Surgery versus radiosurgery for patients with a solitary brain metastasis from non‐small cell lung cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Primary objective: To determine the effectiveness of surgery versus radiosurgery, either combined with whole brain radiotherapy or administered alone, for solitary brain metastases from non‐small cell lung cancer.
Secondary objective: To evaluate the best treatment option(s) according to metastatic location, size of metastasis, and other possible clinical factors.
Background
Non‐small cell lung cancer is one of the leading causes of death in developed countries (Parkin 1999). Patients die of local progression/recurrence of the disease or from metastasic dissemination. One of the distinctive features of the natural history of non‐small cell lung cancer is the very high incidence of central nervous system involvement in comparison with other malignant diseases. According to some authors 37% to 55.7% of brain metastases come from a non‐small cell lung cancer (Varlotto 2003, Jawahar 2002). Although brain metastases from non‐small cell lung cancer are frequently multiple, a subset of patients having a "unique" tumoral brain deposit is regularly seen in clinical practice. In that case, brain metastases have three main clinical presentations: solitary brain metastases which develop some months or a few years after successful management of the primary tumour, a synchronous and operable or not operable primary lung cancer with single brain metastasis and a single brain metatasis from an uncontrolled primary tumour. Only the first clinical presentation mentioned will be considered in this systematic review.
A renewed interest in solitary brain metastasis from non‐small cell lung cancer has arisen following the development of better neurosurgical techniques (O'Neill 2003, Koutras 2003) and new radiotherapeutic opportunities because of the development of radiosurgery (Muacevic 1999). Radiosurgery consists on delivering a very high dose of radiotherapy to a very small volume of tissue using a surgical fixation frame to keep patient's head fixed during radiation treatment. This method is generally used for treating lesions of less than 3 cm in diameter. Over the years since the technique was started, some different forms of radiosurgery have been developed and at present three are the main treatment options: stereotactic Linac radiotherapy with or without relocatable frame and the Leksell gamma knife (Simonova 2000, Laing 1993).
The use of surgery alone with or without whole brain irradiation, radiosurgery or different combinations of these procedures, in addition to the administration of chemotherapy, has produced interesting reports showing that a significant increase in survival can be obtained in these patients and some of them can achieve more than two years disease free survival with a small proportion of patients (2.9%) living more than 5 years (Hall 2000, Wronski 1995).
However, the challenges of solitary metastases and the availability of several therapeutic options can make clinical decisions very difficult, where balancing benefits and toxicities is very important. The goal of this review is to contribute to the clarification of this topic.
Objectives
Primary objective: To determine the effectiveness of surgery versus radiosurgery, either combined with whole brain radiotherapy or administered alone, for solitary brain metastases from non‐small cell lung cancer.
Secondary objective: To evaluate the best treatment option(s) according to metastatic location, size of metastasis, and other possible clinical factors.
Methods
Criteria for considering studies for this review
Types of studies
Randomised or controlled trials that compare surgery (with or without whole brain irradiation) versus all types of radiosurgery (with or without whole brain irradiation) for solitary brain metastasis from non‐small cell lung cancer, independently of the chemotherapy treatment that has been administered.
Prospective or retrospective cohort studies and randomised or controlled clinical trials evaluating surgery (with or without whole brain irradiation) versus radiosurgery (with or without whole brain irradiation) for solitary brain metastasis from non‐small cell lung cancer (NSCLC).
Studies including patients with multiple brain metastasis and studies with patients having synchronous lung tumour and brain metastasis will be excluded. Studies without computed tomography (CT) or magnetic ressonance imaging (MRI) exams (usually before 1980) will also be excluded.
Types of participants
Patients included in the studies should have histologically proven non‐small cell lung cancer, be adults of more than 18 years old and have their primary tumour in complete remission when the diagnosis of a solitary brain metastasis (independently of its size) was made. It will be also mandatory that the included patients have a MRI or a contrast enhanced CT scan as part of their initial evaluation.
Patients with other clinical presentations of brain metastasis from non‐small cell lung cancer will be excluded.
Types of interventions
The interventions that will be considered are:
Linac stereotactic radiotherapy with or without relocatable frame using single or multiple fractions and Leksell gamma knife radiosurgery. Studies with additional whole brain irradiation (WBI) will also be included.
Surgery: Any kind of tumour excision. Studies treating patients with complementary WBI will also be included.
