Effectiveness of MR-guided LITT Therapy in Irresectable Glioblastoma (EMITT)

NCT ID: NCT05318612

Last Updated: 2024-04-10

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 238 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-04-08
• Study Completion Date: 2027-10-31

Brief Summary

The aim of this study is to investigate the (cost-)effectiveness of LITT (Laser Interstitial Thermal Therapy) in primary irresectable glioblastoma. Glioblastoma are the most common malignant brain tumors and are, due to their devastating nature and the fact that these tumors occur at a relatively young age (median 59 years), responsible for up to 7% of total life years lost from cancer before the age of 70.

The current treatment of glioblastoma consists of maximal safe surgery combined with adjuvant chemoradiation therapy (CRT). However, despite this aggressive treatment, these patients still face a poor prognosis (median overall survival 14.5 - 18.5 months). In addition to that, around 30% of the patients diagnosed with a glioblastoma are not suitable for surgery. These patients miss the benefit of a resection and face an even worse prognosis (median overall survival 5.1 months).

The primary aim of this project is to investigate whether laser therapy combined with CRT improves overall survival, without compromising quality of life, in comparison with CRT alone in patients with primary irresectable glioblastoma.

Detailed Description

RATIONALE: Glioblastoma (GBM) is the most common primary brain tumor with about 1000 new patients facing this diagnosis each year in the Netherlands alone. It is also one of the most devastating malignancies and due to relatively young age at presentation (median 59 years), GBMs are responsible for up to 7% of total life years lost from cancer before the age of 70. Despite many efforts, patients with glioblastoma face a poor prognosis, with 2-year survival less than 20%. Current standard of care includes maximal safe surgical resection followed by adjuvant chemoradiation therapy (CRT). Subtotal and gross total resection have been associated with significantly longer survival (median OS: 14.5-18.5 months; RR: 0.71-0.84) 6,7, but in 30% of patients surgery is not feasible. These patients miss the benefit of surgical resection and with CRT alone have a profoundly worse survival (median 5.1 months). Laser interstitial thermal therapy (LITT) is recently growing as a minimally invasive alternative to treat brain tumors. Multiple studies have shown the application of LITT in newly diagnosed and recurrent glioblastoma, in radiotherapy and chemotherapy resistant metastases or in tumors in difficult accessible locations, with promising initial results. A recent systematic review of current phase I/II studies in patients with newly diagnosed irresectable glioblastoma who received LITT yields a mean survival of 10.2 months, i.e. twice as long as with CRT alone (5.1 months). However, there is currently no high-quality prospective evidence directly comparing LITT with standard of care, precluding any conclusions on (cost-)effectiveness. After conducting a pilot study at Radboud University Medical Center to locally confirm safety and feasibility of LITT in patients with irresectable glioblastoma, we propose a prospective multicenter randomized controlled study to evaluate (cost-)effectiveness of this technique.

OBJECTIVE: The primary objective is to prove an improvement in survival without substantially compromising quality-of-life (QoL) in patients with primary irresectable glioblastoma (GBM) treated with LITT plus chemoradiation therapy (CRT) vs. CRT alone.

STUDY DESIGN: Prospective multicenter randomized controlled trial. Study population: Adult (>18 years old) patients with a radiologically suspected diagnosis of primary glioblastoma not amenable for surgical resection.

INTERVENTION: Patients will be randomized to receive either (i) biopsy and LITT, followed by standard CRT or (ii) biopsy alone, followed by standard CRT.

MAIN STUDY PARAMETERS/ENDPOINTS: The primary endpoints are overall survival (OS) and quality-of-life (QoL) using QLQ-C30+BN20 questionnaire 5 months after randomization.

Secondary endpoints are disease-specific and progression-free survival (PFS), generic QoL using EQ5D-5L and QLQ-C30+BN20, complication rates, tumor volume response, effects on adjuvant treatment and costs.

