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

Study Overview
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Brief Summary
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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

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

Conditions
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Cavernous Sinus Meningioma, Proton-therapy, Photon Radiotherapy, Cognitive Impairment

Intervention / Treatment
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* Radiation: Proton-therapy
* Radiation: Photon radiotherapy


Participation Criteria
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Eligibility Criteria
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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 <60 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter prospective comparative phase 3 randomized 1:1 trial
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |