Clinical trialPhase 3Brain tumours

Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial

JAMA · 2016213 patients (111 radiosurgery alone, 102 radiosurgery + WBRT)

Brown PD, Jaeckle K, Ballman KV, et al. JAMA. 2016. 316:401-409

Study type: Clinical trial
Study name: N0574 (Alliance)
Phase: Phase 3
Design: Multicentre randomised trial (34 centres in North America, NCCTG/Alliance group), 1:1 randomisation, open-label (patients and physicians knew the assigned treatment, but the neuropsychologists scoring the cognitive tests were blinded)
Sample size: 213 patients (111 radiosurgery alone, 102 radiosurgery + WBRT)
Source: JAMA · 2016
Trial registration: NCT00377156

In plain words

When cancer has spread to the brain and there are only a few spots (1 to 3), they can be treated with radiosurgery (very precise, focused radiation aimed at the spots themselves, such as Gamma Knife). This study showed that adding radiotherapy to the whole brain on top of radiosurgery, although it lowers the chance of new spots appearing in the brain, does not help people live longer and clearly causes more decline in memory and thinking and a lower quality of life. For this reason, radiosurgery alone with regular MRI scans is usually recommended for these patients today.

Key results

63.5% vs 91.7%

Cognitive deterioration at 3 months

SRS alone (40 of 63) vs SRS + WBRT (44 of 48); difference −28.2% (90% CI −41.9% to −14.4%); P<0.001

10.4 vs 7.4 months

Median overall survival

HR 1.02 (95% CI 0.75–1.38); P=0.92 (no significant difference)

HR 3.6, unfavourable for SRS alone

Time to intracranial failure

95% CI 2.2–5.9; P<0.001. 3-month intracranial control: 93.7% with WBRT vs 75.3% with SRS alone (full text)

−0.1 vs −12.0 points

Change in overall quality of life at 3 months

Mean difference 11.9 (95% CI 4.8–19.0); P=0.001

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

1Stereotactic radiosurgery (SRS) alone

Single-fraction SRS: 24 Gy for lesions smaller than 2 cm and 20 Gy for lesions 2 to 2.9 cm (prescribed to the highest isodose line encompassing the target, 50 to 80% of the maximum dose).

2SRS + whole-brain radiotherapy (WBRT)

Single-fraction SRS: 22 Gy for lesions smaller than 2 cm and 18 Gy for lesions 2 to 2.9 cm; plus WBRT 30 Gy in 12 fractions of 2.5 Gy, 5 days per week, starting within 14 days after SRS.

Source of the regimen details: SRS doses (20 to 24 Gy in the SRS-alone group; 18 to 22 Gy with WBRT) and WBRT (30 Gy in 12 fractions) are given in the published abstract of the JAMA 2016 paper; dose by lesion size, WBRT start timing and eligibility criteria from the “Study Treatment” and methods sections of the full text (author manuscript, PMC5313044).

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

Adults (18 years and older) with 1 to 3 brain metastases, each smaller than 3 cm, with a pathologically confirmed extracranial primary tumour (such as lung, breast, prostate) and ECOG 0 to 2; no prior surgical resection of brain metastases. Mean age 60.6 years; 48% women.

Endpoints

Primary outcome: cognitive deterioration at 3 months (decline of more than 1 standard deviation from baseline on at least one cognitive test).

Secondary outcomes: time to intracranial failure, quality of life, functional independence, long-term cognitive status and overall survival.

Safety and side effects

According to the full text, the proportion of patients with grade 3 or higher adverse events did not differ significantly between the groups. The main safety outcome in this study was cognitive deterioration, which was markedly more frequent with the addition of WBRT (91.7% versus 63.5%); among long-term survivors, cognitive deterioration at 12 months was also more frequent with WBRT (94.4% versus 60%).

Clinical significance and place in guidelines

This trial made SRS alone with regular MRI surveillance the preferred strategy for patients with 1 to 3 (and in guidelines 1 to 4) brain metastases. The EANO-ESMO 2021 guideline recommends radiosurgery for 1 to 4 brain metastases [EANO: I, A; ESMO: I, A] and considers WBRT after SRS or surgery “not recommended” [EANO: I, A; ESMO: I, E].

Limitations

A substantial number of patients did not complete the 3-month cognitive assessment (primary outcome analysis in 111 patients), which may introduce bias. Open-label design. Accrual was long (2002 to 2013), and today's brain-penetrant systemic therapies (tyrosine kinase inhibitors, immunotherapy) were not common at that time. Hippocampal-avoidance WBRT and memantine were not used.

Original article (DOI)PubMed ClinicalTrials.gov

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.