Optimisation De La

Resection Des

Gliomes De

Haut Grade

Par La

Thiébaud Picart
email: picart@chu-lyon.fr

M Berhouma

C Dumot

RESECTION USING 5-ALA FLUORESCENCE-GUIDED SURGERY: LITERATURE REVIEW AND PRACTICAL RECOMMENDATIONS FROM THE NEURO-ONCOLOGY CLUB OF THE FRENCH SOCIETY OF NEUROSURGERY

Keywords: high-grade glioma, 5-ALA, fluorescence-guided surgery, extent of resection, efficacy, safety

whether they are published or not. The documents may come

INTRODUCTION

Lorsqu'elle est réalisable, la résection chirurgicale demeure la première étape de la prise en charge des gliomes de haut grade. La chirurgie guidée par fluorescence avec le (CGF-5-ALA) fut développée pour faciliter le repérage des limites tumorales et optimiser l'étendue de résection.

METHODES

La base de données Medline fut consultée afin de sélectionner les articles rédigés en anglais et publiés entre Janvier 1998 et Juillet 2018, en respectant les recommandations PRISMA.

RESULTATS

Le 5-ALA est considéré comme un marqueur spécifique mais manque de sensibilité (niveau 2). Son utilisation permet d'augmenter significativement le taux de résection complète qui atteint plus de 90% dans certaines séries (niveau 1). La CGF-5-ALA améliore la survie sans progression (niveau 1). L'augmentation de la survie globale est davantage débattue. La CGF-5-ALA est possible en zone éloquente mais nécessite de réaliser simultanément un monitoring électrophysiologique des fonctions cérébrales (niveau 2). Le 5-ALA est utilisable lors de la première résection tumorale mais également à la récidive (niveau 2).

Le 5-ALA doit être administré 3 heures avant l'induction de l'anesthésie à la dose de 20 mg/kg. Pendant la chirurgie, la procédure est réalisée comme habituellement avec un évidement central puis une dissection périphérique pendant laquelle le chirurgien passe alternativement de la lumière blanche à la lumière bleue. A condition de respecter certaines précautions, la chirurgie guidée par fluorescence n'induit pas de complications particulières.

CONCLUSION

La CGF-5-ALA contribue à améliorer la prise en charge des gliomes mais présente encore quelques limites. Prochainement, des améliorations techniques pourraient optimiser sa sensibilité.

(250 mots) Mots-clés: gliome de haut grade; 5-ALA; chirurgie guidée par fluorescence; étendue de résection; efficacité; sécurité

INTRODUCTION

High-grade glioma (HGG) is the most common and aggressive primary brain tumor in adults, with incidence of more than 3,000 new cases per year in France [START_REF] Louis | The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary[END_REF][START_REF] Lacroix | A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival[END_REF].

When feasible, surgical resection is the standard first-line treatment [START_REF] Olson | Guidelines for the treatment of newly diagnosed glioblastoma: introduction[END_REF]. It has been demonstrated that safe maximal tumor resection improves symptom management, quality of life, PFS (Progression-Free Survival), and OS (Overall Survival) in both DLGG (Diffuse Low-Grade Glioma) and HGG [START_REF] Yordanova | Supratotal resection of diffuse gliomas -an overview of its multifaceted implications[END_REF][START_REF] Duffau | Surgery of low-grade gliomas: towards a "functional neurooncology[END_REF][START_REF] D'amico | Extent of Resection in Glioma-A Review of the Cutting Edge[END_REF][START_REF] Jenkinson | Intraoperative imaging technology to maximise extent of resection for glioma[END_REF][START_REF] Sanai | Glioma extent of resection and its impact on patient outcome[END_REF]. So-called "maximal cytoreduction" allows the most proliferative and therapy-resistant cancer cells to be removed and increases the effectiveness of adjuvant therapies [START_REF] Stummer | Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article[END_REF][START_REF] Stummer | The importance of surgical resection in malignant glioma[END_REF][START_REF] Valle | To what extent will 5-aminolevulinic acid change the face of malignant glioma surgery?[END_REF][START_REF] Stummer | Prospective cohort study of radiotherapy with concomitant and adjuvant temozolomide chemotherapy for glioblastoma patients with no or minimal residual enhancing tumor load after surgery[END_REF]. Survival analyses clearly showed that prognosis in HGG directly depends on the quality of tumor removal [START_REF] Chaichana | When gross total resection of a glioblastoma is possible, how much resection should be achieved?[END_REF][START_REF] Li | The influence of maximum safe resection of glioblastoma on survival in 1229 patients: Can we do better than gross-total resection?[END_REF][START_REF] Pichlmeier | Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients[END_REF][START_REF] Simpson | Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: results of three consecutive Radiation Therapy Oncology Group (RTOG) clinical trials[END_REF][START_REF] Mineo | Prognosis factors of survival time in patients with glioblastoma multiforme: a multivariate analysis of 340 patients[END_REF]. A relatively recent analysis emphasized that increasing the GTR (Gross Total Resection) rate from 78% to 100% of the contrast-enhanced portion of HGG increases OS from 12.5 to 16 months [START_REF] Sanai | An extent of resection threshold for newly diagnosed glioblastomas[END_REF]. Benefit in OS becomes significant for Extent Of Resection (EOR) greater than 98% or tumor remnant smaller than 2 cm 3 [START_REF] Lacroix | A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival[END_REF][START_REF] Grabowski | Residual tumor volume versus extent of resection: predictors of survival after surgery for glioblastoma[END_REF]. EOR also positively impacts PFS: 6-month PFS is 32% in case of incomplete resection versus 45% in case of GTR [START_REF] Roder | Maximizing the extent of resection and survival benefit of patients in glioblastoma surgery: high-field iMRI versus conventional and 5-ALA-assisted surgery[END_REF]. These results were validated in older patients in a retrospective analysis of 103 patients with a median age of 70.8 years [START_REF] Ewelt | Glioblastoma multiforme of the elderly: the prognostic effect of resection on survival[END_REF].

Stratifying patients as above or below 60 years old showed that the survival advantage of total resection was significant in both subgroups [START_REF] Stummer | Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias[END_REF]. Consequently, optimizing the quality of tumor resection is a major challenge in neuro-oncology [START_REF] Lacroix | A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival[END_REF][START_REF] Sanai | Glioma extent of resection and its impact on patient outcome[END_REF][START_REF] Hardesty | The value of glioma extent of resection in the modern neurosurgical era[END_REF][START_REF] Sanai | Extent of resection influences outcomes for patients with gliomas[END_REF].

Unfortunately, accurate intraoperative tumor delineation is challenging because diffuse gliomas, whatever the grade of malignancy, do not have clear boundaries: the tumor resembles the healthy parenchyma and visual assessment of resection quality is not reliable [START_REF] Albert | Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis[END_REF][START_REF] Hadjipanayis | What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?[END_REF]. Various tools have therefore been developed to help neurosurgeons improve EOR, including intraoperative image-based technologies such as ultrasonography, MRI-based neuro-navigation or intraoperative MRI (iMRI) [START_REF] Willems | Neuronavigation and surgery of intracerebral tumours[END_REF][START_REF] Senft | Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial[END_REF].

However, the main limitation of these techniques is that it is not possible to identify tumor infiltration extending beyond the contrast enhancement area [START_REF] Stummer | Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article[END_REF][START_REF] Li | The influence of maximum safe resection of glioblastoma on survival in 1229 patients: Can we do better than gross-total resection?[END_REF]. FGS (Fluorescence-Guided Surgery) was first described in 1948 [START_REF] Moore | The clinical use of sodium fluorescein and radioactive diiodofluorescein in the localization of tumors of the central nervous system[END_REF], and many fluorophores have since been tested [START_REF] Li | Intraoperative fluorescenceguided resection of high-grade gliomas: a comparison of the present techniques and evolution of future strategies[END_REF]. Despite the promises of this technology, it has not been widely used over recent decades. 5-AminoLevulinic Acid-FGS (5-ALA-FGS), which was first introduced in Germany in 1998 [START_REF] Stummer | In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid[END_REF], is now considered a standard of care in many countries, including Switzerland, Australia, Canada, China, Japan [START_REF] Stummer | Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial[END_REF][START_REF] Jacquesson | Surgery of high-grade gliomas guided by fluorescence: a retrospective study of 22 patients[END_REF][START_REF] Panciani | 5aminolevulinic acid and neuronavigation in high-grade glioma surgery: results of a combined approach[END_REF][START_REF] Kim | Impact of fluorescence-guided surgery on the improvement of clinical outcomes in glioblastoma patients[END_REF][START_REF] Valle | Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience[END_REF][START_REF] Chan | 5-Aminolevulinic acid fluorescence guided resection of malignant glioma: Hong Kong experience[END_REF] and, very recently, the USA [START_REF] Lakomkin | Fluorescence-guided surgery for high-grade gliomas[END_REF]. In France, market authorization was obtained in 2007, but routine use of 5-ALA-FGS is limited to a small number of neurosurgical centers. In 2017, approximately 60 patients underwent 5-ALA-FGS according to the supplier (Medac, France). This may be explained by the absence of specific national health insurance reimbursement to cover the cost of the drug in French hospitals, and persisting doubt regarding efficacy [START_REF] Henaine | Current trends in the management of glioblastoma in a French University Hospital and associated direct costs[END_REF] awaiting results from the French RESECT phase III trial (ClinicalTrials.gov Identifier: NCT01811121).

