Observational studyBrain tumours

Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study

Lancet Oncol · 20141194 patients

Yamamoto M, Serizawa T, Shuto T, et al. Lancet Oncol. 2014. 15:387-395

Study type: Observational study
Study name: JLGK0901
Design: Multicentre prospective observational study (23 Gamma Knife centres in Japan) with a non-inferiority design; registered as UMIN000001812
Sample size: 1194 patients
Source: Lancet Oncol · 2014

In plain words

In the past, if there were more than 3 or 4 brain metastases, whole-brain radiotherapy was usually given, which can affect memory. This large Japanese study showed that in patients with 5 to 10 small metastases (with a limited total volume), treatment with radiosurgery (Gamma Knife) alone gave the same length of life as in patients with 2 to 4 metastases, and serious side effects were uncommon. So for many patients with a moderate number of brain metastases, whole-brain radiotherapy can also be avoided.

Key results

10.8 vs 10.8 months

Median overall survival (2–4 vs 5–10 tumours)

HR 0.97 (95% CI 0.81–1.18); p=0.78; p for non-inferiority<0.0001

13.9 months

Median overall survival with 1 tumour

95% CI 12.0–15.6

8% (101 patients)

Radiosurgery-induced adverse events

Grade 3–4 events: 2% (1 tumour), 2% (2–4), 3% (5–10)

Dose and schedule cards

Stereotactic radiosurgery (N0574 and JLGK0901)

1 to 3 metastases smaller than 3 cm (N0574); in the JLGK0901 study, up to 10 metastases with the largest lesion smaller than 10 mL and a total volume of no more than 15 mL, KPS 70 or higherOn the page “Brain tumours” · Brain metastases: local treatment

1 to 3 metastases smaller than 3 cm (N0574); in the JLGK0901 study, up to 10 metastases with the largest lesion smaller than 10 mL and a total volume of no more than 15 mL, KPS 70 or higher

Drug	Dose	Route	Schedule
SRS alone (N0574)
Single-fraction radiosurgery	24 Gy for lesions smaller than 2 cm; 20 Gy for 2 to 2.9 cm	Radiosurgery	One session
JLGK0901 (Gamma Knife)
Single-fraction radiosurgery	22 Gy at the margin for lesions smaller than 4 mL; 20 Gy for 4 to 10 mL	Radiosurgery	One session
If WBRT is added (N0574)
Radiosurgery + whole-brain radiotherapy	SRS 22 or 18 Gy (depending on size) + WBRT 30 Gy in 12 fractions	Radiotherapy	WBRT within 14 days after SRS, 5 days a week

Duration: One SRS session (WBRT about 2.5 weeks)

Grade 3 to 4 adverse events of radiosurgery in JLGK0901 occurred in 2 to 3%. If whole-brain radiotherapy becomes necessary, memantine and hippocampal avoidance are recommended (next regimen).

On the page “Brain tumours” · Brain metastases: local treatment

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

11-tumour group

455 patients; stereotactic radiosurgery (Gamma Knife) without WBRT: tumours smaller than 4 mL received 22 Gy and tumours of 4 to 10 mL received 20 Gy at the lesion margin.

22–4-tumour group

531 patients; same radiosurgery protocol without WBRT.

35–10-tumour group

208 patients; same radiosurgery protocol without WBRT.

Source of the regimen details: The radiosurgery dose (22 Gy for tumours smaller than 4 mL and 20 Gy for tumours of 4 to 10 mL at the lesion margin) is stated in the published abstract of the Lancet Oncol 2014 paper.

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with 1 to 10 newly diagnosed brain metastases; largest lesion less than 10 mL in volume and less than 3 cm in diameter; total cumulative tumour volume ≤15 mL; Karnofsky performance score 70 or higher.

Endpoints

Primary endpoint: overall survival; non-inferiority comparison of patients with 5 to 10 tumours versus 2 to 4 tumours (non-inferiority margin: upper limit of the 95% CI for the HR of 1.30).

Other endpoints: radiosurgery-induced adverse events and neurocognitive function.

Safety and side effects

Radiosurgery-induced adverse events occurred in 101 patients (8%). Grade 3–4 events: 9 patients (2%) in the 1-tumour group, 13 patients (2%) in the 2–4-tumour group and 6 patients (3%) in the 5–10-tumour group. The proportion of patients with any treatment-related adverse event did not differ between the two multiple-tumour groups (9% versus 9%; p=0.89). Four patients died, mainly because of radiosurgery complications.

Clinical significance and place in guidelines

This study is the main basis for extending radiosurgery to patients with 5 to 10 brain metastases. The EANO-ESMO 2021 guideline states that radiosurgery can be considered for patients with a larger number of metastases (5 to 10) and a cumulative tumour volume below 15 mL [EANO: II, B; ESMO: II, B].

Limitations

The study is observational and non-randomised (a comparison between patient groups, not between two treatments); there was no WBRT comparison group. Patients were carefully selected (cumulative volume ≤15 mL, KPS ≥70) and all were treated at experienced Gamma Knife centres in Japan. Neurocognitive outcomes were not presented in this initial report.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.