What is the clinical benefit of resection of brain metastasis?

From Cancer Guidelines Wiki

Introduction

Brain metastases manifest clinically approximately equally as multiple or single brain metastases.[1] The term “single brain metastasis” is more correctly used to describe an isolated brain metastasis found in a patient presenting with an inoperable lung cancer or from an uncontrolled primary tumour, whilst the term “solitary brain metastasis” is most correctly used when the brain metastasis is diagnosed after radical, potentially curative treatment and remains the only site of disease. [2]

After diagnosis of brain metastasis median survival is around one month. Survival may increase with the addition of corticosteroids to two months and with whole brain radiotherapy (WBRT) to three to six months. [1]

Most patients will not be suitable for surgery because of multiple lesions, a surgically inaccessible lesion location, active primary disease, or co-morbidity.

Up to 40% of patients with cancer are found at autopsy to harbor brain metastases [1] and around 40% of these are due to NSCLC [2], but despite the prevalence of the problem the majority of studies are retrospective or at best prospective phase 2 trials and include various primary tumour origins.

These studies of cohorts undergoing surgery and WBRT (most often for a variety of histologies, and including single, solitary and multiple brain metastases) consistently identify improved survival (with apparent cure in 2.5 – 5%) based on the following prognostic factors:

  1. Solitary brain metastasis;
  2. Single brain metastasis and control of extra cranial disease;
  3. Better performance status; and
  4. Younger age.

It is impossible to determined from these retrospective or single arm prospective studies if improvements in survival are attributable to the addition of surgery to WBRT or rather simply selection bias.

Surgery offers an opportunity for histological confirmation (in approximately 30% of patients there is an unknown primary site) and molecular analysis, which is increasingly important not only to confirm metastatic malignancy (up to 11% may have alternate diagnosis on biopsy[3]) but also to guide choice of systemic chemotherapy or targeted therapy.

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Clinical benefit of surgery plus WBRT compared to WBRT alone: Randomised controlled trials

Only three randomised trials have addressed the issue of the addition of surgery to WBRT. [3][4][5][6] These randomised trials in turn have included a wide range of histologies of the primary tumour and included highly selected populations so as to make their conclusions applicable to only a specific subset of patients. Limitations in the general applicability of the outcomes also relate to the time frame (1985 - 1993) of the studies and therefore imaging, surgical and radio therapeutic methods that are no longer ‘state of the art’.

Patchell et al[3]randomly assigned 48 patients at a single US center with single brain metastases from various primary sites (37 with NSCLC) to surgery plus 36Gy WBRT versus WBRT alone. Recurrence at original site (20% versus 50%, [p=0.02]); overall median survival (15 versus 40 weeks, [p=0.01]); and functional independence (8 versus 38 weeks, [p<0.005]) all favoured addition of surgery in a statistically and clinically significant manner. The only limitation to the quality of the study was that analysis was not undertaken on an 'intention to treat' basis i.e. six (11%) patients were excluded after initial biopsy.

Vecht et al [4][5] randomly assigned 63 patients at multiple institutions in the Netherlands with single brain metastases from various primary sites (33 with NSCLC) to surgery plus 40Gy WBRT versus WBRT alone. Overall median survival (6 vs. 10 months, [p=0.04]); and functional independent survival (FIS) (3.5 versus 7.5 months [p=0.06], reaching statistical significance in the stratum with stable extra cranial disease [p=0.01]) favoured addition of surgery in a clinically significant manner. Of note in the stratum with progressive extra cranial disease there was no significant difference in FIS and absolute values were similarly poor in each arm.

Mintz et al [6] randomly assigned 84 patients at multiple institutions in Canada with single brain metastases from various primary sites (45 with NSCLC) to surgery plus 30Gy WBRT versus WBRT alone. The study was powered to detect a 50% increase in overall survival with 80% chance. Overall median survival and QOL did not differ in a clinically or statistically significant manner between the groups.

