Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.
BACKGROUND
It is unclear whether the benefit of adding whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) for the control of brain-tumours outweighs the potential neurocognitive risks. We proposed that the learning and memory functions of patients who undergo SRS plus WBRT are worse than those of patients who undergo SRS alone. We did a randomised controlled trial to test our prediction.


METHODS
Patients with one to three newly diagnosed brain metastases were randomly assigned using a standard permutated block algorithm with random block sizes to SRS plus WBRT or SRS alone from Jan 2, 2001, to Sept 14, 2007. Patients were stratified by recursive partitioning analysis class, number of brain metastases, and radioresistant histology. The randomisation sequence was masked until assignation, at which point both clinicians and patients were made aware of the treatment allocation. The primary endpoint was neurocognitive function: objectively measured as a significant deterioration (5-point drop compared with baseline) in Hopkins Verbal Learning Test-Revised (HVLT-R) total recall at 4 months. An independent data monitoring committee monitored the trial using Bayesian statistical methods. Analysis was by intention-to-treat. This trial is registered at www.ClinicalTrials.gov, number NCT00548756.


RESULTS
After 58 patients were recruited (n=30 in the SRS alone group, n=28 in the SRS plus WBRT group), the trial was stopped by the data monitoring committee according to early stopping rules on the basis that there was a high probability (96%) that patients randomly assigned to receive SRS plus WBRT were significantly more likely to show a decline in learning and memory function (mean posterior probability of decline 52%) at 4 months than patients assigned to receive SRS alone (mean posterior probability of decline 24%). At 4 months there were four deaths (13%) in the group that received SRS alone, and eight deaths (29%) in the group that received SRS plus WBRT. 73% of patients in the SRS plus WBRT group were free from CNS recurrence at 1 year, compared with 27% of patients who received SRS alone (p=0.0003). In the SRS plus WBRT group, one case of grade 3 toxicity (seizures, motor neuropathy, depressed level of consciousness) was attributed to radiation treatment. In the group that received SRS, one case of grade 3 toxicity (aphasia) was attributed to radiation treatment. Two cases of grade 4 toxicity in the group that received SRS alone were diagnosed as radiation necrosis.


CONCLUSIONS
Patients treated with SRS plus WBRT were at a greater risk of a significant decline in learning and memory function by 4 months compared with the group that received SRS alone. Initial treatment with a combination of SRS and close clinical monitoring is recommended as the preferred treatment strategy to better preserve learning and memory in patients with newly diagnosed brain metastases.
Department of Radiation Oncology, The University of Texas, M D Anderson Cancer Center, Houston, TX, USA. echang@mdanderson.org
Eric L
EL
Chang
Jeffrey S
JS
Wefel
Kenneth R
KR
Hess
Pamela K
PK
Allen
Frederick F
FF
Lang
David G
DG
Kornguth
Rebecca B
RB
Arbuckle
J Michael
JM
Swint
Almon S
AS
Shiu
Moshe H
MH
Maor
Christina A
CA
Meyers
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001499:Bayes Theorem; D001932:Brain Neoplasms / Q000401:mortality / Q000523:psychology / Q000532:radiotherapy* / Q000556:secondary / Q000601:surgery*; D003071:Cognition / Q000528:radiation effects*; D016371:Cranial Irradiation / Q000009:adverse effects*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008568:Memory / Q000528:radiation effects*; D008875:Middle Aged; D009483:Neuropsychological Tests; D018579:Patient Selection; D016016:Proportional Hazards Models; D011832:Radiation Injuries / Q000209:etiology* / Q000523:psychology; D016634:Radiosurgery; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects; D018570:Risk Assessment; D016879:Salvage Therapy; D013997:Time Factors; D016896:Treatment Outcome; D014706:Verbal Learning / Q000528:radiation effects*