The present study on behalf of the Neuro-Oncology Club of the French Neurosurgery Society (SFNC) aimed to provide practical recommendations for routine surgical practice, founded on an evidence-based analysis of 5-ALA-FGS efficacy and safety.

PRINCIPLE OF TUMOR FLUORESCENCE INDUCED BY ORAL

ADMINISTRATION OF 5-ALA 5-ALA is the endogenous precursor of protoporphyrin IX (PpIX), which is then converted into heme by ferro-chelatase in healthy cells [START_REF] Novotny | Mechanisms of 5aminolevulinic acid uptake at the choroid plexus[END_REF]. Biodistribution after oral intake is particularly good in HGG cells, in which the blood-brain barrier, physiologically impermeable to 5-ALA, is broken [START_REF] Novotny | Mechanisms of 5aminolevulinic acid uptake at the choroid plexus[END_REF]. Moreover, tumor cells overexpress membrane ABC-transporters that ease 5-ALA cell entry [START_REF] Collaud | On the selectivity of 5-aminolevulinic acidinduced protoporphyrin IX formation[END_REF][START_REF] Zhao | Increased expression of ABCB6 enhances protoporphyrin IX accumulation and photodynamic effect in human glioma[END_REF]. In HGG, tumor cells are able to transform 5-ALA into PpIX but are deficient in ferro-chelatase.

Thus, extra oral administration of 5-ALA before surgery results in PpIX accumulation [START_REF] Stummer | In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid[END_REF][START_REF] Collaud | On the selectivity of 5-aminolevulinic acidinduced protoporphyrin IX formation[END_REF][START_REF] Ennis | Transport of 5aminolevulinic acid between blood and brain[END_REF][START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF][START_REF] Stummer | Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue[END_REF][START_REF] Stepp | ALA and malignant glioma: fluorescence-guided resection and photodynamic treatment[END_REF]. Moreover, exogenous administration bypasses the negative feedback control exerted by heme on the enzyme that synthesizes 5-ALA, enhancing the generation of PpIX [START_REF] Collaud | On the selectivity of 5-aminolevulinic acidinduced protoporphyrin IX formation[END_REF]. Excitation of PpIX is then obtained by light radiation at a wavelength corresponding to its absorption spectrum (375-440 nm) [START_REF] Stummer | In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid[END_REF][START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF][START_REF] Stummer | Fluorescence-guided resections of malignant gliomas--an overview[END_REF]. When excited, PpIX returns to its equilibrium state, emitting a red fluorescence detectable between 635 and 704 nm (Figure 1) [START_REF] Stummer | Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue[END_REF][START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF]. To visualize the fluorescence, a combination of excitation and emission filters are positioned in the surgical microscope: a short-pass filter in the excitation light path filters out the PpIX excitation wavelength, which is shorter than the fluorescence emission wavelength; and a longpass filter in the observer light path blocks out any excited light at wavelengths < 440 nm, allowing only red porphyrin-induced fluorescence to pass. The excitation and emission spectra have a small overlap, so that a small fraction of excited light is also re-emitted from tissue, giving the normal brain a blue color in contrast to the bright red porphyrin fluorescence of glioma [START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF]. During the procedure, when the surgeon switches from traditional white light (WL) to blue light, the fluorescence becomes easily and rapidly visible without interruption of surgery.

Consequently, 5-ALA acts as a "chemical neuronavigator" [START_REF] Yamada | Role of neurochemical navigation with 5-aminolevulinic acid during intraoperative MRI-guided resection of intracranial malignant gliomas[END_REF] and, unlike MRI-based technologies, theoretically highlights all tumor cells. However, the cellular and extracellular environment can also affect cell function and the formation of PpIX.

For instance, hypoglycemia, hyperthermia or acidosis increase PpIX accumulation, while hypoxia slightly decreases it [START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF][START_REF] Georgakoudi | Hypoxia significantly reduces aminolaevulinic acidinduced protoporphyrin IX synthesis in EMT6 cells[END_REF][START_REF] Wyld | The influence of hypoxia and pH on aminolaevulinic acidinduced photodynamic therapy in bladder cancer cells in vitro[END_REF][START_REF] Wyld | Aminolaevulinic acid-induced photodynamic therapy: cellular responses to glucose starvation[END_REF]. Moreover, Heme Oxygenase 1 protein expression was identified as a negative regulator of 5-ALA-induced fluorescence in GBM cells, and it was recently demonstrated that co-expression of EGFR variant III influences the activity of this enzyme, interfering with cell fluorescence [START_REF] Fontana | Epithelial growth factor receptor expression influences 5-ALA induced glioblastoma fluorescence[END_REF].

Furthermore, tumor remnants are more likely to be fluorescent in MGMT-methylated than MGMT-unmethylated tumors [START_REF] Coburger | Histopathological Insights on Imaging Results of Intraoperative Magnetic Resonance Imaging, 5-Aminolevulinic Acid, and Intraoperative Ultrasound in Glioblastoma Surgery[END_REF].

LITERATURE SEARCH AND REVIEW METHODOLOGY

Following the PRISMA guidelines (55), we undertook a literature review to identify articles dealing with the clinical efficacy, safety and cost-effectiveness of 5-

ALA-FGS.

We included all types of study design (including systematic reviews with metaanalysis) conducted on 5-ALA-FGS (used as stand-alone intervention or in combination with intraoperative MRI) in patients of any age undergoing surgery for HGG, low-grade glioma, meningioma, brain metastasis or lymphoma. Studies that assessed several fluorophores (i.e., not solely 5-ALA) and case reports were excluded.

Study endpoints comprised: diagnostic performance of 5-ALA, gross total resection compared with conventional WL surgery, survival, safety (3-month functional outcome, and HGG location within or not within eloquent areas), and costeffectiveness (expressed as incremental cost-effectiveness ratio).

English-language studies were retrieved from the Medline database for the period January 1998 to July 2018. The keywords "5-ALA", "5-Aminolevulinic acid" and "fluorescence-guided surgery" were used in combination with "high-grade glioma", "glioblastoma", "low-grade glioma", "meningioma", "metastasis" and "lymphoma". One reviewer (T.P.) screened all titles and Abstracts and then assessed potentially relevant full-text articles against eligibility criteria. The same reviewer undertook a quality assessment of each included article using the "Study Quality Assessment Tools" of the National Heart, Lung and Blood Institute, in relation to individual study design. Lastly, the levels of evidence of included studies were determined on the French Health Authority (HAS) classification (56). The reference lists of selected articles were also examined.

We summarized study, intervention, population and outcome characteristics narratively and in summary tables by indication type. Finally, we detailed the practical information necessary to integrate this technique in the armamentarium.

EVIDENCE-BASED DATA FOR THE CONTRIBUTION OF 5-ALA TO HGG RESECTION

Diagnostic performance of 5-ALA fluorescence-guided surgery

Assessment of the diagnostic performance of 5-ALA-FGS for HGG requires histologic confirmation of the presence or absence of tumor cells in fluorescent and non-fluorescent glioblastoma samples [START_REF] Kiesel | Systematic histopathological analysis of different 5-aminolevulinic acid-induced fluorescence levels in newly diagnosed glioblastomas[END_REF].

