5-Aminolevulinic Acid Hydrochloride (5-ALA)-Guided Surgical Resection of High-Grade Gliomas: A Health Technology Assessment.

Background: High-grade gliomas are a type of malignant brain tumour. Optimal management often includes maximal surgical resection. 5-aminolevulinic acid hydrochloride (5-ALA) is an imaging agent that makes a high-grade glioma fluoresce under blue light, which can help guide the surgeon when removing the tumour. We conducted a health technology assessment of 5-ALA-guided surgical resection of high-grade gliomas, which included an evaluation of effectiveness, safety, the budget impact of publicly funding 5-ALA, and patient preferences and values.

Methods: We performed a systematic literature search of the clinical evidence to retrieve systematic reviews, and selected and reported results from one review that was recent, of high quality, and relevant to our research question. We complemented the identified systematic review with a literature search to identify randomized controlled trials published after the review. We reported the risk of bias of each included study and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We also performed a systematic economic literature search to identify economic studies that compared 5-ALA-guided surgical resection of high-grade gliomas with standard surgical care or other intraoperative imaging modalities. We did not conduct a primary economic evaluation due to lack of high-quality published clinical evidence evaluating 5-ALA-guided surgical resection. From the perspective of the Ontario Ministry of Health, we analyzed the 5-year budget impact of publicly funding 5-ALA-guided surgical resection for adults with newly diagnosed, primary, high-grade gliomas for which resection is considered feasible. To contextualize the potential value of 5-ALA, we spoke with someone who had experience with high-grade glioma, 5-ALA-guided resection, and standard surgical treatment.

Results: We included one systematic review reporting on a single randomized controlled trial in the clinical evidence review. 5-ALA increased the proportion of patients achieving complete tumour resection compared with standard care (relative risk of incomplete resection 0.55, 95% confidence interval 0.42-0.71; GRADE: Low). Evidence was uncertain for an effect on overall survival with 5-ALA (hazard ratio for death 0.82, 95% confidence interval 0.62-1.07; GRADE: Low), but there may be an improvement in 6-month progression-free survival (GRADE: Very low). Adverse events between groups was insufficiently reported, but appeared similar between groups for overall and neurological adverse events, with an observed increase in neurological deficits 48 hours after surgery with 5-ALA (GRADE: Very low). The economic literature search identified five studies that met our inclusion criteria because they evaluated the cost-effectiveness of 5-ALA-guided surgical resection as compared with surgery with a standard operating microscope under white light ("white-light microscopy"). Most of these studies found 5-ALA-guided surgical resection was cost-effective compared to white-light microscopy for high-grade gliomas. However, all studies derived clinical model inputs of the comparative safety and effectiveness parameters of 5-ALA from limited and low-quality evidence. Public funding of 5-ALA-guided surgical resection in Ontario over the next 5 years would result in a budget impact of about $930,000 in year 1 to about $1,765,000 in year 5, yielding a total budget impact of about $7,500,000 over this period. The one participant we interviewed had experience with high-grade glioma, standard surgical treatment, and 5-ALA-guided resection. The participant felt that 5-ALA-guided resection resulted in accurate tumour removal and also found it reassuring that 5-ALA could help the surgeon better visualize the tumour.

Conclusions: 5-ALA-guided surgical resection appears to improve the extent of resection of high-grade gliomas compared with surgery using standard white-light microscopy (GRADE: Low). The evidence suggests 5-ALA-guided resection may improve overall survival; however, we cannot exclude the possibility of no effect (Grade: Low). 5-ALA may improve 6-month progression-free survival, although the results are highly uncertain (GRADE: Very low). There is an uncertain impact on overall or neurological adverse events (GRADE: Very low). We did not identify any economic studies conducted from the perspective of the Ontario or Canadian public health care payer. Of the studies that met our inclusion criteria, most found 5-ALA-guided surgical resection was cost-effective compared to white-light microscopy for high-grade gliomas. However, clinical model inputs for the comparative effectiveness and safety of 5-ALA were based on limited and low-quality evidence. We estimate that publicly funding 5-ALA-guided surgical resection in Ontario over the next 5 years would result in a total 5-year budget impact of about $7,500,000. For people diagnosed with high-grade gliomas, 5-ALA is seen positively as a useful imaging tool for brain tumour resection.