Salvatore Chibbaro, Charles-Henry Mallereau, Mario Ganau, Ismail Zaed, Guillaume Dannhoff, Julien Todeschi, Alex Alfieri, Julien Haemmerli, Andrea Cardia, Carmen Bruno, Nikolaos Syrmos, Antonio Romano, Giuseppe Maria Vincenzo Barbagallo, Biagio Roberto Carangelo, Alessandro Zalaffi, Franco Moruzzi, Giacomo Tiezzi, Ludovica Cellini, Giovanni Di Pietro, Maria Grazia Pluchino, Vitaliano Francesco Muzii, Laura Lippa, Nicola Montemurro, Giovanni Muscas, Alessandro Della Puppa, Alfonso Cerase, Giacomo Gualtieri, Victoria Dembour, Giuseppe Battaglia, Paolo Tini
SF was associated with higher rates of CE-defined GTR and greater resection of the contrast-enhancing tumor compartment than 5-ALA. However, attenuation in the center fixed-effects analysis indicates that institutional practices and case selection contributed to the observed difference. No consistent center-independent survival advantage was demonstrated. These findings do not establish the intrinsic superiority of SF, particularly because non-enhancing and supramaximal resection could not be assessed.
BACKGROUND: Sodium fluorescein (SF) and 5-aminolevulinic acid (5-ALA) have distinct biological mechanisms and may highlight different tumor compartments. Comparative multicenter data remain limited, and interpretation depends on the imaging endpoint used.
METHODS: We performed a retrospective analysis of prospectively maintained databases from 12 European neurosurgical centers, including 1389 consecutive patients with locally documented IDH-wildtype glioblastoma undergoing fluorescence-guided surgery. Patients received SF alone (n = 650), 5-ALA alone (n = 457), or dual fluorescence (n = 282). The primary endpoint was contrast-enhancement-defined gross total resection (CE-GTR); secondary endpoints were contrast-enhancing extent of resection (CE-EOR), postoperative KPS, and overall survival (OS). Conventional multivariable models were supplemented by center-clustered generalized estimating equations (GEE), center fixed-effects logistic regression, a Cox model with center-clustered robust standard errors, and a center-stratified Cox sensitivity analysis.
RESULTS: CE-GTR was achieved in 74.9% of the SF group, 62.6% of the 5-ALA group, and 68.4% of the dual-fluorescence group (overall p < 0.001). In conventional multivariable analysis, 5-ALA was associated with lower odds of CE-GTR than SF (OR 0.63, 95% CI 0.49-0.81; p < 0.001). The association persisted in the center-clustered GEE model (OR 0.57, 95% CI 0.36-0.90; p = 0.015) but was attenuated after inclusion of center fixed effects (OR 0.65, 95% CI 0.37-1.12; p = 0.121). In the adjusted center-clustered CE-EOR analysis, SF remained associated with a 6.7% points higher mean CE-EOR than 5-ALA (95% CI 3.3-10.0; Bonferroni-adjusted p = 0.003), whereas the other pairwise contrasts were not significant. Median OS was 18.2 months (95% CI 16.8-19.6) with SF, 17.9 months (95% CI 16.6-19.5) with 5-ALA, and 18.5 months (95% CI 17.5-20.2) with dual fluorescence. In the center-clustered Cox model, 5-ALA was associated with a lower hazard than SF (HR 0.84, 95% CI 0.74-0.97; p = 0.014), but this association was attenuated in the center-stratified model (HR 0.88, 95% CI 0.64-1.22; p = 0.451). Dual fluorescence was not associated with survival.
CONCLUSIONS: SF was associated with higher rates of CE-defined GTR and greater resection of the contrast-enhancing tumor compartment than 5-ALA. However, attenuation in the center fixed-effects analysis indicates that institutional practices and case selection contributed to the observed difference. No consistent center-independent survival advantage was demonstrated. These findings do not establish the intrinsic superiority of SF, particularly because non-enhancing and supramaximal resection could not be assessed.
CLINICAL TRIAL NUMBER: Not applicable.