Protocol Summary

Amanda Tabar

This was a randomized phase III clinical trial aimed at comparing the effectiveness of

stereotactic radiation therapy (SRS) alone versus SRS combined with whole-brain radiation

therapy (WBRT) in treating patients with 1 to 3 brain metastases from extracranial cancers

(e.g., lung, breast, prostate). The study assessed several outcomes: including overall survival,

time to central nervous system (CNS) failure, quality of life, duration of independence,

cognitive status, and post-treatment toxicity.

The primary purpose of this trial was to determine whether the addition of WBRT to

SRS improved overall survival in patients with brain metastases; while secondary objectives

included evaluating neurocognitive status, tumor control, quality of life, and post-treatment

toxicity. The study design was randomized and multicenter; with patients grouped based on

age, disease status, and the number of brain metastases.

To quality for this study, participants had to have 1 to 3 brain metastases, each

measuring less than 3.0 cm, confirmed by contrast MRI within 21 days of start. They had to be

eligible for treatment with either gamma knife or linear accelerator-based radiosurgery.

Patients with primary germ cell tumors, small cell carcinoma, lymphoma, or leptomeningeal

metastases were excluded. Next, the trial randomly assigned participants to two treatment arms:

Arm I: Patients will undergo SRS alone. Arm II: Patients will receive SRS followed by WBRT

within 14 days.

The study assessed neurocognitive progression, local and distant tumor control at 3

months, overall quality of life from baseline to 3 months, long-term neurocognitive status at

12 months, and overall survival up to 5 years. The findings at the 3-month mark indicated that
patients who received WBRT + SRS experienced more cognitive decline compared to those

who received SRS alone (88.0% vs. 61.9%). Specifically, deterioration was observed in

immediate recall (31% vs. 8%), delayed recall (51% vs. 20%, p = 0.002), and verbal abilities

(19% vs. 2%). However, SRS + WBRT led to better intracranial tumor control at 6 and 12

months compared to SRS alone (66.1% and 50.5% vs. 88.3% and 84.9%). Nonetheless,

regardless of tumor control, overall survival did not extensively differ between the two

groups: with average survival being 10.7 months for SRS alone and 7.5 months for SRS +

WBRT.1

In conclusion, the addition of WBRT to SRS led to a higher frequency of cognitive

decline, particularly in immediate recall, memory, and verbal abilities. Despite improving brain

tumor control, the addition of WBRT to SRS did not result in improved overall survival. The

study authors recommended initial treatment with SRS as the best approach to preserve

cognitive function in patients with newly diagnosed brain metastases that are responsive to

SRS alone.
 References

1. Brown PD, Asher AL, Ballman KV, et al. NCCTG N0574 (Alliance): A phase III

randomized trial of whole brain radiation therapy (WBRT) in addition to

radiosurgery (SRS) in patients with 1 to 3 brain metastases.

2015;33(18_suppl):LBA4-LBA4. doi:https://doi.org/10.1200/

jco.2015.33.18_suppl.lba4

2. CTG Labs - NCBI. clinicaltrials.gov. https://clinicaltrials.gov/study/NCT00377156

3. Stereotactic Radiation Therapy With or Without Whole-Brain Radiation Therapy in

Treating Patients With Brain Metastases - Full Text View - ClinicalTrials.gov.

clinicaltrials.gov. https://classic.clinicaltrials.gov/ct2/show/NCT00377156