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A Randomized Controlled Trial

Hidefumi Aoyama, MD, PhD; Hiroki Shirato, MD, PhD; Masao Tago, MD, PhD; Keiichi Nakagawa, MD, PhD; Tatsuya Toyoda, MD, PhD; Kazuo Hatano, MD, PhD; Masahiro Kenjyo, MD, PhD; Natsuo Oya, MD, PhD; Saeko Hirota, MD, PhD; Hiroki Shioura, MD, PhD; Etsuo Kunieda, MD, PhD; Taisuke Inomata, MD, PhD; Kazushige Hayakawa, MD, PhD; Norio Katoh, MD; Gen Kobashi, MD, PhD

JAMA. 2006;295:2483-2491.

Context  In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone.

Objective  To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death.

Design, Setting, and Patients  Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003.

Interventions  Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients).

Main Outcome Measures  The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death.

Results  The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation.

Conclusions  Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used.

Trial Registration  umin.ac.jp/ctr Identifier: C000000412

Author Affiliations: Departments of Radiology (Drs Aoyama, Shirato, and Katoh) and Global Health and Epidemiology, Division of Preventive Medicine (Dr Kobashi), Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Radiology, University of Tokyo Hospital, Tokyo, Japan (Drs Tago and Nakagawa); Department of Radiology, Kanto Medical Center NTT EC, Tokyo, Japan (Dr Toyoda); Department of Radiology, Chiba Cancer Center, Chiba, Japan (Dr Hatano); Department of Radiology, Hiroshima University School of Medicine, Hiroshima, Japan (Dr Kenjyo); Department of Radiology, Kyoto University School of Medicine, Kyoto, Japan (Dr Oya); Department of Radiology, Hyogo Medical Center for Adults, Akashi, Japan (Dr Hirota); Department of Radiology, Izumisano General Hospital, Izumisano, Japan (Dr Shioura); Department of Radiology, Keio University School of Medicine, Tokyo, Japan (Dr Kunieda); Department of Radiology, Osaka Medical College, Osaka, Japan (Dr Inomata); Department of Radiology, Kitazato Medical School, Sagamihara, Japan (Dr Hayakawa).

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