Personalized Rendering of Motor System Functional Plasticity Potential to Improve Glioma Resection and Quality of Life

Overview

Background Lower-grade-gliomas affect young patients, thus the longest progression-free-survival (PFS) with a high level quality of life is crucial. Surgery most significantly impacts on tumor natural history, postponing recurrence, improving symptoms, decreasing the need of adjuvant therapies, with extent of resection, gross-total and supra-total (GTR and STR), strongly associating with longest PFS. Achievement of GTR or STR depends on the degree of functional reorganization induced by glioma. Consequently, a successful treatment fostering neural circuit reorganization before surgery, would increase the chance of GRT/STR. Hypothesis The plastic potential of motor system suggests that reorganization of circuits controlling hand movements could be presurgically fostered in LGG patients by enhancing plasticity with up-front motor-rehabilitation and/or by decreasing tumor infiltration with up-front chemotherapy. Advanced neuroimaging allows to infer the neuroplasticity potential. Intraoperative assessment of the motor circuits functionality will validate reliability of preoperative analyses. Aims The project has 4 aims, investigating: A) the presurgical functional (FC) and structural (SC) connectomics of the hand-motor network to picture the spontaneous reorganization and the influence of clinical, imaging and histomolecular variables; B) the dynamic of FC and SC after tumor resection; C) changes in FC and SC maps after personalized upfront motor rehabilitation and/or chemotherapy; D) the effect of FC and SC upfront treatment on the achievement of GTR/STR preserving hand dexterity. Experimental Design Resting-state fMRI and diffusion-MRI will provide FC and SC maps pre- and post-surgery; personalized up-front motor rehabilitation and/or chemotherapy will be administered; Intraoperative brain mapping procedures will generate data to validate the maps. Expected Results 1. Provide a tool to render the motor functional reorganization predictive of surgical outcome. 2. Identify demographic, clinical and imaging variables associated with functional reorganization. 3. Describe the gain induced by up-front treatment. 4. Distinguish "patterns" predicting chance for GTR/STR from "patterns" suggesting need for up-front treatment. Impact On Cancer Results will increase the achievement of GTR/STR, preserving motor integrity, with dramatic impact on LGGs natural history.

Interventions

• Diagnostic test Resting State Functional Magnetic Resonance Imaging (rs-fMRI)
  rs-fMRI + neurological and neuropsychological evaluation at preoperative timepoint and 1-2 months postop, 3-4 months postop, 6-8 months postop, 12 months postop
• Behavioral Up-front Motor Rehabilitation
  personalized motor rehabilitation for 6 months + rs-fMRI + neurological and neuropsychological evaluation before starting motor rehabilitation, at 2-3 months during rehabilitation, 6-9 months during rehabilitation, before surgery (if surgery indicated by tumour board), 1 month postop, 2-3 months postop
• Drug Up-front Chemotherapy
  Temozolomide at either 6 cycles consisting of 150-200 mg per square meter for 5 days during each 28-day cycle, or metronomic schedule, + rs-fMRI + neurological and neuropsychological evaluation before starting motor rehabilitation, at 2-3 months during rehabilitation, 6-9 months during rehabilitation, before surgery (if surgery indicated by tumour board), 1 month postop, 2-3 months Post

Primary outcome measures

• Muscle power [Time frame: ARM 1: preop, 1-2 months postop, 3-4 months postop, 6-8 months postop, 12 months postop; ARM 2/3/4: before starting treatment, at 2-3 and 6-9 months during treatment, before surgery (if indicated), 1 month postop, 2-3 months postop]
• Motor praxia [Time frame: ARM 1: preop, 1-2 months postop, 3-4 months postop, 6-8 months postop, 12 months postop; ARM 2/3/4: before starting treatment, at 2-3 and 6-9 months during treatment, before surgery (if indicated), 1 month postop, 2-3 months postop]

Secondary outcome measures (1)

• Comprehensive neuropsychological assessment [Time frame: ARM 1: preop, 1-2 months postop, 3-4 months postop, 6-8 months postop, 12 months postop; ARM 2/3/4: before starting treatment, at 2-3 and 6-9 months during treatment, before surgery (if indicated), 1 month postop, 2-3 months postop]