Three meta-analyses (level 2) published between 2012 and 2015 assessed the performance of 5-ALA-FGS in HGG resection (58-60) (Table 1). The meta-analysis by Zhao et al. [START_REF] Zhao | Intraoperative fluorescence-guided resection of high-grade malignant gliomas using 5-aminolevulinic acid-induced porphyrins: a systematic review and meta-analysis of prospective studies[END_REF], based on 5 studies [START_REF] Valle | Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience[END_REF][START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF][START_REF] Hefti | 5-aminolevulinic acid induced protoporphyrin IX fluorescence in high-grade glioma surgery: a one-year experience at a single institution[END_REF][START_REF] Panciani | Fluorescence and image guided resection in high grade glioma[END_REF][START_REF] Roberts | Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between δaminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article[END_REF], estimated the pooled sensitivity and specificity of 5-ALA-FGS as 0.87 and 0.89, respectively, and pooled positive and negative likelihood ratios as 7.62 and 0.14, respectively. Although sensitivity and specificity vary according to fluorescence intensity [START_REF] Valle | Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience[END_REF][START_REF] Idoate | Pathological characterization of the glioblastoma border as shown during surgery using 5-aminolevulinic acid-induced fluorescence[END_REF], the pooled results did not take this problem into account. An older meta-analysis (59), partially overlapping with the previous one [START_REF] Zhao | Intraoperative fluorescence-guided resection of high-grade malignant gliomas using 5-aminolevulinic acid-induced porphyrins: a systematic review and meta-analysis of prospective studies[END_REF], included a total of 12 studies [START_REF] Valle | Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience[END_REF][START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF][START_REF] Stummer | Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue[END_REF][START_REF] Hefti | 5-aminolevulinic acid induced protoporphyrin IX fluorescence in high-grade glioma surgery: a one-year experience at a single institution[END_REF][START_REF] Roberts | Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between δaminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article[END_REF][START_REF] Idoate | Pathological characterization of the glioblastoma border as shown during surgery using 5-aminolevulinic acid-induced fluorescence[END_REF][START_REF] Ewelt | Finding the anaplastic focus in diffuse gliomas: the value of Gd-DTPA enhanced MRI, FET-PET, and intraoperative, ALA-derived tissue fluorescence[END_REF][START_REF] Ishihara | Quantitative spectroscopic analysis of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence intensity in diffusely infiltrating astrocytomas[END_REF][START_REF] Stockhammer | Association of F18fluoro-ethyl-tyrosin uptake and 5-aminolevulinic acid-induced fluorescence in gliomas[END_REF][START_REF] Utsuki | Histological examination of false positive tissue resection using 5-aminolevulinic acid-induced fluorescence guidance[END_REF][START_REF] Widhalm | 5-Aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement[END_REF][START_REF] Stummer | Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence[END_REF] and reported pooled sensitivity and specificity of 0.91 and 0.59, respectively, and of 0. Seven prospective studies (level 2), not included in the above meta-analyses, also assessed the performance of 5-ALA-FGS in HGG resection as main or secondary endpoint (Table 1). Six of them dealt with macroscopic detection of 5-ALA [START_REF] Yamada | Role of neurochemical navigation with 5-aminolevulinic acid during intraoperative MRI-guided resection of intracranial malignant gliomas[END_REF][START_REF] Coburger | Histopathological Insights on Imaging Results of Intraoperative Magnetic Resonance Imaging, 5-Aminolevulinic Acid, and Intraoperative Ultrasound in Glioblastoma Surgery[END_REF][START_REF] Kiesel | Systematic histopathological analysis of different 5-aminolevulinic acid-induced fluorescence levels in newly diagnosed glioblastomas[END_REF][START_REF] Lau | A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas[END_REF][START_REF] Gessler | Combination of Intraoperative Magnetic Resonance Imaging and Intraoperative Fluorescence to Enhance the Resection of Contrast Enhancing Gliomas[END_REF][START_REF] Hauser | Combining 5-Aminolevulinic Acid Fluorescence and Intraoperative Magnetic Resonance Imaging in Glioblastoma Surgery: A Histology-Based Evaluation[END_REF] while the other was based on spectrometric fluorescence quantification [START_REF] Stummer | 5-Aminolevulinic acidderived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging[END_REF]. Overall, the ranges of sensitivity and specificity were 0.75-0.86 and 0.43-1, respectively, and ranges of positive and the negative predictive values were 0.86-0.98 and 0.125-0.69, respectively. Thus, 5-ALA-FGS is highly specific in detection of HGG and has an excellent positive predictive value, but its sensitivity and negative predictive value are only moderate, especially in zones with low tumor infiltration [START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF][START_REF] Lau | A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas[END_REF][START_REF] Mansouri | Journal club: 5-aminolevulinic acid-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging[END_REF]. Moreover, spectroscopic detection of fluorescence can be more sensitive but less specific, depending on the selected threshold [START_REF] Stummer | 5-Aminolevulinic acidderived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging[END_REF].

The major sources of false positives negatively impacting specificity and positive predictive value are rare, mainly comprising reactive astrocytes, especially in recurrent previously irradiated tumor [START_REF] Hadjipanayis | What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?[END_REF][START_REF] Panciani | 5aminolevulinic acid and neuronavigation in high-grade glioma surgery: results of a combined approach[END_REF][START_REF] Panciani | Fluorescence and image guided resection in high grade glioma[END_REF][START_REF] Utsuki | Histological examination of false positive tissue resection using 5-aminolevulinic acid-induced fluorescence guidance[END_REF][START_REF] Stummer | 5-Aminolevulinic acidderived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging[END_REF][START_REF] Kamp | 5-ALA-induced fluorescence behavior of reactive tissue changes following glioblastoma treatment with radiation and chemotherapy[END_REF]

(see below).

Autofluorescence is also described in healthy brain parenchyma [START_REF] Hadjipanayis | What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?[END_REF][START_REF] Panciani | Fluorescence and image guided resection in high grade glioma[END_REF][START_REF] Masubuchi | Experimental study to understand nonspecific protoporphyrin IX fluorescence in brain tissues near tumors after 5-aminolevulinic acid administration[END_REF], especially from the choroid plexi [START_REF] Ennis | Transport of 5aminolevulinic acid between blood and brain[END_REF] and from ependyma in more than 25% of ventricle walls free of tumor infiltration [START_REF] Moon | Histopathological implications of ventricle wall 5-aminolevulinic acid-induced fluorescence in the absence of tumor involvement on magnetic resonance images[END_REF]. Several factors can lead to false negatives that impair sensitivity and negative predictive value. First, in peri-tumoral areas, where tumor cell density is lower, fluorescence intensity is lower [START_REF] Hadjipanayis | What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?[END_REF][START_REF] Panciani | 5aminolevulinic acid and neuronavigation in high-grade glioma surgery: results of a combined approach[END_REF][START_REF] Valle | Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience[END_REF][START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF][START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF][START_REF] Yamada | Role of neurochemical navigation with 5-aminolevulinic acid during intraoperative MRI-guided resection of intracranial malignant gliomas[END_REF][START_REF] Panciani | Fluorescence and image guided resection in high grade glioma[END_REF][START_REF] Roberts | Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between δaminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article[END_REF][START_REF] Idoate | Pathological characterization of the glioblastoma border as shown during surgery using 5-aminolevulinic acid-induced fluorescence[END_REF][START_REF] Coburger | Tumor detection with 5-aminolevulinic acid fluorescence and Gd-DTPA-enhanced intraoperative MRI at the border of contrast-enhancing lesions: a prospective study based on histopathological assessment[END_REF][START_REF] Yoneda | Spectral Radiance of Protoporphyrin IX Fluorescence and Its Histopathological Implications in 5-Aminolevulinic Acid-Guided Surgery for Glioblastoma[END_REF][START_REF] Stummer | Predicting the "usefulness" of 5-ALA-derived tumor fluorescence for fluorescence-guided resections in pediatric brain tumors: a European survey[END_REF][START_REF] Widhalm | 5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement[END_REF] and the technique is less reliable [START_REF] Hadjipanayis | What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?[END_REF][START_REF] Yamada | Role of neurochemical navigation with 5-aminolevulinic acid during intraoperative MRI-guided resection of intracranial malignant gliomas[END_REF][START_REF] Kiesel | Systematic histopathological analysis of different 5-aminolevulinic acid-induced fluorescence levels in newly diagnosed glioblastomas[END_REF][START_REF] Lau | A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas[END_REF][START_REF] Stummer | 5-Aminolevulinic acidderived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging[END_REF]. Proliferation index also correlates with fluorescence intensity [START_REF] Ishihara | Quantitative spectroscopic analysis of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence intensity in diffusely infiltrating astrocytomas[END_REF][START_REF] Widhalm | 5-Aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement[END_REF][START_REF] Yoneda | Spectral Radiance of Protoporphyrin IX Fluorescence and Its Histopathological Implications in 5-Aminolevulinic Acid-Guided Surgery for Glioblastoma[END_REF][START_REF] Widhalm | 5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement[END_REF][START_REF] Kiesel | Systematic histopathological analysis of different 5-aminolevulinic acid-induced fluorescence levels in newly diagnosed glioblastomas[END_REF][START_REF] Roberts | Glioblastoma multiforme treatment with clinical trials for surgical resection (aminolevulinic acid)[END_REF][START_REF] Valdés | δ-aminolevulinic acidinduced protoporphyrin IX concentration correlates with histopathologic markers of malignancy in human gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy[END_REF][START_REF] Saito | Genetic Factors Affecting Intraoperative 5-aminolevulinic Acid-induced Fluorescence of Diffuse Gliomas[END_REF][START_REF] Jaber | The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors[END_REF]. Moreover, necrotic areas are usually nonfluorescent [START_REF] Hadjipanayis | What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?[END_REF][START_REF] Kiesel | Systematic histopathological analysis of different 5-aminolevulinic acid-induced fluorescence levels in newly diagnosed glioblastomas[END_REF][START_REF] Stummer | Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence[END_REF]. Thus, grade, fluorescence intensity [START_REF] Valdés | δ-aminolevulinic acidinduced protoporphyrin IX concentration correlates with histopathologic markers of malignancy in human gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy[END_REF][START_REF] Jaber | The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors[END_REF] and the diagnostic performance of 5-ALA are strongly interdependent, which explains why performance is better in the core of the tumor than in the peri-tumoral area. Secondly, physical factors such as photobleaching or brain or blood covering can mask fluorescent areas [START_REF] Hadjipanayis | What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?[END_REF][START_REF] Stummer | Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence[END_REF]. Finally, pharmacokinetic parameters, and particularly 5-ALA intake timing, can interfere with fluorescence quality [START_REF] Hadjipanayis | What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?[END_REF][START_REF] Stummer | Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue[END_REF][START_REF] Stummer | Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence[END_REF].

