Long-term Cognitive and Functional Impact of Proton-therapy or Modern Fractionated Radiotherapy in Cavernous Sinus Meningioma: An Open-label Randomized 1:1 Phase III Study (COG-PROTON-01)

Long-term Cognitive and Functional Impact of Proton-therapy or Modern Fractionated Radiotherapy in Cavernous Sinus Meningioma

Cavernous sinus meningiomas are close to optic nerve, pituitary gland, cranial nerve, and hippocampi.

The doses delivered to these structures are crucial and radiotherapy of cavernous sinus meningiomas exposes patients to late secondary effects (pituitary deficit, nerve palsy, cognitive impairment…). In 2012, Gondi reported that a dose given to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade adult brain tumors.

There is no published or recruiting prospective study evaluating the impact of proton-therapy or conventional irradiation on neurocognitive function for meningioma patients. Notably, long-term cognitive or ocular impact of these modern irradiation schemes remains poorly known. Yet, these patients had a long life-expectancy, and are at risk of developing long-term sequelae. Thus, according to its ballistic advantage, an improvement of patient functional outcomes and a reduction of neurocognitive long-term toxicity are expected if tissue sparing proton-therapy is used.

In this context, a randomized prospective study, evaluating long-term toxicity of these two irradiation modalities (Proton Therapy (PRT) and photon radiotherapy (XRT)) seems crucial to further assess proton-therapy indication for these patients.

Although literature reports excellent outcomes for intracranial meningioma patients treated by proton-therapy, none of the eight retrospective studies found in the literature used an accurate and full evaluation of long-term toxicity

Study Overview

• Status: Recruiting
• Conditions: Cognitive Impairment; Cavernous Sinus Meningioma; Proton-therapy; Photon Radiotherapy
• Intervention / Treatment: Radiation: Proton-therapy; Radiation: Photon radiotherapy

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jean-Michel GRELLARD; Phone Number: +33 2 31 45 50 50; Email: jm.grellard@baclesse.unicancer.fr
• Study Contact Backup: Name: Jeanne RIVERAIN, MD; Phone Number: +33 2 31 45 50 50; Email: j.riverain@baclesse.unicancer.fr

Study Locations

• France
  • Caen, France, 14000
    • Recruiting
    • Centre Francois Baclesse
    • Contact: Jeanne RIVERAIN, MD; Phone Number: 33 2 31 45 50 50; Email: j.riverain@baclesse.unicancer.fr
    • Principal Investigator: Jeanne RIVERAIN, MD
  • Clamart, France
    • Not yet recruiting
    • Hopital D'Instruction Des Armees Percy
    • Contact: Damien RICARD, PhD
    • Principal Investigator: Damien RICARD, PhD
  • Grenoble, France
    • Not yet recruiting
    • CHU Grenoble-Alpes
    • Contact: Alexandre, MD
    • Principal Investigator: Alexandre LEBOUCHER, MD
  • Le Havre, France
    • Not yet recruiting
    • Centre Guillaume Le Conquerant
    • Principal Investigator: Paul LESUEUR, MD
    • Contact: Paul LESUEUR, MD; Phone Number: 33 2 35 13 66 13; Email: p.lesueur@cglc.fr
  • Lyon, France
    • Not yet recruiting
    • Centre Léon Bérard
    • Contact: Marie-Pierre SUNYACH, PhD
  • Lyon, France
    • Not yet recruiting
    • Hospices Civils de Lyon
    • Contact: Loic FEUVRET, MD
  • Nice, France
    • Not yet recruiting
    • Centre Antoine Lacassagne
    • Contact: Pierre-Yves BONDIAU, PhD
    • Principal Investigator: Pierre-Yves BONDIAU, PhD
  • Paris, France
    • Not yet recruiting
    • Hopital Pitie Salpetriere
    • Contact: Julian JACOB, MD
    • Principal Investigator: Julian JACOB, MD
  • Paris, France
    • Recruiting
    • Institut Curie
    • Contact: Emmanuel JOUGLAR, MD
    • Principal Investigator: Emmanuel JOUGLAR, MD
  • Saint-Cloud, France
    • Not yet recruiting
    • Institut Curie
    • Contact: Maxime LOO, MD
    • Principal Investigator: Maxime LOO, MD
  • Strasbourg, France
    • Not yet recruiting
    • Centre Paul Strauss
    • Principal Investigator: Georges NOEL, PhD
    • Contact: Georges NOEL, PhD; Phone Number: 33 3 68 76 73 76; Email: g.noel@icans.eu
  • Toulouse, France
    • Recruiting
    • IUCT
    • Contact: Justine ATTAL, MD
    • Principal Investigator: Justine ATTAL, MD
  • Villejuif, France
    • Not yet recruiting
    • Gustave Rousy
    • Contact: Noura SELLAMI, MD; Phone Number: 33142115542; Email: noura.sellami@gustaveroussy.fr
    • Contact: Noura SELLAMI, MD
    • Principal Investigator: Noura SELLAMI, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Cavernous sinus meningioma for which clinical target volume is larger than 3 centimeters
• Anterior skull base meningioma, invading by contiguity the cavernous sinus can be included
• Histologic proven Grade I meningioma
• Meningioma for which biopsy is not safely achievable and for which growing and imaging criteria are in favour of grade I meningioma can be included
• Age >18 years and ≤70 years
• Indication of irradiation validated by a pluridisciplinary meeting
• Adjuvant or exclusive irradiation is allowed.
• Use of conventional fractionation: 1.8Gy (RBE)/fraction
• Signed informed consent form
• WHO Performance status equal to 0 or 1
• Patient affiliated to the French social health insurance
• MoCA score ≥ cut-off of GRECOGVASC normative data (Roussel, 2016, cf annexe 1)
• Patient whose neuropsychological abilities allow to follow the requirements of the protocol

