Introduction: This study was designed to examine whether gamma knife radiosurgery (GKRS) alone for patients with 5-10 brain metastases (BMs) is not inferior to that for patients with 2-4 BMs in terms of overall survival and other clinical results.

Methods: This was a prospective observational study of GKRS-treated patients with 1-10 newly-diagnosed BMs (<10 cc volume of the largest tumor, <15 cc total tumor volume, no findings of meningeal dissemination and KPS <70%) enrolled at 23 facilities in Japan. No attempt at pre-treatment randomization was made. The primary endpoint was overall survival and the secondary endpoints were neurological death, neurological deterioration, local recurrence, appearance of new lesions and meningeal dissemination, repeat GKRS, salvage WBRT, GKRS-induced complications and NCF maintenance.

Results: The recruitment period was from February 2009 to February 2012. There were 1194 eligible patients (471 females, 723 males, mean age; 66 [range; 30-91] years). The database was finalized at the end of November 2012. No interim analyses were attempted. The 1194 patients were categorized into three tumor number groups, i.e., group-A; 1 (455), group-B; 2-4 (531) and group-C; 5-10 (208). Post-GKRS median survival time (MST) was significantly longer in group-A than in group-B (13.9 vs 10.9 months, hazard ratio [HR]; 0.762 [95% CI; 0.656-0.884], p=0.001) and group-C (13.9 vs 10.8 months, HR; 0.787 [95% CI; 0.647-0.96], p=0.02). However, the post-GKRS MSTs did not differ between groups B and C (10.8 vs 10.8 months, HR; 0.974 [95% CI; 0.806-1.177], p=0.78). Among the secondary endpoints, the only significant difference was in meningeal dissemination cumulative incidence, between groups B and C (HR; 1.579, 95% CI; 1.041-2.395, p=0.03), as determined using competing risk analysis.

Conclusions: This study showed the non-inferiority of GKRS as the sole treatment for patients with 5-10 BMs as compared to those with 2-4 (evidence level II).

Patient Care: Stereotactic radiosurgery (SRS) alone for patients with ≥4, or even ≥5, metastatic tumors is not a standard treatment and whole brain radiotherapy (WBRT) is strongly recommended in most industrialized nations. However, decrease of neurocognitive function occurs, with a relatively higher incidence, in longer surviving patients who had undergone WBRT. Such post-WBRT complications can be minimized by SRS alone treatment for patients with multiple brain metastases. Furthermore, the availability of an alternative treatment for multiple brain metastases allows WBRT to be reserved for subsequent treatment attempts, i.e., for meningeal dissemination or miliary metastases treatable only with WBRT.

Learning Objectives: Based on our prospective observational study including 1194 patients with brain metastases, we present the non-inferiority of gamma knife radiosurgery as the sole treatment for patients with 5-10 brain metastase as compared to those with 2-4 (evidence level II).

References: Yamamoto M, Ide M, Nishio S, Urakawa Y: Gamma knife radiosurgery for numerous brain metastases: Is this a safe treatment? Int J Radiat Oncol Biol Phys 53:1279-1283, 2002. Yamamoto M, Kawabe T, Barfod BE: How many metastases can be treated with radiosurgery? Prog Neurol Surg 25:261-272, 2012 Knisely JPS, Yamamoto M, Gross CP, Castrucci WA, Jokura H, Chiang VLS: Radiosurgery alone for five or more brain metastases: Expert opinion survey. J Neurosurg 113(Suppl):84-89, 2010. Yamamoto M, Kawabe T, Sato Y, Higuchi Y, Nariai T, Barfod BE, Kasuya H, Urakawa Y: A case-matched study of stereotactic radiosurgery for patients with multiple brain metastases: comparing treatment results for 1-4 vs =5 tumors. J Neurosurg (accepted for publication on March 17, 2013)