Improvement of surgical resection

Studies of mixed populations with either HGG or DLGG were excluded. Only one randomized controlled multicenter phase III trial (level 1), by Stummer et al., was identified. Patients with HGG amenable to complete resection were assigned to conventional WL-surgery or 5-ALA-FGS. Results based on interim analysis were released in 2006 (32), 5 years before publication of the final results [START_REF] Stummer | Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article[END_REF]. The proportion of patients in whom CRET (Complete Resection of the contrast-Enhancing Tumor) was achieved was significantly higher with 5-ALA-FGS (interim analysis: 65% vs. 36%, p<0.0001; final analysis: 63.6% vs. 37.6%, p<0.0001) (Table 2A), independently of patient age or tumor location in eloquent areas [START_REF] Stummer | Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article[END_REF][START_REF] Stummer | Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial[END_REF].

A meta-analysis (level 2) that included 11 prospective or retrospective studies, for a total of 565 patients, reported a pooled complete resection rate of 75.4% (95% CI, 67.4-83.5%; p<0.001) [START_REF] Eljamel | 5-ALA Fluorescence Image Guided Resection of Glioblastoma Multiforme: A Meta-Analysis of the Literature[END_REF]. However, definitions of complete resection differed between studies, which may have led to slightly overestimated results.

Five prospective [START_REF] Kim | Impact of fluorescence-guided surgery on the improvement of clinical outcomes in glioblastoma patients[END_REF][START_REF] Idoate | Pathological characterization of the glioblastoma border as shown during surgery using 5-aminolevulinic acid-induced fluorescence[END_REF][START_REF] Schucht | Gross total resection rates in contemporary glioblastoma surgery: results of an institutional protocol combining 5-aminolevulinic acid intraoperative fluorescence imaging and brain mapping[END_REF][START_REF] Cordova | Semi-Automated Volumetric and Morphological Assessment of Glioblastoma Resection with Fluorescence-Guided Surgery[END_REF][START_REF] Teixidor | Safety and Efficacy of 5-Aminolevulinic Acid for High Grade Glioma in Usual Clinical Practice: A Prospective Cohort Study[END_REF] (level 2) and 2 retrospective studies (level 3) [START_REF] Slotty | The impact of improved treatment strategies on overall survival in glioblastoma patients[END_REF][START_REF] Picart | Is fluorescence-guided surgery with 5-ala in eloquent areas for malignant gliomas a reasonable and useful technique?[END_REF] specifically assessed EOR after 5-ALA-FGS (Table 2A). Although they did not systematically compare 5-ALA-FGS versus WL surgery, the results deserve to be analyzed. Again, heterogeneity in the definition of complete resection together with varying surgeon experience hampered comparison. However, rates of complete resection ranged from 30% to 96% and median EOR was consistently greater than 94%. In the 2 non-randomized studies that compared 5-ALA versus WL surgery, EOR was significantly higher with 5-ALA-FGS [START_REF] Kim | Impact of fluorescence-guided surgery on the improvement of clinical outcomes in glioblastoma patients[END_REF][START_REF] Slotty | The impact of improved treatment strategies on overall survival in glioblastoma patients[END_REF]. Gain in EOR is consistently independent of tumor size [START_REF] Teixidor | Safety and Efficacy of 5-Aminolevulinic Acid for High Grade Glioma in Usual Clinical Practice: A Prospective Cohort Study[END_REF], but some studies suggest that age [START_REF] Cordova | Semi-Automated Volumetric and Morphological Assessment of Glioblastoma Resection with Fluorescence-Guided Surgery[END_REF] or location in eloquent areas [START_REF] Schatlo | Outcomes after combined use of intraoperative MRI and 5-aminolevulinic acid in high-grade glioma surgery[END_REF] influence EOR; a study comparing the two techniques in HGG specifically located in eloquent areas (96) reported higher GTR rates with 5-ALA-FGS, although the difference was not significant.

Interestingly, in a detailed remnologic study of 13 patients with CRET, Schucht et al. showed that mean resection volume under 5-ALA-FGS was significantly greater than the volume of the preoperative contrast-enhancing tumor (84 cm 3 vs. 39 cm 3 ; p = 0.0087) [START_REF] Schucht | 5-ALA complete resections go beyond MR contrast enhancement: shift corrected volumetric analysis of the extent of resection in surgery for glioblastoma[END_REF]. Moreover, in a series of 33 patients reported by Stummer et al. [START_REF] Stummer | 5-Aminolevulinic acidderived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging[END_REF], 23 still had unresected fluorescing tissue at the end of the procedure; residual MRI enhancement was detected in only 65% of them. These results suggest that 5-ALA also stains non-enhanced tumor tissue, and are consistent with the reported improvement in EOR compared to conventional WL surgery, whether or not guided by MRI-based neuronavigation.

Improvement in surgical resection by combining 5-ALA-FGS and iMRI (intraoperative MRI)

Five prospective studies (4 level 2 (49,78,106,107) and 1 level 3 (20)) and 2 retrospective studies (level 3) (108,109) compared EOR on protocols combining 5-ALA and iMRI or not (Table 2B). Three additional prospective studies compared diagnostic performance between 5-ALA-FGS and iMRI [START_REF] Coburger | Histopathological Insights on Imaging Results of Intraoperative Magnetic Resonance Imaging, 5-Aminolevulinic Acid, and Intraoperative Ultrasound in Glioblastoma Surgery[END_REF][START_REF] Coburger | Tumor detection with 5-aminolevulinic acid fluorescence and Gd-DTPA-enhanced intraoperative MRI at the border of contrast-enhancing lesions: a prospective study based on histopathological assessment[END_REF][START_REF] Gessler | Combination of Intraoperative Magnetic Resonance Imaging and Intraoperative Fluorescence to Enhance the Resection of Contrast Enhancing Gliomas[END_REF].

A prospective study directly compared the EOR achieved by 5-ALA-FGS alone or iMRI alone [START_REF] Roder | Maximizing the extent of resection and survival benefit of patients in glioblastoma surgery: high-field iMRI versus conventional and 5-ALA-assisted surgery[END_REF]. EOR was significantly greater with iMRI, but the results were vitiated by likely non-comparability between groups. Moreover, in another study combining iMRI and 5-ALA-FGS, use of 5-ALA was a strong predictor of GTR on multivariate analysis (Odds Ratio = 3.19; 95% CI, 1.28-7.93; p = 0.01) [START_REF] Schatlo | Outcomes after combined use of intraoperative MRI and 5-aminolevulinic acid in high-grade glioma surgery[END_REF]. reported that iMRI was slightly more sensitive but equally specific in comparison with 5-ALA [START_REF] Gessler | Combination of Intraoperative Magnetic Resonance Imaging and Intraoperative Fluorescence to Enhance the Resection of Contrast Enhancing Gliomas[END_REF]. Although these findings are inconsistent, it seems to be generally agreed that combining 5-ALA and iMRI increases EOR.

Comparison with F18-FET PET (F18-fluoroethyl-tyrosine-positron emission tomography)

Although the gold-standard for glioblastoma EOR quantification is early postoperative MRI, 2 prospective studies (level 2) and 1 retrospective study (level 3) assessed the use of F18-fluoroethyl-tyrosine (FET)-positron emission tomography (PET) [START_REF] Stockhammer | Association of F18fluoro-ethyl-tyrosin uptake and 5-aminolevulinic acid-induced fluorescence in gliomas[END_REF][START_REF] Floeth | Comparison of (18)F-FET PET and 5-ALA fluorescence in cerebral gliomas[END_REF]112), with contradictory results.

In a series of 30 patients with grade II to IV glioma, in which 38 biopsies were taken [START_REF] Floeth | Comparison of (18)F-FET PET and 5-ALA fluorescence in cerebral gliomas[END_REF], only 57% of tumors were fluorescent, although 86% of HGGs showed 18F-FET PET uptake. In low-grade glioma, there was 18F-FET uptake in 41% of cases, whereas only 5% were fluorescent. The authors concluded that 18F-FET PET is more sensitive than 5-ALA.

In contrast, Stockhammer et al. reported a series of 13 patients (12 HGGs) who underwent 5-ALA-FGS combined to pre-and post-operative 18F-FET PET [START_REF] Stockhammer | Association of F18fluoro-ethyl-tyrosin uptake and 5-aminolevulinic acid-induced fluorescence in gliomas[END_REF].

Correlation between FET uptake and fluorescence was particularly good: median FET SUV (Standardized Uptake Value) was significantly higher in fluorescent areas (p<0.0001). Roessler et al. retrospectively analyzed a series of 10 patients operated on by 5-ALA-FGS for resection of glioblastoma (11 surgeries) (112); at end of procedure, there was residual fluorescence corresponding to tumor infiltration in samples from the corresponding areas. As there was no postoperative FET uptake in 3 cases, it appeared that 5-ALA was more sensitive than 18F-FET PET for detection of tumor remnant.