Eligibility criteria

Inclusion Criteria (ARM 1):

• Patients signing informed consent for participation in the study
• Males and females
• Age ≥ 18 years
• Patients with lower-grade gliomas with involvement of the motor pathways who are candidates for surgery

Inclusion Criteria (ARM 2/3/4):

• Patients signing informed consent for participation in the study
• Males and females
• Age ≥ 18 years
• Patients with lower-grade gliomas treated over two years with tumors only biopsied and/or partially resected and eligible for second surgery

Exclusion criteria

• Age <18 years
• Inability to adhere to standard study controls
• Subjects unable to understand and freely provide consent to the study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Italy · 1 center

• IRCCS Ospedale Galeazzi Sant'Ambrogio — Milan

Publications

• Bello L, Riva M, Fava E, Ferpozzi V, Castellano A, Raneri F, Pessina F, Bizzi A, Falini A, Cerri G. Tailoring neurophysiological strategies with clinical context enhances resection and safety and expands indications in gliomas involving motor pathways. Neuro Oncol. 2014 Aug;16(8):1110-28. doi: 10.1093/neuonc/not327. Epub 2014 Feb 4. PMID 24500420
• Castellano A, Donativi M, Ruda R, De Nunzio G, Riva M, Iadanza A, Bertero L, Rucco M, Bello L, Soffietti R, Falini A. Evaluation of low-grade glioma structural changes after chemotherapy using DTI-based histogram analysis and functional diffusion maps. Eur Radiol. 2016 May;26(5):1263-73. doi: 10.1007/s00330-015-3934-6. Epub 2015 Aug 30. PMID 26318368
• Cochereau J, Deverdun J, Herbet G, Charroud C, Boyer A, Moritz-Gasser S, Le Bars E, Molino F, Bonafe A, Menjot de Champfleur N, Duffau H. Comparison between resting state fMRI networks and responsive cortical stimulations in glioma patients. Hum Brain Mapp. 2016 Nov;37(11):3721-3732. doi: 10.1002/hbm.23270. PMID 27246771
• Fornia L, Ferpozzi V, Montagna M, Rossi M, Riva M, Pessina F, Martinelli Boneschi F, Borroni P, Lemon RN, Bello L, Cerri G. Functional Characterization of the Left Ventrolateral Premotor Cortex in Humans: A Direct Electrophysiological Approach. Cereb Cortex. 2018 Jan 1;28(1):167-183. doi: 10.1093/cercor/bhw365. PMID 27920095
• Fornia L, Rossi M, Rabuffetti M, Leonetti A, Puglisi G, Vigano L, Simone L, Howells H, Bellacicca A, Bello L, Cerri G. Direct Electrical Stimulation of Premotor Areas: Different Effects on Hand Muscle Activity during Object Manipulation. Cereb Cortex. 2020 Jan 10;30(1):391-405. doi: 10.1093/cercor/bhz139. PMID 31504261
• Fornia L, Rossi M, Rabuffetti M, Bellacicca A, Vigano L, Simone L, Howells H, Puglisi G, Leonetti A, Callipo V, Bello L, Cerri G. Motor impairment evoked by direct electrical stimulation of human parietal cortex during object manipulation. Neuroimage. 2022 Mar;248:118839. doi: 10.1016/j.neuroimage.2021.118839. Epub 2021 Dec 25. PMID 34963652
• Howells H, Puglisi G, Leonetti A, Vigano L, Fornia L, Simone L, Forkel SJ, Rossi M, Riva M, Cerri G, Bello L. The role of left fronto-parietal tracts in hand selection: Evidence from neurosurgery. Cortex. 2020 Jul;128:297-311. doi: 10.1016/j.cortex.2020.03.018. Epub 2020 Apr 10. PMID 32362441
• Kong NW, Gibb WR, Badhe S, Liu BP, Tate MC. Plasticity of the Primary Motor Cortex in Patients with Primary Brain Tumors. Neural Plast. 2020 Jul 3;2020:3648517. doi: 10.1155/2020/3648517. eCollection 2020. PMID 32714384

Identifiers

NCT: NCT06381726 · Progetto AIRC IG-2022 ID 27184

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