NATURE AND EXTENT OF THE BURDER AND RISKS ASSOCIATED WITH PARTICIPATION, BENEFIT AND GROUP RELATEDNESS: We hypothesize that the addition of LITT provides patients with an irresectable glioblastoma a relevant survival benefit without compromising their quality of life as compared to current standard treatment. LITT has been shown to carry limited risk of post-operative complications, mostly reversible, and has been associated with fast recovery post-treatment. The main risks associated to the procedure are bleeding, brain edema, neurological deterioration, operation site infection, epilepsy. The results of our near-finished pilot study are showing that the procedure seems to be safe and feasible.

Conditions

Primary Glioblastoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Control group (biopsy group)

Standard of care: biopsy + adjuvant treatment

Group Type: OTHER

Biopsy

Intervention Type: PROCEDURE

A sample of tissue from the tumor is obtained to confirm the diagnosis.

Intervention group (LITT group)

Biopsy + LITT + adjuvant treatment

Group Type: EXPERIMENTAL

Laser Interstitial Thermal Therapy (LITT)

Intervention Type: PROCEDURE

LITT is a minimally invasive neurosurgical procedure in which a laser catheter is placed into the tumor and warms the tumor to such an extent that tumor tissue is destroyed. LITT is performed under MR-guidance.

Interventions

Laser Interstitial Thermal Therapy (LITT)

LITT is a minimally invasive neurosurgical procedure in which a laser catheter is placed into the tumor and warms the tumor to such an extent that tumor tissue is destroyed. LITT is performed under MR-guidance.

Intervention Type: PROCEDURE

Biopsy

A sample of tissue from the tumor is obtained to confirm the diagnosis.

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• Informed consent, age >18 years
• Suspected glioblastoma
• Supratentorial localization
• Patient is not amendable for surgical resection as decided by the tumor board
• Safe trajectory/trajectories possible for ablation of at least 70% of the tumor, avoiding eloquent structures
• Karnofsky Performance Status (KPS) >=70

Exclusion Criteria

• Contra-indication for general anesthesia or MRI
• Non-glioblastoma diagnosis on pathology analysis
• No final pathology available
• Pregnancy
• Insufficient command of the Dutch language by the patient or a family member, making it impossible to fill in the questionnaires

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dutch National Health Care Institute

OTHER

Sponsor Role: collaborator

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

UMC Utrecht

OTHER

Sponsor Role: collaborator

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mark ter Laan, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

Locations

Amsterdam Medical Center

Amsterdam, , Netherlands

University Medical Center Groningen

Groningen, , Netherlands

Maastricht University Medical Center

Maastricht, , Netherlands

Radboud University Medical Center

Nijmegen, , Netherlands

Erasmus Medical Center

Rotterdam, , Netherlands

Elisabeth Tweesteden Ziekenhuis

Tilburg, , Netherlands

University Medical Center Utrecht

Utrecht, , Netherlands

Countries

Netherlands

References

Incidentie Hersentumoren. IKNL. https://www.iknl.nl/kankersoorten/hersentumoren/registratie/incidentie. Accessed October 7, 2020.

Reference Type: BACKGROUND

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015 Jan-Feb;65(1):5-29. doi: 10.3322/caac.21254. Epub 2015 Jan 5.

Reference Type: BACKGROUND

PMID: 25559415 (View on PubMed)

Rouse C, Gittleman H, Ostrom QT, Kruchko C, Barnholtz-Sloan JS. Years of potential life lost for brain and CNS tumors relative to other cancers in adults in the United States, 2010. Neuro Oncol. 2016 Jan;18(1):70-7. doi: 10.1093/neuonc/nov249. Epub 2015 Oct 12.

Reference Type: BACKGROUND

PMID: 26459813 (View on PubMed)

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.

Reference Type: BACKGROUND

PMID: 15758009 (View on PubMed)

Weller M, van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A, Cohen-Jonathan-Moyal E, Frappaz D, Henriksson R, Balana C, Chinot O, Ram Z, Reifenberger G, Soffietti R, Wick W; European Association for Neuro-Oncology (EANO) Task Force on Malignant Glioma. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol. 2014 Aug;15(9):e395-403. doi: 10.1016/S1470-2045(14)70011-7.

