The NXDC-MEN-301 Study on 5-ALA for Meningiomas Surgery: An Innovative Study Design for the Assessing the Benefit of Intra-Operative Fluorescence Imaging

Abstract

Background: 5-aminolevulinic acid (5-ALA; GleolanTM, NX Development Corps., Lexington, USA) is approved for fluorescence-guided resections of suspected malignant gliomas. Experience has demonstrated that meningiomas also show fluorescence, which may be a useful surgical adjunct. We present an innovative design for a multi-center, prospective study to determine the clinical safety and potential benefit of fluorescence-guided resection of meningiomas with utmost bias reduction. Methods: All patients with suspected meningioma (all grades) receive GleolanTM 20 mg/kg 2–4 h prior to surgery supported by fluorescence excitation from a blue light source (Blue400, Zeiss Meditech, Oberkochen, Germany; FL400, Leica Microsystems, Heerbrugg, Switzerland). Surgeons are asked whether a residual tumor can be observed to fluoresce under blue light (BL) after the tumor is no longer recognizable using conventional illumination at the end of surgery. In addition, when faced with tissues of uncertain tissue type (so-called “indeterminate” tissue), this study records how often surgeons make a correct decision based on fluorescence and how this influences surgical strategy. The primary endpoint is the percentage of patients in whom one of these two benefits are observed. Other endpoints include the diagnostic accuracy of fluorescence compared to white light (WL) versus correlative histology. For bias reduction, pertinent data are derived from surgical videos reviewed by independent reviewers blinded to surgeons’ assessments of tissue type and fluorescence status. Data will be included from approximately 100 study participants completing the study at approximately 15 centers in the United States, Germany, and Austria. Results: As of May 2022, 88 patients have completed the study. No adverse safety signal has been detected. Conclusions: Preliminary data confirm the feasibility of our study design. Accrual is targeted for completion in the third quarter of 2022.

Intraoperative molecular imaging: 3rd biennial clinical trials update

“…15 Stummer et al described the NXDC-MEN-301 phase 3 open-label single-arm study investigating the safety and efficacy of 5-ALA for visualization of meningiomas during resection. 16 The primary outcome measure for that study is the proportion of participants who have one or more indeterminate tissue of unexpected fluorescence at the end of surgery where 5-ALA fluorescence is consistent with histology. He described the blinding design of the study, i.e., recording all assessments during the study and providing these images to a blinded panel.…”

Meningiomas with CNS invasion

“…Fluorescence-guided microsurgery may also prove helpful when dealing with brain invasive meningiomas ( Linsler et al, 2019 ; Jelke et al, 2021 ; Chotai and Schwartz, 2022 ). In order to further assess the benefit of 5-ALA fluorescence-guided meningioma surgery, the NXDC-MEN-301 phase 3 open-label single arm study is currently being conducted in 16 centers of USA, Germany and Austria ( Stummer et al, 2022 ).…”

Commentary: A new uPAR-targeting fluorescent probe for optical guided intracranial surgery in resection of a meningioma-a case report

“…Others have defined several possible biases and confounders which need to be respected during validation studies of fluorescent agents [2][3][4] based on biopsies. To overcome such biases, studies certainly require a certain degree of complexity to be accepted as approval studies by FDA and EMA for intra-operative imaging agents [5]. This standard is listed in the EQUATOR network database (https:// www.…”