Elsevier

The Lancet Oncology

Volume 10, Issue 11, November 2009, Pages 1037-1044
The Lancet Oncology

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Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial

https://doi.org/10.1016/S1470-2045(09)70263-3Get rights and content

Summary

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.

Findings

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.

Interpretation

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.

Funding

No external funding was received.

Introduction

About 170 000 new brain metastases are diagnosed in the USA each year.1 For over 50 years, whole brain radiotherapy (WBRT) has served as the standard palliative treatment for brain metastases. More recently, randomised trials have established the added survival benefit of either surgery or stereotactic radiosurgery (SRS) combined with WBRT over WBRT alone for patients with single brain metastases,2, 3, 4 raising questions about the role of WBRT and its possible effect on neurocognitive function.

A strategy to preserve neurocognition in patients with one to three newly diagnosed brain metastases is to use SRS alone with clinical monitoring to defer or completely avoid WBRT.5 However, SRS plus WBRT is frequently given to maximise disease control, since the omission of WBRT increases the risk of recurrent brain metastases.6, 7, 8, 9, 10 We did a randomised controlled trial to help clarify whether elective WBRT should be given with SRS, or deferred. We proposed that patients treated with SRS plus WBRT would have inferior neurocognitive function based on the Hopkins Verbal Learning Test–Revised (HVLT–R) compared with patients treated with SRS alone.

Section snippets

Patients

Eligible patients who presented at the Departments of Radiation Oncology, and Neurosurgery, and at the Brain and Spine Center, MD Anderson Cancer Center, Houston, TX, USA, were recruited to the study. Eligibility requirements were: age 18 years or greater; recursive partitioning analysis (RPA) class one or two (Karnofsky Performance Status [KPS] ≥70); one to three newly diagnosed brain metastases eligible for SRS; brain MRI within 1 month of enrolment; and signed written informed consent. A

Results

58 patients were enrolled and randomly assigned to SRS alone (n=30) or SRS plus WBRT (n=28) from Jan 2, 2001, to Sept 14, 2007 (figure 1) before the trial was halted by the data monitoring committe. The date of last follow-up was Oct 20, 2008. Patient characteristics are presented in table 1. The median follow-up was 9·5 months (range 0·3–66) for the entire study. For the SRS alone group, the median SRS tumour margin dose was 19 Gy (range 15–20). For the SRS plus WBRT group, the median SRS

Discussion

Patients randomly assigned to SRS plus WBRT were more likely to show a significant drop in HVLT–R total recall at 4 months than were patients randomly assigned to SRS alone (52% vs 24%, respectively), despite the fact that patients in the SRS alone group showed a higher overall brain tumour recurrence than did those patients in the SRS plus WBRT group. This finding persisted at 6-month follow-up.

We proposed that memory would be likely to be affected by radiation therapy, given the adverse

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