Studies where a chemotherapy combination for the treatment of solitary brain metastasis has been administered in any study group, different from the CT regimes administered in the other groups, will be excluded.
Types of outcome measures
Main outcome measures:
1. Overall survival after the diagnosis of brain relapse and disease free survival according to the study interventions.
2. Overall survival from the first diagnosis of NSCLC.
Additional outcome measures to be considered when reported:
1. Survival free of brain relapse when available
2. Treatment related toxicity of radiosurgery and complications of surgery
3. Quality of life.
Search methods for identification of studies
A search for identification of studies on the review topic will be undertaken of the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, 2004 Issue 2), MEDLINE (1966 to present), EMBASE (1974 to present), CINAHL (1982 to present). Further, the Cochrane Lung Cancer Groups Specialised Register will also be searched.
Databases will be searched using the recommended Cochrane search strategy for controlled trials (see also: Cochrane Lung Cancer Group Search) in addition to the following:
1. exp radiosurgery/
2. Radiosurg*.tw.
3. Stereotactic surgery.tw.
4. Stereotactic radiotherapy.tw.
5. Whole brain irradiation.tw.
6. Whole brain radiotherapy.tw.
7. WBI.tw.
8. or/1‐7
9. exp brain neoplasms/
10. central nervous system neoplasm/
11. exp neoplasm metastasis/
12. brain adj5 metastas*.tw.
13. cerebral adj5 metastas*.tw.
14. intracranial tum*.tw.
15. (single adj5 metastas*).tw.
16. (solitary adj5 metastas*).tw.
17. or/9‐16
18. #8 and #17
19. exp lung neoplasms/
20. exp carcinoma non‐small‐cell lung/
21. lung cancer.tw.
22. lung carcinoma.tw.
23. non‐oat cell.tw.
24. non small cell.tw.
25. NSCLC.tw.
26. or/19‐25
27. #18 and #26
A search for identification of prospective or retrospective cohort studies will be searched using a specific methodological search strategy.
Further, reference lists from identified studies will be scrutinised for any other additional studies. All searches will be conducted without any limitation for language.
Data collection and analysis
All studies will be evaluated by two authors in order to assess whether the studies match inclusion criteria. To evaluate the methodological quality of selected randomised controlled trials (RCTs), the authors will independently assess the methods section of the trials, considering the randomisation process, the presence or not of adequate randomisation concealment, the description or not of follow up and losses of included patients. Each trial will be classified into categories A, B or C following the criteria set out in the Cochrane Lung Cancer module. Any non‐randomised study which meets the inclusion criteria of the review will be critically appraised following the criteria of the Evidence‐Based Medicine Working Group.
Interventions will be classified as:
1.‐ Surgery alone
2.‐ Surgery and whole brain irradiation
3.‐ Exclusive radiosurgery, including any technique: radiosurgery using either gamma knife, radiosurgery using Linac and stereotactic radiotherapy using any kind of realocatable frame.
4.‐ Any radiosurgery technique plus whole brain irradiation.
Statistical analysis:
The statistical analysis will be conducted with the RCT included, if any. Where possible, outcomes from included trials will be combined using the Review Manager. However if the number of trials is small it may not be feasible to perform a meta‐analysis. For dichotomous outcomes a pooled relative risk (random effects method) will be calculated with 95% confidence interval. For survival analysis, estimation of the hazard ratio and its variance will be used as the summary statistic if the data allows. If there is insufficient data for this approach then a secondary analysis will be conducted with survival at five years. For continuous data, a pooled standardised mean difference (random effects method) will be calculated with 95% confidence interval. Quality of life data will be described in the results but a meta‐analysis will not be performed.
The statistical analysis will be conducted in accordance with the intention to treat principle. Patients will be analysed in the groups to which they were randomised to, regardless of whether or not they received the treatment they were assigned or whether they were observed until the completion of the follow up period or not.
Homogeneity of effect sizes among studies being pooled will be tested using the chi‐squared statistic for homogeneity, with p < 0.1 as the level for significance. Meta‐analysis will be conducted using the random effects model if the data is sufficiently homogeneous both clinically and statistically.
If meta‐analysis is performed then sensitivity analyses will be conducted based on the following:
(1) Methodological quality: studies with inadequate or unclear allocation concealment will be excluded from meta‐analysis.
(2) Methods of meta‐analysis: random and fixed effects models will be compared.
Descriptive analysis:
The included cohort studies, if any, will be described in a separate table.
