What is the clinical benefit of adjuvant whole brain radiotherapy following resection or stereotactic radiosurgery to the brain metastasis(es)?

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Introduction

Patients with one to three brain metastases may undergo surgical resection or stereotactic radiosurgery. The question then is whether whole brain radiotherapy is necessary in this setting.

Radiotherapy dose and fractionation for adjuvant whole brain radiotherapy

Clinical benefit of adjuvant whole brain radiotherapy

Patchell et al randomised patients with a solitary brain metastasis which had been resected to observation or adjuvant whole brain radiotherapy (WBRT).[1] Patients with both active and stable systemic disease were included. The addition of whole brain radiotherapy significantly reduced brain recurrences from 70% to 18% and reduced death from neurological causes from 44% to 14%. However there was no significant difference in median survival (48 weeks WBRT arm versus 43 weeks observation arm) or time of functional independence (37 weeks WBRT arm versus 35 weeks observation arm).

Aoyama et al conducted a similar study randomising patients with one to four brain metastases to stereotactic radiosurgery (SRS) alone or stereotactic radiosurgery followed by whole brain radiotherapy.[2] They found no difference in survival (median 7.5 months WBRT arm versus 8 months SRS alone arm), performance status or neurological function. Adjuvant whole brain radiotherapy did reduce actuarial brain recurrences at 12 months from 64% to 42%.

The largest trial examining this question has been conducted by the EORTC in patients with one to three brain metastases and stable systemic disease.[3] 359 underwent either surgical resection or stereotactic radiosurgery and were randomised to adjuvant whole brain radiotherapy or observation. The primary endpoint of the trial, survival with functional independence was similar between the arms. The median time to WHO performance status 2 was 10 months in the observation arm and 9.5 months in the WBRT arm. Median survival was also similar being 10.9 months in the observation arm and 10.7 months in the WBRT arm. The addition of WBRT significantly reduced intracranial progression from 78% to 48% and neurological deaths from 44% to 28%.

Sahgal et al conducted a meta-analysis of three randomised trials evaluating SRS with or without adjuvant WBRT.[4] Distant brain failures were reduced from 53% to 34% with adjuvant WBRT, and neurological deaths from 30% to 25%. Median survival was similar being 10 months with SRS alone and 8.2 months with SRS and WBRT.

A Cochrane systematic review of the same three trials included in the Sahgal et al meta-analysis concluded that the addition of WBRT following SRS significantly improved local brain metastasis control and distant brain control without any statistically difference in overall survival.[5]

WBRT has an impact on patients’ quality of life. The EORTC randomised trial is the only trial which has measured this prospectively. Patients receiving WBRT had worse Health Related Quality of Life scores than the observation group.[6] This was significant for physical functioning and fatigue at 8 weeks, global health status at 9 months, and cognitive functioning at 12 months after treatment.

The commonest dose for adjuvant WBRT was 30Gy in 10 fractions.[3][2] This dose was associated with mild acute toxicity (13% brisk skin erythema or dry desquamation, 10% moderate to severe nausea or vomiting, 4% severe headache).[3] Late Grade 3 effects occurred in 2-22% and Grade 4 1-4% with no difference between the observation and WBRT arms in the EORTC study.[3] The WBRT dose was higher in the Patchell study (50.4Gy in 28 fractions) and toxicity was not reported.

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Evidence summary and recommendations

Evidence summary Level References
Adjuvant whole brain radiotherapy following surgical resection or radiosurgery for one to three brain metastases reduces brain recurrences and neurological deaths.

Last reviewed September 2015

I, II [3], [4], [5]
Adjuvant whole brain radiotherapy following surgical resection or radiosurgery for one to three brain metastases does not improve survival or patient functional status.

Last reviewed September 2015

I, II [3], [4], [5]
Adjuvant whole brain radiotherapy following surgical resection or radiosurgery for one to three brain metastases is associated with a reduction in health related quality of life.

Last reviewed September 2015

II [6]
Evidence-based recommendationQuestion mark transparent.png Grade
Routine adjuvant whole brain radiotherapy is not recommended following surgical resection or radiosurgery for brain metastases.

Last reviewed September 2015

A


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References

  1. Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998 Nov 4;280(17):1485-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9809728.
  2. 2.0 2.1 Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006 Jun 7;295(21):2483-91 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16757720.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 2011 Jan 10;29(2):134-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21041710.
  4. 4.0 4.1 4.2 Sahgal A, Aoyama H, Kocher M, Neupane B, Collette S, Tago M, et al. Phase 3 Trials of Stereotactic Radiosurgery With or Without Whole-Brain Radiation Therapy for 1 to 4 Brain Metastases: Individual Patient Data Meta-Analysis. Int J Radiation Oncol Biol Phys 2015;91(4):710-717 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25752382.
  5. 5.0 5.1 5.2 Tsao MN, Lloyd N, Wong RK, Chow E, Rakovitch E, Laperriere N, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 2012 Apr 18;4:CD003869 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22513917.
  6. 6.0 6.1 Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG, et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol 2013 Jan 1;31(1):65-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23213105.

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Appendices

Further resources

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