Search strategy
6. Treatment of brain metastasis
What is the most effective treatment for brain metastasis?
Brain metastasis are usually multiple and occur most often in the setting of active disease elsewhere. In this instance, the management is mainly palliative, since the prognosis is poor.
A small subgroup of those with a single brain metastasis may enjoy longer survival, particularly if it is the only site of metastatic disease (solitary metastasis). Treatment options for brain metastases can involve surgical resection or radio-therapy [54,55]. The later can be in the form of WBRT, or as a focal technique (SRS or stereotactic radiotherapy). Chemo-therapy is seldom used as primary Chemo-therapy alone.
WBRT has long been considered the palliative treatment of choice. Historical retrospective series have demonstrated survival beyond which was encountered from palliative 168 Part 3: Neurological diseases
Table 17.3 Recent meta-analysis/RCTs on chemotherapy for malignant glioma.
Type of study Intervention No. of patients Patients Outcome Comment
(reference) (no. of trials) characteristics
SR Nitrosourea alone or in 3004 (12) Post-surgery Hazard ratio Individual patient
GMTG [48] combination surgery and RT RT 40–60 Gy focal 0.85 (95% CI 0.78–0.91) data analysis
versus surgery and RT alone or WBRT P 0.0001
RCT Gliadel (BCNU impregnated 240 (1) First operation Median survival Multi-institution
Double-blinded wafers) RT GBM RT 11.6 months Expensive
placebo control versus RT Age 18–65 years Gliadel RT treatment
Westphal et al. [51] KPS 60 13.9 months
RCT Temozolomide 573 (1) Post-operative Hazard ratio 16% grade III/IV
Stupp et al. [53] (concomitant and GBM (mainly) 0.63 (95% CI 0.52–0.75) Haematologic
adjuvant) RT Age 18–70 P 0.001 toxicity
versus RT alone WHO 2 Median survival Only 37% completed
(chemotherapy on Exclusions: unstable RT 12.1 months concomitant six
relapse if indicated) or increasing RT temozolomide courses adjuvant
steroid dose 14.6 months 2-year survival RT 10.4%
RT temozolomide 26.5%
BCNU: bischloroethylnitrosourea; RT: radiotherapy; WBRT: whole brain radiotherapy; GBM: Glioblastoma Multiforme.
therapy, for instance from 3 months with steroids alone to up to 7 months with WBRT [56]. It provides symptomatic relief and can prevent neurological deterioration. Neurological side effects can occur early or later in long-term survivors.
The most common late neurological side effect of radiation is leuco-encephalopathy and is characterized by dementia, ataxia and incontinence. However, these rarely become rele-vant due to the poor survival and their incidence is likely to be less than 11%, which was found in one retrospective series using inordinately high doses of radiation [57]. Although the benefits have not been thoroughly assessed in RCTs, clin-ical experience and ease of administration have led WBRT to become the standard palliative treatment. This has only recently been challenged by focal therapies, for example sur-gery or SRS plus or minus WBRT.
Surgery has been proposed for lesions that are usually well demarcated and superficial, suggesting resection can be complete and with minimal damage to surrounding neural tissue. It may also relieve symptoms, prevent death from neu-rological deterioration due to the metastasis, and even increase survival. Three RCTs from the 1990s have com-pared surgery followed by WBRT versus WBRT alone (stan-dard palliative treatment) [18,58,59]. These trials have recently been analysed in a Cochrane Review, which did not demonstrate a significant survival advantage from surgery, or in reducing death from neurological cause [60]. Only one trial provided information on functionally independent sur-vival for the complete sample population, and although this did suggest an improvement with surgery, the small sample size was very small. At best very few highly selected patients may benefit from surgery.
Before this meta-analysis, the results of the three RCTs for surgery in single brain metastasis had generally been inter-preted as evidence in favour of resection and a survival benefit.
The first two trials generally found an increase in survival for surgery, although for the later this was only in those with sta-ble extracranial disease. The final trial did not report a signifi-cant difference in survival, and many were quick to highlight the main reason for this being the less strict entry criteria and a poorer prognosis of patients. However, only a minority of patients were actually of poorer performance status than in the first two trials, and this alone is unlikely to account for the dif-ference in results. Meta-analysis provides the most reliable results, particularly when faced with small conflicting studies, as in this case. The overall results for surgery in single brain metastasis hence suggest no clear improvement in outcomes from resection, other than in a few very highly selected cases.
