Fluorescence-guided resection of malignant gliomas using 5-aminolevulinic acid: practical use, risks, and pitfalls.

The need for novel, effective, and safe treatments for malignant glioma is obvious. Despite surgery, radiotherapy, and chemotherapy, the median survival time of patients with glioblastoma multiforme (World Health Organization Grade IV) still does not exceed 15 months. Patients with anaplastic astrocytoma (World Health Organization Grade III) have a slightly better prognosis. As a result of the infiltrative nature of these tumors, there is controversy about the usefulness of gross total resection. Nevertheless, in the view of most neurosurgeons, surgical cytoreduction of tumor and adjacent tissue containing infiltrating cells of high density is an accepted treatment modality for these tumors. For malignant gliomas, an important aim is the safe removal of all contrast-enhancing tumor. In the past, this has been viewed to be a major factor determining progression and, ultimately, survival.1,2,6,13 Furthermore, emerging novel adjuvant therapies such as immune therapy, gene therapy, or strategies for chemotherapy will most likely rely on maximal cytoreduction to be as effective as possible. In this context, it was observed that concomitant radiochemotherapy followed by adjuvant chemotherapy was most efficacious in patients treated by complete resections as compared with incomplete resections or biopsy.18 However, the goal of removing all contrast-enhancing tumor on magnetic resonance imaging (MRI) has traditionally been reached only in less than 30% of cases1,5,12 because viable tumor tissue at the margin of a resection cavity is often difficult to distinguish intraoperatively. Therefore, a number of technical adjuncts to surgery, such as intraoperative MRI,9 neuronavigation,20 and ultrasound,7 have been explored in the past.7 Moreover, MRI is expensive, neuronavigation has a problem of brain shift, and ultrasound is prone to artefacts and problems of image interpretation. Few data exist from prospective randomized trials to prove efficacy. Integration of diffusion tensor-weighted imaging and fiber tract imaging into resection planning for gliomas led to improved functional outcome with the benefit for survival.21 However, systematic reviewing of radicality of resection was not a primary end point of that study. Willems et al. conducted a small randomized trial to investigate the usefulness of neuronavigation in glioma surgery in view of procedural aspects and functional outcome.19 They could not detect survival benefit for the additional use of neuronavigation, possibly as a result of the small sample size (45 patients) and short follow-up (3 months). Therefore, none of these methods has evolved into a standard for surgery on malignant gliomas with the aim of optimizing resection. Recently, 5-aminolevulinic acid (ALA) has emerged as a drug with great practical usefulness as a metabolic marker of malignant glioma cells that can be used intraoperatively for identifying residual tumor. ALA is the body’s own metabolite in the heme biosynthesis pathway. Experimental and clinical studies have shown ALA to be taken up by malignant glioma cells, where it is converted into strongly fluorescing porphyrins.16 Using specifically modified surgical microscopes, the resulting fluorescence can be used for resecting residual malignant glioma tissue (Fig. 3.1).13,15 Fluorescence-guided resections using ALA have since been tested for efficacy and safety in a prospectively randomized setting.14 The study was able to demonstrate early postoperative MRI to be devoid of residual, contrast-enhancing tumor in 65% of patients with glioblastoma multiforme in the ALA group compared with only 36% in a conventional microsurgical control group. Kaplan-Meier analyses revealed significantly prolonged progression-free survival in patients on ALA compared with white light alone with cumulative 6-month progression-free survival rates of 41 and 21% (P 0.01), respectively. Because of its benefits and an acceptable safety profile, marketing approval for ALA has recently been granted by the European Medicines Evaluation Agency for use in the European community in adult patients for visualization of malignant tissue during surgery for malignant glioma (World Health Organization Grades III and IV). Copyright © 2008 by The Congress of Neurological Surgeons 0148-703/08/5501-0020