Multiple studies have identified the prognostic relevance of extent of resection in the management of glioma. Different intraoperative technologies have emerged in recent years with unknown comparative efficacy in optimising extent of resection. One previous Cochrane Review provided low‐ to very low‐certainty evidence in single trial analyses and synthesis of results was not possible. The role of intraoperative technology in maximising extent of resection remains uncertain. Due to the multiple complementary technologies available, this research question is amenable to a network meta‐analysis methodological approach.
To establish the comparative effectiveness and risk profile of specific intraoperative imaging technologies using a network meta‐analysis and to identify cost analyses and economic evaluations as part of a brief economic commentary.
We searched CENTRAL (2020, Issue 5), MEDLINE via Ovid to May week 2 2020, and Embase via Ovid to 2020 week 20. We performed backward searching of all identified studies. We handsearched two journals, Neuro‐oncology and the Journal of Neuro‐oncology from 1990 to 2019 including all conference abstracts. Finally, we contacted recognised experts in neuro‐oncology to identify any additional eligible studies and acquire information on ongoing randomised controlled trials (RCTs).
RCTs evaluating people of all ages with presumed new or recurrent glial tumours (of any location or histology) from clinical examination and imaging (computed tomography (CT) or magnetic resonance imaging (MRI), or both). Additional imaging modalities (e.g. positron emission tomography, magnetic resonance spectroscopy) were not mandatory. Interventions included fluorescence‐guided surgery, intraoperative ultrasound, neuronavigation (with or without additional image processing, e.g. tractography), and intraoperative MRI.
Data collection and analysis
Two review authors independently assessed the search results for relevance, undertook critical appraisal according to known guidelines, and extracted data using a prespecified pro forma.
We identified four RCTs, using different intraoperative imaging technologies: intraoperative magnetic resonance imaging (iMRI) (2 trials, with 58 and 14 participants); fluorescence‐guided surgery with 5‐aminolevulinic acid (5‐ALA) (1 trial, 322 participants); and neuronavigation (1 trial, 45 participants). We identified one ongoing trial assessing iMRI with a planned sample size of 304 participants for which results are expected to be published around winter 2020. We identified no published trials for intraoperative ultrasound.
Network meta‐analyses or traditional meta‐analyses were not appropriate due to absence of homogeneous trials across imaging technologies. Of the included trials, there was notable heterogeneity in tumour location and imaging technologies utilised in control arms. There were significant concerns regarding risk of bias in all the included studies.
One trial of iMRI found increased extent of resection (risk ratio (RR) for incomplete resection was 0.13, 95% confidence interval (CI) 0.02 to 0.96; 49 participants; very low‐certainty evidence) and one trial of 5‐ALA (RR for incomplete resection was 0.55, 95% CI 0.42 to 0.71; 270 participants; low‐certainty evidence). The other trial assessing iMRI was stopped early after an unplanned interim analysis including 14 participants; therefore, the trial provided very low‐quality evidence. The trial of neuronavigation provided insufficient data to evaluate the effects on extent of resection.
Reporting of adverse events was incomplete and suggestive of significant reporting bias (very low‐certainty evidence). Overall, the proportion of reported events was low in most trials and, therefore, issues with power to detect differences in outcomes that may or may not have been present. Survival outcomes were not adequately reported, although one trial reported no evidence of improvement in overall survival with 5‐ALA (hazard ratio (HR) 0.82, 95% CI 0.62 to 1.07; 270 participants; low‐certainty evidence). Data for quality of life were only available for one study and there was significant attrition bias (very low‐certainty evidence).
Intraoperative imaging technologies, specifically 5‐ALA and iMRI, may be of benefit in maximising extent of resection in participants with high‐grade glioma. However, this is based on low‐ to very low‐certainty evidence. Therefore, the short‐ and long‐term neurological effects are uncertain. Effects of image‐guided surgery on overall survival, progression‐free survival, and quality of life are unclear. Network and traditional meta‐analyses were not possible due to the identified high risk of bias, heterogeneity, and small trials included in this review. A brief economic commentary found limited economic evidence for the equivocal use of iMRI compared with conventional surgery. In terms of costs, one non‐systematic review of economic studies suggested that, compared with standard surgery, use of image‐guided surgery has an uncertain effect on costs and that 5‐ALA was more costly. Further research, including completion of ongoing trials of ultrasound‐guided surgery, is needed.
Plain language summary
Image‐guided surgery for brain tumours
Surgery has a key role in the management of many types of brain tumour. Removing as much tumour as possible is very important, as in some types of brain tumour this can help people to live longer and to feel better. However, removing a brain tumour may be difficult because the tumour either looks like normal brain tissue or is near brain tissue that is needed for normal functioning. New methods of seeing tumours during surgery (called imaging) have been developed to help surgeons better identify tumour from normal brain tissue.
Is image‐guided surgery more effective at removing brain tumours than surgery without image guidance?
Is one image‐guidance technology or tool better than another?
Our search strategy is up to date as of May 2020. We found four trials looking at three different tools to help improve the amount of tumour that is removed. The tumour being evaluated was glioma. Imaging interventions used during surgery included:
– magnetic resonance imaging during surgery to assess the amount of remaining tumour;
– fluorescent dye to mark out the tumour (5‐aminolevulinic acid);
– imaging before surgery to map out the location of a tumour, which was then used at the time of surgery to guide the surgery (neuronavigation); or
– ultrasound imaging during surgery to assess the amount of remaining tumour.
All the studies had compromised methods, which could mean their conclusions were biased. Some studies were funded by the manufacturers of the image guidance technology being evaluated. We intended to use a form of analysis called network meta‐analysis (which can incorporate comparisons of interventions even if they have not been directly compared within trials) to compare each of these interventions and identify which single technology might be best.
We found low‐ to very low‐certainty evidence that use of image‐guided surgery may result in more of the tumour being removed surgically in some people. The short‐ and long‐term neurological effects are uncertain. We did not have the data to determine whether any of the evaluated technologies affected overall survival, time until disease progression, or quality of life. There was very low‐certainty evidence for neuronavigation across all outcomes in one very small trial, and we identified no trials for ultrasound guidance. We were unable to perform a network meta‐analysis to compare imaging interventions. In terms of costs, compared with standard surgery, use of image‐guided surgery has an uncertain effect on costs and that 5‐aminolevulinic acid was more costly than conventional surgery.
Quality of the evidence
Evidence for intraoperative imaging technology for use in removing brain tumours is sparse and of low to very low certainty. Further research is needed to assess three main questions:
– Is removing more of the tumour better for the patient in the long term?
– What are the risks of causing a patient to have worse symptoms by taking out more of the tumour?
– How does resection affect a patient’s quality of life?