5-Aminolevulinic acid (5-ALA)-induced tumor fluorescence can be used to identify tissue for resection using an adapted operating microscope. A multi-institutional clinical trial comparing fluorescence-guided versus white light tumor resection reported significant improvement in completeness of resection and 6-month progression-free survival. The degree of 5-ALA-induced fluorescence correlates with histopathologic grade of tumor, degree of tumor cell infiltration, and proliferation indices. Quantitative methodologies for assessment of tissue fluorescence have significantly improved the ability to detect tumor tissue and intraoperative diagnostic performance. These developments extend the applicability of this technology to additional tumor histologies and provide the rationale for further instrumentation development.
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5-aminolevulinic acid (5-ALA)-induced fluorescence is a user-friendly, technologically efficient, and clinically safe surgical adjunct for the identification of malignant glial tumor tissue.
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A multi-institutional clinical trial comparing fluorescence-guided versus white light tumor resection reported significant improvement in completeness of resection and 6-month progression-free survival; the trial was underpowered to show improvement in overall survival.
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The degree of 5-ALA-induced fluorescence correlates with histopathologic grade of tumor, degree of tumor cell infiltration, and proliferation indices.
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Quantitative methodologies for assessment of tissue fluorescence have significantly improved the ability to detect tumor tissue and intraoperative diagnostic performance, as assessed by receiver operating characteristic curve analysis.
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These developments extend the applicability of this technology to additional tumor histologies and provide the rationale for further instrumentation development.
5-ALA is a precursor in the hemoglobin synthesis pathway, and exogenous, oral administration of this molecule several hours before surgery leads to the preferential accumulation of the molecule protoporphyrin IX (PpIX) within tumor cells. Under blue-violet light conditions, the fluorophore PpIX emits light in the red region of the visible spectrum, enabling identification of tumor tissue that might otherwise be difficult to distinguish from normal brain. Several commercial operating microscope systems have been adapted to use this phenomenon, providing the illumination and optical apparatus for reliable and efficient fluorescence guidance during surgery.
The greatest impediment to wider clinical application of this technology has been the limited access to 5-ALA for use in intracranial tumor resection. Approved for intracranial use in Europe, Canada, and Japan, 5-ALA in the United States has not yet received such approval by the US Food and Drug Administration (FDA). Clinical investigation in the United States at the time of this writing requires an Investigational New Drug (IND) exemption, and all clinical studies in the United States have been performed under this exemption.
Early work
One of the earliest reports of the use of 5-ALA-induced fluorescence for tumor resection was that published by Stummer in 2000. In this study, 52 patients with subsequently confirmed glioblastoma multiforme (GBM) underwent fluorescence-guided resection in which all fluorescent tissue considered safe to resect was removed. Absence of contrast-enhancing tumor on postoperative magnetic resonance imaging (MRI) was documented in 33 patients (63%), with 18 of the 19 patients with residual enhancement having had residual fluorescence intraoperatively, the location of which was considered to preclude safe resection. Intraoperatively, 2 types of fluorescence were noted: solid fluorescence, which corresponded with coalescent tumor on histology, and vague fluorescence, representing infiltrative tumor. Independent factors significantly associated with survival in multivariate analysis were patient age, residual intraoperative fluorescence, and residual contrast enhancement on postoperative MRI. There was no perioperative mortality, 1 case of new, permanent morbidity (severe hemiparesis), and 3 patients with transient worsening of preexisting symptoms. No serious adverse events related to the ingestion of 5-ALA were observed. This positive and encouraging experience showed the safety and feasibility of using 5-ALA-induced fluorescence as a surgical guide.
The German multi-institutional trial
The publication in 2006 of a randomized multi-institutional study comparing 5-ALA-induced fluorescence-guided surgery with conventional white light surgery for malignant glioma represented the first randomized surgical study for malignant glioma and was a landmark in fluorescence-guided surgical resection. Seventeen centers enrolled 322 patients in this study, the primary end points of which were residual contrast-enhancing tumor on early postoperative MRI and 6-month progression-free survival assessed by MRI. The study was terminated at interim analysis, with 270 patients randomized between the 5-ALA (139 patients) and white-light (131 patients) groups.