Reference Type: BACKGROUND

PMID: 25079102 (View on PubMed)

Brown TJ, Brennan MC, Li M, Church EW, Brandmeir NJ, Rakszawski KL, Patel AS, Rizk EB, Suki D, Sawaya R, Glantz M. Association of the Extent of Resection With Survival in Glioblastoma: A Systematic Review and Meta-analysis. JAMA Oncol. 2016 Nov 1;2(11):1460-1469. doi: 10.1001/jamaoncol.2016.1373.

Reference Type: BACKGROUND

PMID: 27310651 (View on PubMed)

De Witt Hamer PC, Ho VKY, Zwinderman AH, Ackermans L, Ardon H, Boomstra S, Bouwknegt W, van den Brink WA, Dirven CM, van der Gaag NA, van der Veer O, Idema AJS, Kloet A, Koopmans J, Ter Laan M, Verstegen MJT, Wagemakers M, Robe PAJT; Quality Registry Neuro Surgery glioblastoma working group from the Dutch Society of Neurosurgery. Between-hospital variation in mortality and survival after glioblastoma surgery in the Dutch Quality Registry for Neuro Surgery. J Neurooncol. 2019 Sep;144(2):313-323. doi: 10.1007/s11060-019-03229-5. Epub 2019 Jun 24.

Reference Type: BACKGROUND

PMID: 31236819 (View on PubMed)

Haj A, Doenitz C, Schebesch KM, Ehrensberger D, Hau P, Putnik K, Riemenschneider MJ, Wendl C, Gerken M, Pukrop T, Brawanski A, Proescholdt MA. Extent of Resection in Newly Diagnosed Glioblastoma: Impact of a Specialized Neuro-Oncology Care Center. Brain Sci. 2017 Dec 25;8(1):5. doi: 10.3390/brainsci8010005.

Reference Type: BACKGROUND

PMID: 29295569 (View on PubMed)

Ashraf O, Patel NV, Hanft S, Danish SF. Laser-Induced Thermal Therapy in Neuro-Oncology: A Review. World Neurosurg. 2018 Apr;112:166-177. doi: 10.1016/j.wneu.2018.01.123. Epub 2018 Feb 2.

Reference Type: BACKGROUND

PMID: 29410102 (View on PubMed)

Viozzi I, Guberinic A, Overduin CG, Rovers MM, Ter Laan M. Laser Interstitial Thermal Therapy in Patients with Newly Diagnosed Glioblastoma: A Systematic Review. J Clin Med. 2021 Jan 19;10(2):355. doi: 10.3390/jcm10020355.

Reference Type: BACKGROUND

PMID: 33477796 (View on PubMed)

Williams D, Loshak H. Laser Interstitial Thermal Therapy for Epilepsy and/or Brain Tumours: A Review of Clinical Effectiveness and Cost-Effectiveness [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019 Jun 17. Available from http://www.ncbi.nlm.nih.gov/books/NBK545597/

Reference Type: BACKGROUND

PMID: 31449372 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 33293629 (View on PubMed)

Maringwa J, Quinten C, King M, Ringash J, Osoba D, Coens C, Martinelli F, Reeve BB, Gotay C, Greimel E, Flechtner H, Cleeland CS, Schmucker-Von Koch J, Weis J, Van Den Bent MJ, Stupp R, Taphoorn MJ, Bottomley A; EORTC PROBE Project and Brain Cancer Group. Minimal clinically meaningful differences for the EORTC QLQ-C30 and EORTC QLQ-BN20 scales in brain cancer patients. Ann Oncol. 2011 Sep;22(9):2107-2112. doi: 10.1093/annonc/mdq726. Epub 2011 Feb 15.

Reference Type: BACKGROUND

PMID: 21324954 (View on PubMed)

Taphoorn MJ, Stupp R, Coens C, Osoba D, Kortmann R, van den Bent MJ, Mason W, Mirimanoff RO, Baumert BG, Eisenhauer E, Forsyth P, Bottomley A; European Organisation for Research and Treatment of Cancer Brain Tumour Group; EORTC Radiotherapy Group; National Cancer Institute of Canada Clinical Trials Group. Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol. 2005 Dec;6(12):937-44. doi: 10.1016/S1470-2045(05)70432-0.