SRS has received increased attention recently as a means of delivering a high dose of radiation to a tumour. It avoids damage to surrounding brain, and as it avoids craniotomy it should afford fewer side effects and allow treatment of a greater range of patients, including those with multiple meta-stases. Numerous phase II studies have suggested a survival time on a par with the best achieved from current best therapy.
Due to selection bias, these results have to be disregarded in favour of RCTs. There are three published trials and two presently under way.
Unfortunately the first two RCTs of SRS are not inter-pretable due to serious methodological shortcomings [61,62].
The only analysable RCT stratified patients into two groups depending on the presence of single or up to three metastases who had WBRT with or without SRS first [63]. Those with single brain metastasis treated by SRS had an increase in median survival from 4.9 to 6.5 months which was statisti-cally significant, and they were also more likely to maintain or improve their KPS at 6 months follow-up. There was no change in the proportion of patients dying from neurological disease. For two or three metastases no improvement was found for SRS in terms of survival, local control or death from neurological disease. A trial is currently ongoing to compare the use of surgery or SRS, both followed by WBRT, for single brain metastasis; this should help decide the optimum treat-ment for these patients.
Following focal therapy of a single lesion by either surgery or SRS, there is debate as to whether WBRT is necessary.
Previously radiology was less accurate in detecting the pres-ence of multiple metastases, and WBRT had the advantage of treating undetected micrometastases. However, better imaging now detects more multiple metastases, and theoretically a single metastasis should be able to be definitively treated. It has been suggested from some phase II studies that WBRT does not improve outcomes after successful SRS.
If surgery is completed, then a single RCT of 95 patients has demonstrated advantages for post-operative WBRT [64].
This found that although overall survival was not increased, there was a decrease in death from neurological disease from 44% to 14% and a decrease in recurrence rates both locally (46–10%) and throughout the brain (37–14%). For SRS, an RCT currently in progress will hopefully allow evidence-based guidelines on the use of WBRT following SRS.
The main cause of death in patients with brain metastases is the activity of extracranial disease. There is good evidence that surgery does not afford any advantage over WBRT in sin-gle brain metastasis other than in very highly selected patients (Table 17.4). The results of these RCTs were all in a highly selected group of those of good prognosis which will be the minority of those with brain metastases in clinical practice, and are not applicable to other patient groups. Further trials are underway to fully define the role of SRS in the manage-ment of brain metastases. The managemanage-ment for the majority of those with brain metastases will be palliative.
Summary
It must be remembered in neuro-oncology as in other spe-cialities, large numbers of uncontrolled phase II studies point-ing in the direction of benefit for an intervention do not necessarily strengthen proof that the therapy is effective (it just Chapter 17: Brain tumours 169
magnifies the same errors in design, compounded by publi-cation bias and ‘gearing’). Good outcomes in good prognosis patients are to be expected!
With an increasing evidence basis for practice in neuro-oncology, it is important to remember some important prin-ciples when interpreting trials. The fact that a study is a RCT trial is not by itself an indication of quality or that the results are valid. Statistical significance must not be confused with clinical significance. Although survival is an important end-point, quality of life is as important. The study power, method of randomization, blinding, selection and stratification criteria are each important and can confound results. For example, if studies are not blinded, patients who realize that they are receiving the ‘standard’ rather than ‘novel’ arm may wish to switch after randomization and find a reason for coming out of the standard limb of the study (such as side effects or tox-icity). If studies are not double blinded, doctors can have an influence, whether intentional or not on further interven-tions. Blinding of doctors can also affect the reporting of quality of life data and disease progression. Very few RCTs in gliomas are able to report on quality of life, and where they have attempted to do so, studies are fraught with missing data and attrition of return of questionnaires due to illness or death.
There are small but growing number of good quality trials in neuro-oncology with which to base evidence-based prac-tice. With chemotherapy for gliomas and surgery for single metastasis, excellent quality Cochrane Reviews have pro-vided results that have challenged previously held beliefs and breathed new air into treatment areas. Furthermore, thorough literature searches have identified clear areas of
weakness in our knowledge, for example for surgery in HGG.
Continuing this growth of evidence-based research will no doubt lead to changes and hopefully improvements in the way these devastating conditions are managed.
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Table 17.4 Comparison of RCTs on surgery and WBRT for single brain metastasis.
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