Larger-scale prospective series are required for more definite conclusions.

EVIDENCE-BASED DATA FOR GAIN IN SURVIVAL WITH 5-ALA-FGS

One phase III randomized controlled trial (level 1) by a German group [START_REF] Stummer | Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article[END_REF][START_REF] Stummer | Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias[END_REF][START_REF] Stummer | Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial[END_REF] compared survival (PFS and OS) between 5-ALA and conventional WL surgery. 5-ALA-FGS was associated with significant gain in PFS but not in OS (Table 3) [START_REF] Stummer | Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article[END_REF][START_REF] Stummer | Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial[END_REF].

Conversely, adjustment for bias revealed that achievement of GTR resulted in significantly higher OS (16.7 vs. 11.8 months; p = 0.0001) [START_REF] Stummer | Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias[END_REF]. These survival gains were significant across all subgroups of patients, and revision surgery was marginally later in patients with GTR (6.7 vs. 9.5 months; p = 0.0582). On multivariate analysis, the other factors associated with improved prognosis were young age and high KPS (Karnofsky Performance Status) index [START_REF] Stummer | Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias[END_REF][START_REF] Stummer | Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial[END_REF].

A meta-analysis (level 2) (60) of pooled data from 4 prospective and retrospective studies [START_REF] Stummer | Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias[END_REF][START_REF] Jacquesson | Surgery of high-grade gliomas guided by fluorescence: a retrospective study of 22 patients[END_REF][START_REF] Slotty | The impact of improved treatment strategies on overall survival in glioblastoma patients[END_REF]105) reported mean PFS after 5-ALA-FGS of 8.146 months. Gain in OS was 6.167 months compared with WL surgery. After exclusion of 1 study (105) in which concomitant PDT (PhotoDynamic Therapy) was performed, results were more or less similar: PFS, 7.922 months; OS gain, 6.250 months.

Five prospective [START_REF] Kim | Impact of fluorescence-guided surgery on the improvement of clinical outcomes in glioblastoma patients[END_REF][START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF][START_REF] Cordova | Semi-Automated Volumetric and Morphological Assessment of Glioblastoma Resection with Fluorescence-Guided Surgery[END_REF][START_REF] Teixidor | Safety and Efficacy of 5-Aminolevulinic Acid for High Grade Glioma in Usual Clinical Practice: A Prospective Cohort Study[END_REF]113) and 5 retrospective [START_REF] Cordova | Semi-Automated Volumetric and Morphological Assessment of Glioblastoma Resection with Fluorescence-Guided Surgery[END_REF][START_REF] Picart | Is fluorescence-guided surgery with 5-ala in eloquent areas for malignant gliomas a reasonable and useful technique?[END_REF]109,111,114) studies reported additional data on outcome in HGG patients operated on with 5-ALA-FGS. In studies comparing the two techniques, 5-ALA-FGS provided better PFS [START_REF] Kim | Impact of fluorescence-guided surgery on the improvement of clinical outcomes in glioblastoma patients[END_REF]104) and OS [START_REF] Kim | Impact of fluorescence-guided surgery on the improvement of clinical outcomes in glioblastoma patients[END_REF][START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF]113,114) than WL surgery. An inverse correlation was noted between residual fluorescence intensity at end of resection and lower PFS [START_REF] Jacquesson | Surgery of high-grade gliomas guided by fluorescence: a retrospective study of 22 patients[END_REF] and OS (p = 0.01) [START_REF] Jacquesson | Surgery of high-grade gliomas guided by fluorescence: a retrospective study of 22 patients[END_REF][START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF]. On multivariate analysis, the independent predictors of better prognosis were young age [START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF][START_REF] Teixidor | Safety and Efficacy of 5-Aminolevulinic Acid for High Grade Glioma in Usual Clinical Practice: A Prospective Cohort Study[END_REF], high KPS [START_REF] Cordova | Semi-Automated Volumetric and Morphological Assessment of Glioblastoma Resection with Fluorescence-Guided Surgery[END_REF]113), extensive resection [START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF][START_REF] Cordova | Semi-Automated Volumetric and Morphological Assessment of Glioblastoma Resection with Fluorescence-Guided Surgery[END_REF][START_REF] Teixidor | Safety and Efficacy of 5-Aminolevulinic Acid for High Grade Glioma in Usual Clinical Practice: A Prospective Cohort Study[END_REF], use of 5-ALA (114), and hypermethylation of MGMT promotor [START_REF] Cordova | Semi-Automated Volumetric and Morphological Assessment of Glioblastoma Resection with Fluorescence-Guided Surgery[END_REF].

Compared to iMRI alone, combined iMRI and 5-ALA-FGS led to supra-total resection, associated with significantly better OS in one study (111), although this benefit was not found by Coburger et al. (109).

Finally, in a study dedicated to tumors located in the vicinity of eloquent areas, significantly better PFS was achieved with 5-ALA-FGS, although OS did not differ [START_REF] Picart | Is fluorescence-guided surgery with 5-ala in eloquent areas for malignant gliomas a reasonable and useful technique?[END_REF]. On another multivariate analysis, 5-ALA-FGS was also independently associated with better PFS [START_REF] Picart | Is fluorescence-guided surgery with 5-ala in eloquent areas for malignant gliomas a reasonable and useful technique?[END_REF].

5-ALA FLUORESCENCE-GUIDED SURGERY FOR RECURRENT HGG

Some of the above studies assessing performance and resection rates after 5-ALA-FGS included mixed populations of patients, with newly diagnosed or recurrent HGG [START_REF] Valle | Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience[END_REF][START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF][START_REF] Yamada | Role of neurochemical navigation with 5-aminolevulinic acid during intraoperative MRI-guided resection of intracranial malignant gliomas[END_REF][START_REF] Idoate | Pathological characterization of the glioblastoma border as shown during surgery using 5-aminolevulinic acid-induced fluorescence[END_REF][START_REF] Coburger | Tumor detection with 5-aminolevulinic acid fluorescence and Gd-DTPA-enhanced intraoperative MRI at the border of contrast-enhancing lesions: a prospective study based on histopathological assessment[END_REF][START_REF] Lau | A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas[END_REF][START_REF] Stummer | 5-Aminolevulinic acidderived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging[END_REF][START_REF] Schucht | Gross total resection rates in contemporary glioblastoma surgery: results of an institutional protocol combining 5-aminolevulinic acid intraoperative fluorescence imaging and brain mapping[END_REF][START_REF] Schucht | 5-ALA complete resections go beyond MR contrast enhancement: shift corrected volumetric analysis of the extent of resection in surgery for glioblastoma[END_REF]100). Only 4 studies (81,115-117) and a recent review (118) specifically assessed the use of 5-ALA-FGS for recurrent HGG.

In terms of diagnostic performance, in a prospective non-controlled phase II study (level 2) including 36 patients (115), PPV was as high as 91.7% in strongly and 83.3% in weakly fluorescent areas in recurrent HGG. On the other hand, in a retrospective study (level 3) of 313 patients treated by 5-ALA-FGS for suspicion of HGG recurrence, reactive changes without active tumor cells were found in 13 cases and attributed to several factors: chemoradiotherapy, inflammation, etc. [START_REF] Utsuki | Histological examination of false positive tissue resection using 5-aminolevulinic acid-induced fluorescence guidance[END_REF][START_REF] Kamp | 5-ALA-induced fluorescence behavior of reactive tissue changes following glioblastoma treatment with radiation and chemotherapy[END_REF]118); strong or vague fluorescence was found in respectively 7 and 5 of these patients [START_REF] Kamp | 5-ALA-induced fluorescence behavior of reactive tissue changes following glioblastoma treatment with radiation and chemotherapy[END_REF]. Thus, prior chemoradiotherapy may not dramatically impair the accuracy of 5-ALA-FGS in recurrent HGG, but 5-ALA-FGS is unable to discriminate between true progression and pseudo-progression.

In terms of outcome, Hickmann et al. reported a retrospective series (level 3) of 58 patients undergoing iterative surgical resection of HGG under 5-ALA. Overall mean EOR was 91.1%. Interestingly, 15.9% of tumors did not display any fluorescence intraoperatively. Compared to a control group operated on under WL, patients operated on with 5-ALA had longer PFS and OS, but not significantly (respectively, 10.7 vs. 10.6 months, p = 0.4; and 17.6 vs. 14.6 months, p =0.26); however, use of 5-ALA was an independent predictor of increased OS (p = 0.025). Moreover, the global rate of new permanent focal deficits was 6.3% (117).

As not all recurrent HGGs display fluorescence, a prospective study (level 2) assessed the combined use of 5-ALA-FGS and iMRI in 7 patients. GTR was achieved in all patients, and median survival after the second intervention was 7.6 months (116).

Finally, these results suggest that the benefit of 5-ALA-FGS is similar in recurrent and primary HGG.