Complete resection of contrast-enhancing tumor on MRI was achieved in 90 (65%) of 5-ALA patients and in 47 (36%) of white-light patients, a difference significant to P <.0001. Six-month progression-free survival was observed in 41% versus 21.1% of patients in the respective treatment groups, a difference that again was highly significant ( P <.0003). There was no difference in severe adverse events at 7 days. The study was not powered to show a difference in overall survival, although restratification based on early postoperative MRI showed that patients without residual contrast-enhancing tumor of postoperative MRI had a survival advantage. Subgroup analysis also showed a longer time to reintervention for older patients (age >55 years: 10.2 months [5-ALA group] versus 7.1 months [white-light group]).
The large number of well-documented patients undergoing GBM resection in the German ALA Glioma Study Group afforded an opportunity to look at the effect of completeness of resection on postoperative MRI with overall survival in patients stratified with respect to the recursive partitioning analysis (RPA) of the Radiation Therapy Oncology Group (RTOG). Historically, the confounding variable of patient selection bias has rendered difficult the interpretation of any intervention effect in malignant glioma, and this partitioning strategy recognizes the important prognostic variables of age, Karnofsky Performance Scale (KPS), neurologic condition, and mental status.
The 243 patients with newly diagnosed GBM in the multicenter German study, independent of their assignment to 5-ALA or white-light groups, were looked at with respect to their RTOG-RPA class. Median overall survival times for classes III, IV, and V were 17.8, 14.7, and 10.7 months, respectively; 2-year survival in these classes were 26%, 12%, and 7%. Stratification for completeness of resection within RPA class revealed clear differences: for class IV, survival with complete resection was 17.7 months versus 12.9 months with incomplete resection, and for class V, survival of 13.7 months versus 10.4 months. Two-year survival within class IV was 21.0% versus 4.4%, and within class V, 11.1% versus 2.6%. The number of patients within class III was too small to detect significant differences. Overall, the predictive capability of the RTOG-RPA classes was confirmed by the ALA Glioma Study Group, and differences in survival seen in class IV and class V support a relationship between maximum cytoreduction and survival.
In the 2006 report of the ALA Glioma Study Group, only marginal differences were found between the 5-ALA and white-light groups. In a 2011 study, the investigators looked more closely at the issue of neurologic morbidity using the final intent-to-treat patient populations of their study (176 patients in the 5-ALA group and 173 in the white-light group). This analysis again confirmed the earlier findings of more complete tumor resection and improved progression-free survival. Using the National Institutes of Health Stroke Scale (NIH-SS) as a measure of neurologic status, the analysis also showed a higher incidence of deterioration in the NIH-SS by 1 or more points at the 48-hour postoperative time point in the 5-ALA group (26.2% vs 14.5%; P = .02). This measure was no longer statistically significant at 7 days, and at 3 months, the percentages with neurologic deterioration of 1 point or greater were 19.6% versus 18.6%, respectively. KPS scores showed no statistically significant differences between the 2 groups (deterioration in the KPS score at 6 weeks postoperatively seen in 32.9% for the ALA group vs 28.8% for the white-light group, P = 1.0, and deterioration at 6 months seen in 35.7% and 49.1%, respectively, P = .12). Patients at risk of neurologic deterioration were those with preexisting neurologic deficits unresponsive to steroids, consistent with these deficits more likely related to tumor infiltration than surrounding edema.
Further analysis in this same study attempted to assess the trade-off between a higher incidence of temporary and generally mild neurologic deterioration with 5-ALA-guided resection and improved likelihood of complete resection. In long-term follow-up, a higher incidence of repeat surgery was found in the white-light group (39% vs 30%, P = .0311). Stratification by completeness of resection showed quicker time to progression and neurologic deterioration in those patients with incomplete resection ( P = .0036).
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