Local tumor progression treated with Gamma Knife radiosurgery: differences between patients with 2–4 versus 5–10 brain metastases based on an update of a multi-institutional prospective observational study (JLGK0901)

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OBJECTIVE

The Japanese Leksell Gamma Knife (JLGK)0901 study proved the efficacy of Gamma Knife radiosurgery (GKRS) in patients with 5–10 brain metastases (BMs) as compared to those with 2–4, showing noninferiority in overall survival and other secondary endpoints. However, the difference in local tumor progression between patients with 2–4 and those with 5–10 BMs has not been sufficiently examined for this data set. Thus, the authors reappraised this issue, employing the updated JLGK0901 data set with detailed observation via enhanced MRI. They applied sophisticated statistical methods to analyze the data.

METHODS

This was a prospective observational study of 1194 patients harboring 1–10 BMs treated with GKRS alone. Patients were categorized into groups A (single BM, 455 cases), B (2–4 BMs, 531 cases), and C (5–10 BMs, 208 cases). Local tumor progression was defined as a 20% increase in the maximum diameter of the enhanced lesion as compared to its smallest documented maximum diameter on enhanced MRI. The authors compared cumulative incidence differences determined by competing risk analysis and also conducted propensity score matching.

RESULTS

Local tumor progression was observed in 212 patients (17.8% overall, groups A/B/C: 93/89/30 patients). Cumulative incidences of local tumor progression in groups A, B, and C were 15.2%, 10.6%, and 8.7% at 1 year after GKRS; 20.1%, 16.9%, and 13.5% at 3 years; and 21.4%, 17.4%, and not available at 5 years, respectively. There were no significant differences in local tumor progression between groups B and C. Local tumor progression was classified as tumor recurrence in 139 patients (groups A/B/C: 68/53/18 patients), radiation necrosis in 67 (24/31/12), and mixed/undetermined lesions in 6 (1/5/0). There were no significant differences in tumor recurrence or radiation necrosis between groups B and C. Multivariate analysis using the Fine-Gray proportional hazards model revealed age < 65 years, neurological symptoms, tumor volume ≥ 1 cm3, and prescription dose < 22 Gy to be significant poor prognostic factors for local tumor progression. In the subset of 558 case-matched patients (186 in each group), there were no significant differences between groups B and C in local tumor progression, nor in tumor recurrence or radiation necrosis.

CONCLUSIONS

Local tumor progression incidences did not differ between groups B and C. This study proved that tumor progression after GKRS without whole-brain radiation therapy for patients with 5–10 BMs was satisfactorily treated with the doses prescribed according to the JLGK0901 study protocol and that results were not inferior to those in patients with a single or 2–4 BMs.

Clinical trial registration no.: UMIN000001812 (umin.ac.jp)

ABBREVIATIONS BM = brain metastasis; CITV = cumulative intracranial tumor volume; ECD = extracranial disease; EGFR = epidermal growth factor receptor; GKRS = Gamma Knife radiosurgery; JLGK = Japanese Leksell Gamma Knife; KPS = Karnofsky Performance Status; RANO = Response Assessment in Neuro-Oncology; SRS = stereotactic radiosurgery; TKI = tyrosine kinase inhibitor; WBRT = whole-brain radiation therapy.

Article Information

Correspondence Toru Serizawa: Tsukiji Neurological Clinic, Tokyo, Japan. gamma-knife.serizawa@nifty.com.

INCLUDE WHEN CITING Published online April 26, 2019; DOI: 10.3171/2019.1.JNS183085.

T. Serizawa and M. Yamamoto contributed equally to this study.

Disclosures Dr. Jokura is a consultant for Elekta. This study received financial support from the Japan Brain Foundation (nongovernmental organization).

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Cumulative incidences of local tumor progression according to tumor number groups (1194 patients). Cumulative local tumor progression incidences determined with competing risk analysis of groups A (single lesion), B (2–4 BMs), and C (5–10 BMs) were 15.2%, 10.6%, and 8.7% at 1 year after GKRS; 20.1%, 16.9%, and 13.5% at 3 years; and 21.4%, 17.4%, and not available at 5 years, respectively. Local tumor progression was mostly observed within 3 years after GKRS (196 cases [92.5%]). There were no significant differences among the three groups. Cases lacking enhanced MRI follow-up were excluded from the number at risk (group A, 41 cases; group B, 57; group C, 21; total, 119). Figure is available in color online only.

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    Cumulative incidences of local tumor progression according to tumor volume (1194 cohort patients). Cumulative local tumor progression incidences with small, medium, and large tumor volumes were 6.5%, 13.3%, and 21.0% at 1 year after GKRS; 10.8%, 17.1%, and 25.9% at 2 years; 12.3%, 18.1%, and 19.4% at 3 years; 12.8%, 19.4%, and 27.1% at 4 years; and 21.0%, 27.1%, and 28.2% at 5 years, respectively. There were significant differences between pairs of the three groups (p values for small vs medium, medium vs large, small vs large: 0.0054, 0.0085, <0.0001). Cases lacking enhanced MRI follow-up were excluded from the number at risk (small, 44 cases; medium, 50; large, 25; total, 119). Figure is available in color online only.

  • View in gallery

    Cumulative incidences of local tumor progression according to tumor number groups (558 case-matched patients). Cumulative incidences of local tumor progression at 1, 3, and 5 years after GKRS were 13.4%, 17.8%, and 19.8% in group A (single lesion); 12.9%, 20.0%, and 20.6% in group B (2–4 BMs); and 8.1%, 12.9%, and not available in group C (5–10 BMs), respectively. There were no statistically significant differences between any pairs of the three tumor number groups (p values for A vs C, A vs B, and B vs C: 0.22, 0.70, 0.10). Cases lacking enhanced MRI follow-up were excluded from the number at risk (group A, 16 cases; group B, 21; group C, 19; total, 56). Figure is available in color online only.

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