial metastases. Int J Radiat Oncol Biol Phys. 2006;64:898-903.
4. Grandhi R, Kondziolka D, Panczykowski D, et al. Stereotactic radiosurgery using the Leksell Gamma Knife Perfexion unit in the management of patients with 10 or more brain metastases. J Neurosurg. 2012;117:237-45.
5. Mohammadi AM, Recinos PF, Barnett GH, et al. Role of Gamma Knife surgery in patients with 5 or more brain metastases. J Neurosurg. 2012;117(suppl):5-12.
6. Kim SH, Weil RJ, Chao ST, et al. Stereotactic radiosurgical treatment of brain metastases in older patients. Cancer. 2008;113:834-40.
7. Serizawa T, Iuchi T, Ono J, et al. Gamma knife treatment for multiple metastatic brain tumors compared with whole-brain radiation therapy. J Neurosurg. 2000;93(suppl 3):32-6.
8. Serizawa T, Hirai T, Nagano O, et al. Gamma knife surgery for 1-10 brain metastases without prophylactic whole-brain radiation therapy: analysis of cases meeting the Japanese prospective multi-institute study (JLGK0901) inclusion criteria. J Neurooncol. 2010;98:163-7.
9. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15:387-95.
10. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10:1037-44.
11. Monaco EA 3rd, Faraji AH, Berkowitz O, et al. Leukoencephalopathy after whole-brain radiation therapy plus radiosurgery versus radiosurgery alone for metastatic lung cancer. Cancer. 2013;119:226-32.
12. Stokes TB, Niranjan A, Kano H, et al. White matter changes in breast cancer brain metastases patients who undergo radiosurgery alone compared to whole brain radiation therapy plus radiosurgery. J Neurooncol. 2015;121:583-90.