Neurocognitive Impact of Whole Brain Radiation on Patients With Brain Metastases: Secondary Analysis of RTOG BR-0018

Reviewer: Charles B. Simone, II, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 1, 2007

Presenter: Young Kwok, MD
Presenter's Affiliation: University of Maryland Medical Center
Type of Session: Scientific


  • In studies involving the treatment of patients with brain metastases, survival and time to progression may not fully describe therapeutic effects. Since both brain metastases and the treatment modalities for these lesions can impact brain functioning, traditional survival and progression outcome measures may fail to describe neurocognitive, neuropsychiatric, and day-to-day functioning of patients.
  • RTOG BR-0018 was a prospective feasibility study of neurocognitive evaluation in patients treated with whole brain radiation (WBRT) for brain metastases (Regine WF, et al. Int J Radiat Oncol Biol Phys. 2004;58(5):1346-52.).    
  • Previously published findings from RTOG BR-0018 demonstrated that neurocognitive evaluation of patients with brain metastases is possible using the test battery employed in the study.
  • This secondary analysis aims to report on the impact of WBRT on neurocognitive and quality of life measures.

Materials and Methods

  • Patients were eligible for this study if they had histologic proof of a primary malignancy, measurable single or multiple brain metastases not amenable to radiosurgery, and neurologic function status of 0 to 2.
  • Participants underwent six distinct neurocognitive and quality of life testing evaluations at baseline, at the end of WBRT, and one month following the completed of irradiation. 
  • Patients were evaluated using the Mini-Mental State Exam (MMSE) for memory, attention and cognition, Hopkins Verbal Learning Test (HVLT) for memory, Verbal Fluency/Controlled Word Association Test (COWAT) for executive functioning, verbal learning, working memory and vocabulary, Ruff 2 and 7 for selective attention, and Trailmaking Test A and B (TMT-A, TMT-B) for focused attention and speed performance. The Profile of Mood States Short Form (POMS) was used to evaluate quality of life by assessing six distinct and transient moods, including tension, anger, depression, vigor, fatigue, and confusion.
  • Radiation consisted of WBRT administered to a total dose of 37.5 Gy in 15 daily fractions.


  • Between November 2000 and August 2001, 59 patients were accrued to RTOG BR-0018. Fifty-five patients were analyzable and included in this secondary analysis. Median follow-up was 56 days.
  • At one month, intracranial progression was seen in 7% of patients.
  • At the time of completion of WBRT, three of four subtests evaluated by HVLT declined. At one month following WBRT, two HVLT returned to baseline levels and two subtests improved above the baseline.
  • All three subtests examined by Ruff 2 and 7 declined at the time of WBRT completion. At one month follow-up, two subsets improved above baseline, while the third continued to decline. 
  • TMT-A and TMT-B scores declined by end of WBRT but were improved over baseline at one month follow-up. 
  • Although COWAT evaluation declined at the end of irradiation, levels returned to baseline one month following WBRT.
  • MMSE score were improved or stable in 53% of patients immediately following WBRT and 63% one month after irradiation.
  • POMS mood scores overall were improved or stable in 53% to 86% of patients by the end of WBRT and 42% to 78% of patients one month following the completion of irradiation. 
  • Analysis of individual mood disorders revealed an improvement or stability of tension in 80% of patients, anger in 74%, depression in 86%, vigor in 54%, fatigue in 53%, and confusion in 84%. By one month following irradiation, improvement or stability was reported for tension in 68% of patients, anger in 75%, depression in 77%, vigor in 42%, fatigue in 47%, and confusion in 78%.

Author's Conclusions

  • Although WBRT has been frequently cited as the primary cause of neurocognitive decline in patients with brain metastases, this study reveals that WBRT can improve quality of life and neurocognitive indices above baseline by one month following irradiation in patients with brain metastasis. 
  • Intracranial tumor progression, irrespective of systemic disease progression, may account for the primary cause of neurocognitive decline in patients with brain metastasis.

Clinical/Scientific Implications

WBRT has been shown to reduce recurrence rates for patients with brain metastases and decrease the likelihood that these patients will die of neurologic causes. However, many physicians share concerns that WBRT leads to cognitive side effects and dementia-like symptoms in patients receiving treatment. Although patients with brain metastases typically do not live long enough to experience late radiation toxicity, concerns of acute cognitive toxicity have hindered patient referrals to radiation oncologists to administer WBRT in this patient population. In a recently published phase III trial involving 208 patients with brain metastases, tumor progression was demonstrated to adversely affect neurocognitive function more strongly than did WBRT (Li J, et al. J Clin Oncol. 2007;25(10):1260-6.). This RTOG BR-0018 analysis gives additional credence to the findings by Li J, et al and demonstrates that WBRT can improve quality of life and neurocognitive indices above baseline by one month following WBRT in patients with brain metastasis. It should be noted, however, that there was no randomization or adjusted analysis for patients who did or did not received corticosteroids in this study. Future investigation should control for corticosteroid usage due to their known ability to impact neurocognitive functioning and mood. Additionally, as results were only reported at up to one month following WBRT, additional investigation will be needed to evaluate for late effects of irradiation on neurocognitive functioning and patient quality of life.

Partially funded by an unrestricted educational grant from Bristol-Myers Squibb.