OTHER INDICATIONS FOR 5-ALA FLUORESCENCE-GUIDED

NEUROSURGERY

It is important to note that there is theoretically no market authorization for 5-ALA in France in the following indications.

Glioma with non-significant contrast enhancement

The spectrophotometric profile is different from that of HGG: the main emission peak is at 620 nm, versus 634 nm for HGG (119). Recently, it was demonstrated that the ratio between the emission peaks at 620 nm/634 nm is close to 0 in HGG and 1.5 in DLGG (unpublished data from Alston et al).

As mentioned above, fluorescence intensity depends on tumor cell density [START_REF] Hadjipanayis | What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?[END_REF][START_REF] Panciani | 5aminolevulinic acid and neuronavigation in high-grade glioma surgery: results of a combined approach[END_REF][START_REF] Valle | Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience[END_REF][START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF][START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF][START_REF] Yamada | Role of neurochemical navigation with 5-aminolevulinic acid during intraoperative MRI-guided resection of intracranial malignant gliomas[END_REF][START_REF] Panciani | Fluorescence and image guided resection in high grade glioma[END_REF][START_REF] Roberts | Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between δaminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article[END_REF][START_REF] Idoate | Pathological characterization of the glioblastoma border as shown during surgery using 5-aminolevulinic acid-induced fluorescence[END_REF][START_REF] Coburger | Tumor detection with 5-aminolevulinic acid fluorescence and Gd-DTPA-enhanced intraoperative MRI at the border of contrast-enhancing lesions: a prospective study based on histopathological assessment[END_REF][START_REF] Yoneda | Spectral Radiance of Protoporphyrin IX Fluorescence and Its Histopathological Implications in 5-Aminolevulinic Acid-Guided Surgery for Glioblastoma[END_REF][START_REF] Stummer | Predicting the "usefulness" of 5-ALA-derived tumor fluorescence for fluorescence-guided resections in pediatric brain tumors: a European survey[END_REF][START_REF] Widhalm | 5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement[END_REF] and proliferation index [START_REF] Kiesel | Systematic histopathological analysis of different 5-aminolevulinic acid-induced fluorescence levels in newly diagnosed glioblastomas[END_REF][START_REF] Ishihara | Quantitative spectroscopic analysis of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence intensity in diffusely infiltrating astrocytomas[END_REF][START_REF] Widhalm | 5-Aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement[END_REF][START_REF] Yoneda | Spectral Radiance of Protoporphyrin IX Fluorescence and Its Histopathological Implications in 5-Aminolevulinic Acid-Guided Surgery for Glioblastoma[END_REF][START_REF] Widhalm | 5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement[END_REF][START_REF] Roberts | Glioblastoma multiforme treatment with clinical trials for surgical resection (aminolevulinic acid)[END_REF][START_REF] Valdés | δ-aminolevulinic acidinduced protoporphyrin IX concentration correlates with histopathologic markers of malignancy in human gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy[END_REF][START_REF] Saito | Genetic Factors Affecting Intraoperative 5-aminolevulinic Acid-induced Fluorescence of Diffuse Gliomas[END_REF][START_REF] Jaber | The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors[END_REF], which finally explains why fluorescence intensity depends on tumor grade [START_REF] Valdés | δ-aminolevulinic acidinduced protoporphyrin IX concentration correlates with histopathologic markers of malignancy in human gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy[END_REF][START_REF] Jaber | The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors[END_REF]. It was also recently demonstrated that tumors with IDH1-mutant or 1p/19 codeletion are significantly less fluorescent that those without [START_REF] Saito | Genetic Factors Affecting Intraoperative 5-aminolevulinic Acid-induced Fluorescence of Diffuse Gliomas[END_REF][START_REF] Jaber | The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors[END_REF].

In 7 prospective (level 2) [START_REF] Ewelt | Finding the anaplastic focus in diffuse gliomas: the value of Gd-DTPA enhanced MRI, FET-PET, and intraoperative, ALA-derived tissue fluorescence[END_REF][START_REF] Widhalm | 5-Aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement[END_REF][START_REF] Widhalm | 5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement[END_REF][START_REF] Saito | Genetic Factors Affecting Intraoperative 5-aminolevulinic Acid-induced Fluorescence of Diffuse Gliomas[END_REF][START_REF] Jaber | The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors[END_REF]120,121) and 1 retrospective (level 3) (108) study, the rate of WHO grade II glioma displaying fluorescence ranged from 0% to 50%. Intraoperative confocal microscopy could improve the intraoperative visibility of fluorescence [START_REF] Sanai | An extent of resection threshold for newly diagnosed glioblastomas[END_REF][START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF][START_REF] Ishihara | Quantitative spectroscopic analysis of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence intensity in diffusely infiltrating astrocytomas[END_REF][START_REF] Valdés | Combined fluorescence and reflectance spectroscopy for in vivo quantification of cancer biomarkers in low-and high-grade glioma surgery[END_REF]120,122). Although it is less reliable than MRI, 5-ALA could facilitate intraoperative identification of anaplastic foci in gliomas with nonsignificant enhancement [START_REF] Ewelt | Finding the anaplastic focus in diffuse gliomas: the value of Gd-DTPA enhanced MRI, FET-PET, and intraoperative, ALA-derived tissue fluorescence[END_REF][START_REF] Widhalm | 5-Aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement[END_REF]121). Very recently, it was established that fluorescence predicts malignant transformation and is independently correlated with OS (123).

Other tumors

A few studies were dedicated to the use of 5

EVIDENCE-BASED DATA ON 5-ALA-FGS SAFETY IN TERMS OF FUNCTIONAL RISK

Results from 2 randomized trials (level 1) (9,115), 4 prospective studies (level 2) (35,100,101,139) and 1 retrospective study (level 3) ( 96) are detailed in Table 4.

They consistently suggest that 5-ALA-FGS in eloquent areas induces a higher rate of early neurological impairment than WL surgery. In eloquent areas, rates of neurological impairment ranged from 3% to 64%. Impairment is transient, and by 3 months the difference is no longer significant and general health status is even sometimes better in 5-ALA groups [START_REF] Kim | Impact of fluorescence-guided surgery on the improvement of clinical outcomes in glioblastoma patients[END_REF]. Moreover, in some cases, severe neurological impairment was related to iatrogenic cerebral infarction due to microvascular injury [START_REF] Gessler | Combination of Intraoperative Magnetic Resonance Imaging and Intraoperative Fluorescence to Enhance the Resection of Contrast Enhancing Gliomas[END_REF][START_REF] Stummer | Predicting the "usefulness" of 5-ALA-derived tumor fluorescence for fluorescence-guided resections in pediatric brain tumors: a European survey[END_REF][START_REF] Feigl | Resection of malignant brain tumors in eloquent cortical areas: a new multimodal approach combining 5aminolevulinic acid and intraoperative monitoring[END_REF]139) and was thus not imputable to 5-ALA-FGS.

Finally, preoperative selection of the "right" candidates has to be particularly thorough.

The risk of postoperative neurological deterioration is higher in patients with preexisting neurological deficits unresponsive to steroids, as these are more probably related to tumor infiltration than to the surrounding edema [START_REF] Stummer | Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial[END_REF][START_REF] Kim | Impact of fluorescence-guided surgery on the improvement of clinical outcomes in glioblastoma patients[END_REF][START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF][START_REF] Schucht | Gross total resection rates in contemporary glioblastoma surgery: results of an institutional protocol combining 5-aminolevulinic acid intraoperative fluorescence imaging and brain mapping[END_REF],100,101,106).

Aldave et al. reported that the rate of definitive functional impairment tends to be higher when all fluorescent areas are resected than when some fluorescent areas remain after resection (114). As it offers no functional information, 5-ALA alone is obviously insufficient to determine the optimal oncologic/functional trade-off, and a multimodal approach is needed to decrease morbidity [START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF]. Preoperative In a study comparing iMRI alone versus combined iMRI + 5-ALA-FGS in HGG located in eloquent areas, the latter did not lead to functional impairment: preand post-operative KPS values were comparable (p = 0.394) and there were no significant differences in terms of neurocognitive impairment between the two groups (111).

COST-EFFECTIVENESS OF 5-ALA-FGS

Depending on whether patient body-weight requires the use of one or two vials, the cost of 5-ALA (Gliolan®, Medac Pharma, Wedel, Germany) per procedure is €1,000 (≤75kg) or €2,000 (>75kg).

Three studies assessed the cost-effectiveness of 5-ALA-FGS (142-144). In one, compared to conventional WL surgery, the extra cost per additional complete resection was €4,550 (143). In another, the extra cost per life-year gained was €6,700 (144). In the third, extra cost per quality-adjusted life-year gained ranged from €9,021 to US$16,218 (142-144), which is 2-fold less than with iMRI (142).

On consensual thresholds, all studies concluded that 5-ALA-FGS was costeffective for the resection of HGG [START_REF] Jenkinson | Intraoperative imaging technology to maximise extent of resection for glioma[END_REF](142)(143)(144).

