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

Glioma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06381726
• Other study ID #: Progetto AIRC IG-2022 ID 27184
• Status: Recruiting
• Phase: N/A
• Start date: March 7, 2024
• Est. completion date: February 28, 2028

Study information

• Verified date: April 2024
• Source: University of Milan
• Contact: Lorenzo Bello, MD
• Phone: 0039-340-217-1453
• Email: lorenzo.bello[@]unimi.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: February 28, 2028
• Est. primary completion date: February 28, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Glioma
• Glioma, Malignant

Intervention

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

Locations

Country	Name	City	State
Italy	IRCCS Ospedale Galeazzi Sant'Ambrogio	Milan	Lombardy

Sponsors (2)

Lead Sponsor	Collaborator
University of Milan	University of Turin, Italy

Country where clinical trial is conducted

Italy, 

References & Publications (27)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Puglisi G, Howells H, Sciortino T, Leonetti A, Rossi M, Conti Nibali M, Gabriel Gay L, Fornia L, Bellacicca A, Vigano L, Simone L, Catani M, Cerri G, Bello L. Frontal pathways in cognitive control: direct evidence from intraoperative stimulation and diffusion tractography. Brain. 2019 Aug 1;142(8):2451-2465. doi: 10.1093/brain/awz178. — View Citation

Raffin E, Siebner HR. Use-Dependent Plasticity in Human Primary Motor Hand Area: Synergistic Interplay Between Training and Immobilization. Cereb Cortex. 2019 Jan 1;29(1):356-371. doi: 10.1093/cercor/bhy226. — View Citation

Rossi M, Ambrogi F, Gay L, Gallucci M, Conti Nibali M, Leonetti A, Puglisi G, Sciortino T, Howells H, Riva M, Pessina F, Navarria P, Franzese C, Simonelli M, Ruda R, Bello L. Is supratotal resection achievable in low-grade gliomas? Feasibility, putative factors, safety, and functional outcome. J Neurosurg. 2019 May 17;132(6):1692-1705. doi: 10.3171/2019.2.JNS183408. — View Citation

Rossi M, Conti Nibali M, Vigano L, Puglisi G, Howells H, Gay L, Sciortino T, Leonetti A, Riva M, Fornia L, Cerri G, Bello L. Resection of tumors within the primary motor cortex using high-frequency stimulation: oncological and functional efficiency of this versatile approach based on clinical conditions. J Neurosurg. 2019 Aug 9:1-13. doi: 10.3171/2019.5.JNS19453. Online ahead of print. — View Citation

Rossi M, Fornia L, Puglisi G, Leonetti A, Zuccon G, Fava E, Milani D, Casarotti A, Riva M, Pessina F, Cerri G, Bello L. Assessment of the praxis circuit in glioma surgery to reduce the incidence of postoperative and long-term apraxia: a new intraoperative test. J Neurosurg. 2018 Feb 23;130(1):17-27. doi: 10.3171/2017.7.JNS17357. — View Citation

Rossi M, Gay L, Ambrogi F, Conti Nibali M, Sciortino T, Puglisi G, Leonetti A, Mocellini C, Caroli M, Cordera S, Simonelli M, Pessina F, Navarria P, Pace A, Soffietti R, Ruda R, Riva M, Bello L. Association of supratotal resection with progression-free survival, malignant transformation, and overall survival in lower-grade gliomas. Neuro Oncol. 2021 May 5;23(5):812-826. doi: 10.1093/neuonc/noaa225. — View Citation

Rossi M, Sciortino T, Conti Nibali M, Gay L, Vigano L, Puglisi G, Leonetti A, Howells H, Fornia L, Cerri G, Riva M, Bello L. Clinical Pearls and Methods for Intraoperative Motor Mapping. Neurosurgery. 2021 Feb 16;88(3):457-467. doi: 10.1093/neuros/nyaa359. — View Citation