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Clinical benefit of surgery plus WBRT compared to WBRT alone: Meta analysis

A meta analysis by Hart et al [1] identified the above 3 RCTs enrolling 195 patients in total. No significant difference in survival was found (HR = 0.72, 95% CI 0.34 to 1.55, P = 0.40). Reduction in the risk of death due to neurological cause with surgery and WBRT approached significance (RR = 0.68, 95% CI: 0.43 - 1.09, [P = 0.11]). The risk of adverse events was not statistically different between arms. The authors concluded that surgery and WBRT may reduce the proportion of deaths due to neurological cause and may improve FIS but not overall survival.

There was substantial heterogeneity between the trials (I2 = 83%). Both trials that implied improved survival after surgery reported better survival in those undergoing surgery and WBRT whilst that implying equivalence of the treatments reported better survival in patients receiving only WBRT. Indeed the Mintz trial enrolled patients with poorer performance status and higher burden of extra cranial disease. It may be therefore that the youngest and fittest patients with control of their extra cranial disease benefit from resection as it is the intra cranial disease that will be their life limiting pathology and as such improved local control may prolong both their quantity and quality of life.

No randomised evidence is available to guide addition of surgery to WBRT in the case of multiple metastases.

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Evidence summary and recommendations

Evidence summary Level References
Cure is possible in only a very small percentage of patients with brain metastasis.

Last reviewed December 2015

I, II [1], [3], [4], [5]
Improvement in long-term survival in unselected patients based on the addition of surgery to WBRT is unlikely.

Last reviewed December 2015

I, II [1], [3], [4], [5]
Improvement in OS due to the addition of surgery to WBRT in individualised cases is most likely in younger patients with good performance status and solitary brain metastasis or single brain metastasis and control of extra cranial disease.

Last reviewed December 2015

II [3], [4], [5]
Addition of surgery to WBRT may reduce the proportion of deaths due to neurological cause and may improve Functionally Independent Survival

Last reviewed December 2015

II [3], [4]
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In the absence of impending neurological emergency or the requirement of histological confirmation, patients with brain metastases may be managed with WBRT alone.

Last reviewed December 2015

B
Evidence-based recommendationQuestion mark transparent.png Grade
In younger patients, with good performance status and solitary brain metastasis or single brain metastasis and control of extra cranial disease, addition of surgery to WBRT is a reasonable approach.

Last reviewed December 2015

C


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Surgery may control symptoms more quickly than WBRT and is reasonable in cases of impending neurological emergency.
Last reviewed December 2015


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Surgery provides histological confirmation and is reasonable in cases where the aetiology of the brain lesions is in question or histological information is not available from the primary tumour.
Last reviewed December 2015


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In cases of multiple metastases, addition of surgery to WBRT may be reasonable for rapid symptom control or for histological confirmation.
Last reviewed December 2015


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In cases of multiple metastases, addition of surgery to WBRT may be reasonable in highly individualised cases with the goal of improvement in local control, overall survival or FIS. Stereotactic radiosurgery may be an alternative to surgery in these patients.
Last reviewed December 2015

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References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 Hart MG, Grant R, Walker M, Dickinson H. Surgical resection and whole brain radiation therapy versus whole brain radiation therapy alone for single brain metastases. Cochrane Database Syst Rev 2005 Jan 25;(1):CD003292 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15674905.
  2. 2.0 2.1 Fuentes R, Bonfill X, Exposito J.. Surgery versus radiosurgery for patients with a solitary brain metastasis from non-small cell lung cancer. Cochrane Database Syst Rev 2010 Abstract available at http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004840.pub2/pdf.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990 Feb 22;322(8):494-500 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2405271.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JH, Hoekstra FH, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 1993 Jun;33(6):583-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8498838.
  5. 5.0 5.1 5.2 5.3 5.4 Noordijk EM, Vecht CJ, Haaxma-Reiche H, Padberg GW, Voormolen JH, Hoekstra FH, et al. The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 1994 Jul 1;29(4):711-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8040016.
  6. 6.0 6.1 Mintz AH, Kestle J, Rathbone MP, Gaspar L, Hugenholtz H, Fisher B, et al. A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 1996 Oct 1;78(7):1470-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8839553.

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Appendices

Further resources

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