PRACTICAL RECOMMENDATIONS

Although 5-ALA-FGS is deemed to be easy, it is essential that neurosurgeons have a complete understanding of its technical specificities. Therefore, a training course sponsored by the manufacturer of 5-ALA, Medac Pharma (Wedel, Germany), is recommended before performing the operation for the first time. The learning curve is around 10 to 15 patients and is one of the limiting factors, as expertise varies between centers, inducing bias [START_REF] Stummer | Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias[END_REF][START_REF] Stummer | Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial[END_REF]. Few studies have detailed the practical aspects, and especially pitfalls that can prevent macroscopically complete resection [START_REF] Stummer | Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue[END_REF]145).

5-ALA administration

France, 5-ALA (Gliolan®) is marketed by Medac. It is a white powder contained in a glass vial (1.5 g/vial). It is administered orally, diluted in 50 mL drinking water.

The solution is slightly sour but usually well tolerated by patients. It is not recommended to dissolve 5-ALA in fruit juice, as the increased acidity modifies absorption (145).

Two randomized phase I clinical trials (level 1) and a prospective study (level [START_REF] Ennis | Transport of 5aminolevulinic acid between blood and brain[END_REF]147). Consequently, optimal dose-efficacy is 20 mg/kg (147,148).

The best time for ALA administration has been also studied [START_REF] Stummer | In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid[END_REF][START_REF] Stummer | Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue[END_REF][START_REF] Stummer | Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence[END_REF]149,150). For optimal fluorescence, 5-ALA has to be administered 3 hours before induction of anesthesia, to enable complete intestinal absorption (approximately 1 hour), followed by conversion into fluorescent PpIX in tumor cells. In humans, halflife varies between 0.85 and 3.05 hours (147). Fluorescence peaks 6 hours after administration, and lasts more than16 hours [START_REF] Stummer | Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue[END_REF].

Stummer et al. reported the importance of dexamethasone pre-treatment (3 x 4 mg for 2 days) to optimize 5-ALA uptake by reducing PpIX efflux and peritumoral fluorescence by tightening up the blood-brain barrier [START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF]145). Pre-treatment with steroids also identifies patients at risk of neurological deficit after 5ALA-FGS: persistence of preoperative deficit after dexamethasone indicates that the deficit is secondary to functional tumor infiltration and not due to edema, and is a contraindication to 5ALA-FGS [START_REF] Stummer | Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial[END_REF][START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF].

Adverse events and precautions for use

Adverse events inherent to 5-ALA administration per se are minor, transient and uncommon [START_REF] Stummer | Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial[END_REF][START_REF] Valle | Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience[END_REF][START_REF] Hefti | 5-aminolevulinic acid induced protoporphyrin IX fluorescence in high-grade glioma surgery: a one-year experience at a single institution[END_REF][START_REF] Panciani | Fluorescence and image guided resection in high grade glioma[END_REF][START_REF] Lau | A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas[END_REF][START_REF] Stummer | 5-Aminolevulinic acidderived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging[END_REF]115,149,150) provided that preventive measures are applied and contraindications are respected [START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF]. 5-ALA should not be given to patients with either inherited or acquired porphyria, hypersensitivity to porphyrins, or severe kidney or liver failure, or during pregnancy [START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF].

The most frequent adverse events are nausea, vomiting and gastroesophageal reflux [START_REF] Cordova | Semi-Automated Volumetric and Morphological Assessment of Glioblastoma Resection with Fluorescence-Guided Surgery[END_REF], with frequency varying from 0% (94) to 3% [START_REF] Yamada | Role of neurochemical navigation with 5-aminolevulinic acid during intraoperative MRI-guided resection of intracranial malignant gliomas[END_REF]. They can be prevented by anti-emetic drugs. The only severe adverse effect potentially attributable to 5-ALA was a second gastro-intestinal perforation 24h after administration, in a patient with history of gastrointestinal perforation [START_REF] Cordova | Semi-Automated Volumetric and Morphological Assessment of Glioblastoma Resection with Fluorescence-Guided Surgery[END_REF].

Another common adverse event is sunlight-induced erythema, with incidence ranging from 0% (94) to 1% [START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF][START_REF] Yamada | Role of neurochemical navigation with 5-aminolevulinic acid during intraoperative MRI-guided resection of intracranial malignant gliomas[END_REF]. It is prevented by avoiding direct sunlight or strong room light and by eviction of other photosensitizers within 24 hours of 5-ALA intake [START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF]145).

The risk of normal brain photosensitization has also been raised but is only theoretical for two reasons. Firstly, in normal brain tissue, PpIX levels are very low.

Secondly, current fluorescence microscopy equipment cannot create high enough energy levels to cause phototoxic damage in normal brain [START_REF] Stummer | In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid[END_REF][START_REF] Stummer | Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue[END_REF][START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF][START_REF] Stummer | Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence[END_REF].

Biologically, the rate of transaminases and GGT (gamma glutamyl transpeptidase) elevation 24 hours after surgery was significantly higher in a 5-ALA group than in the WL group [START_REF] Stummer | Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial[END_REF]. After 5-ALA intake, serum GGT and alanine aminotransferase levels corresponded to Grade 3 toxicity according to the criteria of the National Cancer Institute of Germany in 5.7% of cases [START_REF] Stummer | Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients[END_REF]. Hypoalbuminemia and hyperbilirubinemia are sometimes reported [START_REF] Cordova | Semi-Automated Volumetric and Morphological Assessment of Glioblastoma Resection with Fluorescence-Guided Surgery[END_REF]; they are asymptomatic and disappear within 1 to 6 weeks [START_REF] Stummer | Predicting the "usefulness" of 5-ALA-derived tumor fluorescence for fluorescence-guided resections in pediatric brain tumors: a European survey[END_REF][START_REF] Cordova | Semi-Automated Volumetric and Morphological Assessment of Glioblastoma Resection with Fluorescence-Guided Surgery[END_REF][START_REF] Teixidor | Safety and Efficacy of 5-Aminolevulinic Acid for High Grade Glioma in Usual Clinical Practice: A Prospective Cohort Study[END_REF]. Patients with pre-existing asymptomatic hepatic enzyme elevation were at risk of further increase [START_REF] Teixidor | Safety and Efficacy of 5-Aminolevulinic Acid for High Grade Glioma in Usual Clinical Practice: A Prospective Cohort Study[END_REF]. Pragmatically, hepatic enzyme concentration should be checked postoperatively.

To conclude, 5-ALA is well tolerated and no severe general or biological adverse events have been linked to 5-ALA with certainty [START_REF] Mansouri | Journal club: 5-aminolevulinic acid-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging[END_REF][START_REF] Stummer | Predicting the "usefulness" of 5-ALA-derived tumor fluorescence for fluorescence-guided resections in pediatric brain tumors: a European survey[END_REF]132,146).

5-ALA-FGS procedure

Technically, 5-ALA-FGS does not greatly differ from conventional HGG microneurosurgical resection. It is, however, more time-consuming than WL surgery, which partly explains its limited use. Anesthesia induction, patient positioning, draping and craniotomy are performed in the usual way.

If the tumor is small, cortical and away from eloquent areas, it can be useful to begin by determining corticectomy boundaries by blue light excitation. The interface between fluorescent and non-fluorescent tissue represents the "pseudo dissection plane". Debulking is performed centripetally from periphery to tumor core, switching between WL and blue light during the procedure. More frequently, the tumor is large and/or close to an eloquent area. In this case the surgeon may prefer to remove any easily distinguishable necrotic and solid tumor tissue predominantly under WL [START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF].

However, to remove infiltrating residual tumor not distinguishable under WL, fluorescence-guided resection is essential. Resection progresses centrifugally from core to periphery, switching between white and blue light until all signs of fluorescence have disappeared [START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF]145). Alternatively, some neurosurgeons prefer beginning the resection using anatomical landmarks, performing subpial resection around the glioma core and using fluorescence in the deepest part of the resection, together with intraoperative brain mapping.

During resection, the surgeon usually identifies three areas: necrotic tissue, which is non-fluorescent, solid tumor, with strong red fluorescence (both of which are generally easily distinguishable under WL), and infiltration by isolated glioma cells, which gives a more or less distinctive pink fluorescence visualized only under blue light (Figure 2). Red fluorescence corresponds to contrast-enhanced MRI, whereas pink fluorescence is the equivalent of non-contrast-enhanced MRI. Resection of the necrotic areas and red fluorescence, corresponding to the solid component of the HGG, are not at major risk. However, in eloquent areas, pink fluorescent areas are to be resected with caution and using permanent monitoring [START_REF] Idoate | Pathological characterization of the glioblastoma border as shown during surgery using 5-aminolevulinic acid-induced fluorescence[END_REF][START_REF] Picart | Is fluorescence-guided surgery with 5-ala in eloquent areas for malignant gliomas a reasonable and useful technique?[END_REF].