Rossi M, Vigano L, Puglisi G, Conti Nibali M, Leonetti A, Gay L, Sciortino T, Fornia L, Callipo V, Lamperti M, Riva M, Cerri G, Bello L. Targeting Primary Motor Cortex (M1) Functional Components in M1 Gliomas Enhances Safe Resection and Reveals M1 Plasticity Potentials. Cancers (Basel). 2021 Jul 28;13(15):3808. doi: 10.3390/cancers13153808. — View Citation

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Simone L, Fornia L, Vigano L, Sambataro F, Rossi M, Leonetti A, Puglisi G, Howells H, Bellacicca A, Bello L, Cerri G. Large scale networks for human hand-object interaction: Functionally distinct roles for two premotor regions identified intraoperatively. Neuroimage. 2020 Jan 1;204:116215. doi: 10.1016/j.neuroimage.2019.116215. Epub 2019 Sep 24. — View Citation

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Vigano L, Fornia L, Rossi M, Howells H, Leonetti A, Puglisi G, Conti Nibali M, Bellacicca A, Grimaldi M, Bello L, Cerri G. Anatomo-functional characterisation of the human "hand-knob": A direct electrophysiological study. Cortex. 2019 Apr;113:239-254. doi: 10.1016/j.cortex.2018.12.011. Epub 2018 Dec 24. — View Citation

Vigano L, Howells H, Fornia L, Rossi M, Conti Nibali M, Puglisi G, Leonetti A, Simone L, Bello L, Cerri G. Negative motor responses to direct electrical stimulation: Behavioral assessment hides different effects on muscles. Cortex. 2021 Apr;137:194-204. doi: 10.1016/j.cortex.2021.01.005. Epub 2021 Jan 29. — View Citation

Vigano L, Howells H, Rossi M, Rabuffetti M, Puglisi G, Leonetti A, Bellacicca A, Conti Nibali M, Gay L, Sciortino T, Cerri G, Bello L, Fornia L. Stimulation of frontal pathways disrupts hand muscle control during object manipulation. Brain. 2022 May 24;145(4):1535-1550. doi: 10.1093/brain/awab379. — View Citation

Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, Bendszus M, Balana C, Chinot O, Dirven L, French P, Hegi ME, Jakola AS, Platten M, Roth P, Ruda R, Short S, Smits M, Taphoorn MJB, von Deimling A, Westphal M, Soffietti R, Reifenberger G, Wick W. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021 Mar;18(3):170-186. doi: 10.1038/s41571-020-00447-z. Epub 2020 Dec 8. Erratum In: Nat Rev Clin Oncol. 2022 May;19(5):357-358. — View Citation

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* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Muscle power	MRC Muscle power assessment (0-5)	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
Primary	Motor praxia	ARAT test (Grasp, Grip, Pinch, each consisting of 3 items scoring 0 [not performed, 1/2 abnormal, 3 ok]), De Renzi test (24 complex gestures with individual scoring 0-3 [0 no execution/always abnormal, 2/1 ok after 1 or 2 trials, 3 ok] each evaluating one or more among finger movements [total score 0-36], hand movements [total score 0-36], hand and finger position [total score 0-36], sequence of movements [total score 0-36], meaningful gestures [total score 0-36], meaningless gestures [total score 0-36]; tool pantomime for 10 objects individual score 0 if always incorrect, 1 if correct after command repetition, 2 correct immediately, total score range 0-20)	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	Comprehensive neuropsychological assessment	Language: Naming test; Fhonemic and Semantic Fluency Verbal and Spatial Memory: 15 Rey's Words; Recall Rey figure; Visuo-spatial test: Rey's Copy; Cancellation Test Attention and Executive Functions: Attentive matrice and Trail Making test For each listed test, equivalent score, from 0 to 4, is used.; Mood Disorders. HADS test (score 0-21 : 0-7= Normal; 8-21 Mood disorders	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