Exclusion Criteria:

• Patient with mutation in a known predisposition gene (NF-2, SMARCE-1…)
• Cerebrovascular pathology, presence of other tumors of the nervous system, congenital malformations of the nervous system, multiple sclerosis, Parkinson's disease and other dementias, organic psychosis (other than dementia), schizophrenia, and neurodegenerative disease
• Radiosurgery, hypofractionated regimen
• Other localization than cavernous sinus
• Histologic proven Grade II or III meningioma
• Patient with unadjusted antiepileptic drug
• Contraindication to MRI
• Patient with a history of brain irradiation
• Patient with a history of cancer in the last five years (excluding skin baso-cellular carcinoma)
• Pregnant/breastfeeding woman
• Any geographical conditions, social and associated psychopathology that may compromise the patient's ability to participate in the study
• Participation in a therapeutic trial for less than 30 days
• Patient deprived of freedom or under guardianship

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: proton-therapy; Proton pencil-beam-scanning irradiation (50,4 Gy (RBE) in 28 fractions)	Radiation: Proton-therapy; Proton pencil-beam-scanning irradiation (50,4 Gy (RBE) in 28 fractions)
Active Comparator: photon radiotherapy; Intensity modulated radiotherapy with or without stereotactic positioning (50,4 Gy in 28 fractions)	Radiation: Photon radiotherapy; Intensity modulated radiotherapy with or without stereotactic positioning (50,4 Gy in 28 fractions)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
functional deterioration evaluated by individual neurocognitive test scores	Neurocognitive deterioration defined as the occurrence of cognitive impairment (a total of 5 impaired z-scores (17 z-scores for 6 different tests)	5 years

Collaborators and Investigators

• Sponsor: Centre Francois Baclesse
• Collaborators: National Cancer Institute, France

Publications and helpful links

General Publications

• Lesueur P, Clarisse B, Lequesne J, Licaj I, Feuvret L, Stefan D, Ricard D, Noel G, Balosso J, Lange M, Capel A, Durand-Zaleski I, Castera M, Legrand B, Goliot N, Hedou C, Grellard JM, Valable S. Proton therapy versus conventional radiotherapy for the treatment of cavernous sinus benign meningioma, a randomized controlled phase III study protocol (COG-PROTON-01). BMC Cancer. 2024 Dec 30;24(1):1594. doi: 10.1186/s12885-024-13353-9.

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2024
• Primary Completion (Estimated): February 1, 2032
• Study Completion (Estimated): August 1, 2032

Study Registration Dates

• First Submitted: May 31, 2023
• First Submitted That Met QC Criteria: May 31, 2023
• First Posted (Actual): June 8, 2023

Study Record Updates

• Last Update Posted (Estimated): September 29, 2025
• Last Update Submitted That Met QC Criteria: September 24, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Physical Phenomena; Inorganic Chemicals; Elements; Ions; Electrolytes; Gases; Elementary Particles; Cations, Monovalent; Cations; Hydrogen; Nucleons; Protons
• Other Study ID Numbers: 2023-A00401-44

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No