It is important to remember that blood can mask fluorescent areas, and it is important to keep the surgical cavity as "clean" as possible (151). Unlike other imaging methods, the surgeon never has to look up from the microscope, as switching between WL and blue light is done by finger touch on the microscope. Also, during resection, the neurosurgeon can see tumor tissue 'online' that is not visible to the naked eye [START_REF] Valle | Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience[END_REF][START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF]145).

Where possible, the microscope should be positioned so that the light is perpendicular to the resection surface. The light source should be close to the cavity, as the intensity of light excitation diminishes over distance.

With increasing surgical experience, longer phases of the operation can be performed under blue excitation light alone, although WL illumination may still be necessary to discern anatomical structures such as blood vessels, although they can also be identified on fluorescence by their blue-green color under blue light [START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF]145).

The problem of overhanging margins is recurrent in deep subcortical and cystic tumors [START_REF] Guyotat | 5-Aminolevulinic Acid-Protoporphyrin IX Fluorescence-Guided Surgery of High-Grade Gliomas: A Systematic Review[END_REF]145). During tumor resection, surgeons tend to undercut the cortex, leaving residual tumor hidden under the margins that remains visualizable under blue excitation light outside the surgeon's direct field of vision. This "shadow cone" phenomenon should be kept in mind. Likewise, cyst opening can lead to the collapse of tumor parts that, in some cases, may go unnoticed.

At the end of the procedure, it is important to wipe the resection cavity margins with cotton pads to remove blood and any superficial cell layers. Pink fluorescence may reappear, showing any residual tumor. This phenomenon of fluorescence refreshing is related to PpIX photobleaching, which is the chemical degradation of fluorophores as a result of exposure to light. The level of fluorescence decays to 36% in 87 minutes under WL and in 25 minutes under blue light [START_REF] Stummer | In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid[END_REF][START_REF] Stummer | Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue[END_REF][START_REF] Stummer | Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence[END_REF]. Consequently, exposure to white or blue light has to be minimized.

INTERPRETATION BY THE NEURO-ONCOLOGY CLUB OF THE FRENCH NEUROSURGERY SOCIETY (SFN)

As argued above, 5-ALA shows good specificity for detection of a tumor remnant during resection of HGG but has weaker sensitivity (level 2).

Use of 5-ALA significantly increases the rate of GTR, which was higher than 90% in some series (level 1). Given the known relation between EOR and survival, 5-ALA-FGS can be expected to improve PFS (level 1). Gain in OS is more debatable according to the literature. Nevertheless, the combination of 5-ALA and iMRI could increase both EOR and survival (level 2).

Conversely, impaired neurological status is associated with poorer prognosis [START_REF] Stummer | The importance of surgical resection in malignant glioma[END_REF][START_REF] Li | The influence of maximum safe resection of glioblastoma on survival in 1229 patients: Can we do better than gross-total resection?[END_REF][START_REF] Sanai | An extent of resection threshold for newly diagnosed glioblastomas[END_REF][START_REF] Stummer | Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias[END_REF]152), which emphasizes the importance of striking an individual oncologic/functional trade-off in each patient [START_REF] Hadjipanayis | What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas?[END_REF]139). In HGG located in an eloquent area, conserving and improving recovery of neurological function are thus prime objectives [START_REF] Lacroix | A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival[END_REF][START_REF] Sanai | Glioma extent of resection and its impact on patient outcome[END_REF][START_REF] Li | The influence of maximum safe resection of glioblastoma on survival in 1229 patients: Can we do better than gross-total resection?[END_REF]. Use of 5-ALA-FGS in eloquent areas is totally feasible, but requires simultaneous monitoring to precisely locate and preserve eloquent areas (level 2). The general side-effects of 5-ALA are rare and benign.

Use of 5-ALA is possible in both primary HGG resection and in recurrence, although reactive astrocytes can induce false-positive fluorescence. It could also be useful in other indications, and especially to help resection of high grade meningioma (level 2).

Finally, from an economic viewpoint, the few studies available suggest that 5-ALA is cost-effective.

FUTURE PERSPECTIVES

An ongoing prospective randomized multicenter trial (RESECT -ClinicalTrials.gov Identifier: NCT01811121) including 204 patients has been initiated in 20 French neurosurgical centers to assess the cost-effectiveness of 5-ALA-FGS for the resection of HGG, and may provide interesting data; results will be available in 2019.

In the future, efforts should aim to strengthen the sensitivity of 5-ALA-FGS.

Since fluorescence intensity correlates directly with proliferation index, 40% of nonfluorescent tumor biopsies have PpIX concentrations >0.1 ng/mL, detectable on ex-vivo spectroscopy [START_REF] Stummer | 5-Aminolevulinic acidderived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging[END_REF][START_REF] Valdés | δ-aminolevulinic acidinduced protoporphyrin IX concentration correlates with histopathologic markers of malignancy in human gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy[END_REF], the development of which could contribute to optimizing resection of HGG [START_REF] Ishihara | Quantitative spectroscopic analysis of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence intensity in diffusely infiltrating astrocytomas[END_REF]119).

Both an American study (120) and a recent study by our group (122) suggested that intraoperative in-vivo probe-based confocal laser endomicroscopy with 5-ALA could be used in DLGG, HGG and lymphoma, improving performance by enhancing the contribution of biopsies and providing more precise analysis of resection margins (122).

Other projects are trying to develop PDT, which is based on the phototoxic properties of PpIX (133,151,153). This strategy is currently applied in dermatology for actinic keratosis or basal cell carcinoma [START_REF] Collaud | On the selectivity of 5-aminolevulinic acidinduced protoporphyrin IX formation[END_REF]. The principle consists in producing cytotoxic molecules by light-activation of a photosensitizer (154). Animal experimentation in rats with induced glioblastoma highlighted that interstitial PDT with fractionated light is able to induce intra-tumor necrosis and apoptosis but also peripheral neovascularization (154). An ongoing phase I study (INDYGO trial) is assessing the feasibility of intraoperative PDT in human patients (153).

These strategies are promising and could improve or even transform the prognosis of HGG in the future.

The authors have no conflicts of interest to disclose.

  77 and 0.92, respectively, in areas of strong fluorescence. Pooled positive and negative predictive values were 0.85 and 0.70, respectively, and 0.92 and 0.79 in areas of strong fluorescence. More recently, Eljamel et al. (60) concluded that the technique was highly sensitive (0.826) and specific (0.888), based on a systematic review that included 8 studies (61,62,65,71-75), yet with the same issue of partial overlap with previous meta-analyses.

  Two studies (106,108), comparing 5-ALA alone and combined 5-ALA and iMRI, reported contradictory results. Eyüpoglu et al. found that the combination of the two methods significantly increased EOR (106), whereas the difference was nonsignificant for Tsugu et al. (108), who nevertheless concluded that the combination of techniques had a synergistic effect. Conversely, a case-control study (109) compared iMRI only and combined iMRI and 5-ALA-FGS, and a prospective study (107) compared 5-ALA only, iMRI only, the combination of the two, or neither. Two prospective studies of 5-ALA-FGS and iMRI (49,78,110) reported that each technique can leave some tumor tissue undetected and that the combination optimizes both EOR GTR rate. Likewise, in 30 consecutive patients, Eyüpoglu et al. achieved supra-total resection thanks to the combination of the two techniques (111). Additionally, Coburger et al. concluded that 5-ALA was more sensitive but less specific than iMRI for the detection of HGG remnants (54,71) whereas Gessler et al.

  neuroradiological examinations, including classical MRI, functional MRI (fMRI) and diffusion tensor imaging (DTI) sequences, are essential to visualize eloquent areas and fiber tracts (92,99-101). In eloquent areas, it is also mandatory to associate intraoperative cortical and subcortical monitoring to 5-ALA-FGS (96,99,101,109,139-141). According to Feigl et al.'s experience, based on 18 patients with primary malignant brain tumor located in eloquent areas, resection was stopped in 24% of cases because an eloquent area was identified while a fluorescent tumor remnant was still visible.

Figure 1 :

 1 Figure 1: Principle of tumor fluorescence by 5-ALA accumulation

Figure 2 :

 2 Figure 2: Intraoperative fluorescence is not homogenous within a tumor

  2) were recently conducted to determine the most appropriate dose of 5-ALA (146,147). Dose-escalation up to 50 mg/kg in 10 mg/kg increments was tested by Cozzens et al. in 19 patients. At 50 mg/kg, 33.3% of patients experienced grade I skin toxicity. However, patients with doses >40 mg/kg tended to show stronger

fluorescence, although no statistical analysis was performed (146). Doses >20 mg/kg decrease specificity and increase the risk of resecting non-tumor tissue and thus inducing neurological deficits and systemic adverse effects

[START_REF] Stummer | In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid[END_REF][START_REF] Stummer | Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence[END_REF]

. Conversely, Stummer et al. tested dose-reduction in 21 patients (0.2 vs. 2 vs. 20 mg/kg) (147). At 0.2 mg/kg, no fluorescence was elicited. Increasing doses did not elicit proportional increases in plasma PpIX level or tissue fluorescence, which would suggest that further increases would not enhance the tissue concentration of PpIX and thus the intensity of fluorescence