TUMOUR REVIEW
Radiotherapeutic management of brain metastases: A systematic review and meta-analysis

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Summary

Background

The management of brain metastases is a significant health care problem. An estimated 20–40% of cancer patients will develop metastatic cancer to the brain during the course of their illness.

Methods

A systematic review of randomized trials on adult cancer patients with single or multiple brain metastases from cancer of any histology was conducted. Eligible studies investigated external beam radiotherapy or radiosurgery in one of the study arms. Outcomes of interest included survival, intracranial progression-free duration, response of brain metastases to therapy, quality of life, symptom control, neurological function, and toxicity.

Results

Twenty-seven trials were included in this systematic review of the evidence. Pooled results from three randomized trials of surgical excision combined with whole brain radiotherapy (WBRT) showed no improvement in overall survival as compared to WBRT alone in patients with single brain metastasis.

One randomized study of postoperative WBRT following excision of a single brain metastasis versus surgery alone detected a significant reduction in intracranial tumour recurrence rates but no corresponding difference in overall survival.

Nine trials of altered dose-fractionation schedules compared to a standard control fractionation schedule (3000 cGy in 10 fractions) of WBRT showed no difference in probability of survival at 6 months.

The addition of radiosensitizers, as assessed in five trials, did not confer additional benefit to WBRT in terms of overall survival or the frequency of brain metastases response.

Three trials examined the use of WBRT and radiosurgery boost versus WBRT alone in selected patients with brain metastases. Overall survival did not improve for patients with multiple brain metastases. However, one trial reported an improvement in survival for patients with single brain metastasis treated with WBRT and radiosurgery boost.

One older randomized trial examined the use of WBRT versus supportive care alone (using oral prednisone). Results were not conclusive.

Conclusion

For patients with a single brain metastasis, good performance status, and minimal or no evidence of extracranial disease, surgical excision and postoperative WBRT improves survival (as compared to WBRT alone). There may be a small survival advantage associated with the use of radiosurgery boost and WBRT as compared to WBRT alone in selected patients with a single brain metastasis. There is no difference in overall survival or in neurologic function improvement with the use of altered whole brain dose-fractionation schedules as compared to standard fractionation schedules (3000 cGy in 10 fractions or 2000 cGy in 5 fractions). There is no survival benefit associated with the use of radiosurgery boost and WBRT versus WBRT alone in patients with multiple brain metastases. Currently, neither chemotherapy nor radiosensitizers show a clear benefit in the objective parameters of survival and progression-free survival. For patients with poor performance status and active extracranial disease, steroids and supportive care are an option.

Introduction

The management of brain metastases is a significant health care problem. An estimated 20–40% of cancer patients will develop metastatic cancer to the brain during their illness. While most of these patients will develop symptomatic brain metastases, some may be asymptomatic.1 The burden of brain metastases impacts on the quality and length of survival. Presenting symptoms include headache (49%), focal weakness (30%), mental disturbances (32%), gait ataxia (21%), seizures (18%), speech difficulty (12%), visual disturbance (6%), sensory disturbance (6%), and limb ataxia (6%).2

Brain metastases may develop from any primary tumour site, the most common primary sites being the lung, followed by the breast and the gastrointestinal region.3 Eighty-five percent of brain metastases are found in the cerebral hemispheres, 10–15% in the cerebellum, and 1–3% in the brainstem.4 The literature suggests that patients with breast or lung cancer metastatic to brain are likely to show size reduction of brain metastases with whole brain radiotherapy (WBRT). Patients with melanoma or renal cancer metastatic to brain are less likely to show a reduction in the size of brain metastases with WBRT.5

Important prognostic factors for patients with brain metastases include age, performance status, and the status of extracranial disease. The Radiation Therapy Oncology Group (RTOG) analyzed 1200 patients from three consecutive RTOG trials that tested several dose-fractionation schemes of WBRT and radiosensitizers in the management of patient with brain metastases. Using recursive partitioning analysis (RPA), three prognostic groups were produced. The best survival with a median of 7.1 months was categorized as RPA class I and was seen in patients <65 years of age, with Karnofsky performance status (KPS) of at least 70 and a controlled primary tumour with the brain as the only site of metastases. The worst survival (median 2.3 months) categorized as RPA class III, consisted of patients with KPS less than 70. All other patients fit into RPA class II with a median survival of 4.2 months.38

This systematic review was completed by the Supportive Care Guidelines Group of Cancer Care Ontario’s Program in Evidence-based Care in the context of developing an evidence-based practice guideline. Using the methods of the Practice Guidelines Development Cycle,6 this review will be combined with practitioner feedback to formulate a clinical practice guideline on the optimal radiotherapeutic management of brain metastases. The practice guideline component, outlining the external review process and recommendations, is currently under consideration for publication.7

Section snippets

Literature search strategy

MEDLINE (1966 to June 2004), CANCERLIT (1975 to 2003), CINAHL (1982 to June 2004), EMBASE (1980 to 2004 week 25), and the Cochrane Library (2004, Issue 2) databases were searched through Ovid. The terms “brain neoplasms” (Medical subject heading [MeSH]), “metastas#s” (text word), and “metastatic brain” were combined with the MeSH terms ”radiotherapy”, “radiotherapy, adjuvant”, “combined modality therapy”, “chemotherapy”, “surgery”, and “radiosurgery”. These were combined with terms for the

Single brain metastasis

Three trials evaluated the role of surgery plus WBRT compared with WBRT alone.10, 11, 12 One trial assessed the effectiveness of surgery plus WBRT versus surgery alone.13 One trial examined the use of radiosurgery boost with WBRT versus WBRT alone in selected patients with one to three brain metastases.14

Multiple brain metastases

One randomized controlled trial examined the use of supportive care alone (through oral prednisone) versus supportive care and WBRT.15 Nine studies examined the use of altered WBRT

Single brain metastasis

The pooled results of three trials10, 11, 12 using WBRT with or without surgical excision showed no difference in overall mortality at 6 months (RR 0.72; 95% CI 0.39, 1.32; p = 0.28). In contrast, two11, 12 of the three trials reported a statistically significant improvement in overall median survival. In the Noordijk et al. trial [11], overall median survival was 6 months in the WBRT alone arm and 10 months in the WBRT and surgery arm, p = 0.04. In the Patchell et al. study [12], overall median

Conclusions

Patients with brain metastases represent a heterogeneous group. A proportion may benefit from aggressive treatment for brain metastases (surgery, radiosurgery, WBRT) and systemic therapy for extracranial disease. It is important to note, however, that patients with brain metastases who enter into trials tend to be of better pronosis than the larger number of patients who do not enter trials. These latter patients with poor prognoses (such as those with poor KPS and active progressive

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