Reference Type: BACKGROUND

PMID: 16321761 (View on PubMed)

Garside R, Pitt M, Anderson R, Rogers G, Dyer M, Mealing S, Somerville M, Price A, Stein K. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation. Health Technol Assess. 2007 Nov;11(45):iii-iv, ix-221. doi: 10.3310/hta11450.

Reference Type: BACKGROUND

PMID: 17999840 (View on PubMed)

Medvid R, Ruiz A, Komotar RJ, Jagid JR, Ivan ME, Quencer RM, Desai MB. Current Applications of MRI-Guided Laser Interstitial Thermal Therapy in the Treatment of Brain Neoplasms and Epilepsy: A Radiologic and Neurosurgical Overview. AJNR Am J Neuroradiol. 2015 Nov;36(11):1998-2006. doi: 10.3174/ajnr.A4362. Epub 2015 Jun 25.

Reference Type: BACKGROUND

PMID: 26113069 (View on PubMed)

McDannold NJ, Jolesz FA. Magnetic resonance image-guided thermal ablations. Top Magn Reson Imaging. 2000 Jun;11(3):191-202. doi: 10.1097/00002142-200006000-00005.

Reference Type: BACKGROUND

PMID: 11145211 (View on PubMed)

Leuthardt EC, Duan C, Kim MJ, Campian JL, Kim AH, Miller-Thomas MM, Shimony JS, Tran DD. Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier. PLoS One. 2016 Feb 24;11(2):e0148613. doi: 10.1371/journal.pone.0148613. eCollection 2016.

Reference Type: BACKGROUND

PMID: 26910903 (View on PubMed)

Mohammadi AM, Hawasli AH, Rodriguez A, Schroeder JL, Laxton AW, Elson P, Tatter SB, Barnett GH, Leuthardt EC. The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: a multicenter study. Cancer Med. 2014 Aug;3(4):971-9. doi: 10.1002/cam4.266. Epub 2014 May 9.

Reference Type: BACKGROUND

PMID: 24810945 (View on PubMed)

Ahluwalia M, Barnett GH, Deng D, Tatter SB, Laxton AW, Mohammadi AM, Leuthardt E, Chamoun R, Judy K, Asher A, Essig M, Dietrich J, Chiang VL. Laser ablation after stereotactic radiosurgery: a multicenter prospective study in patients with metastatic brain tumors and radiation necrosis. J Neurosurg. 2019 Mar 1;130(3):804-811. doi: 10.3171/2017.11.JNS171273. Epub 2018 May 4.

Reference Type: BACKGROUND

PMID: 29726782 (View on PubMed)

Rennert RC, Khan U, Bartek J, Tatter SB, Field M, Toyota B, Fecci PE, Judy K, Mohammadi AM, Landazuri P, Sloan AE, Kim AH, Leuthardt EC, Chen CC. Laser Ablation of Abnormal Neurological Tissue Using Robotic Neuroblate System (LAANTERN): Procedural Safety and Hospitalization. Neurosurgery. 2020 Apr 1;86(4):538-547. doi: 10.1093/neuros/nyz141.

Reference Type: BACKGROUND

PMID: 31076762 (View on PubMed)

Cabantog AM, Bernstein M. Complications of first craniotomy for intra-axial brain tumour. Can J Neurol Sci. 1994 Aug;21(3):213-8. doi: 10.1017/s0317167100041184.

Reference Type: BACKGROUND

PMID: 8000976 (View on PubMed)

Patel P, Patel NV, Danish SF. Intracranial MR-guided laser-induced thermal therapy: single-center experience with the Visualase thermal therapy system. J Neurosurg. 2016 Oct;125(4):853-860. doi: 10.3171/2015.7.JNS15244. Epub 2016 Jan 1.

Reference Type: BACKGROUND

PMID: 26722845 (View on PubMed)

Hawasli AH, Bagade S, Shimony JS, Miller-Thomas M, Leuthardt EC. Magnetic resonance imaging-guided focused laser interstitial thermal therapy for intracranial lesions: single-institution series. Neurosurgery. 2013 Dec;73(6):1007-17. doi: 10.1227/NEU.0000000000000144.

Reference Type: BACKGROUND

PMID: 24056317 (View on PubMed)

Stef van Buuren KG-O. mice: Multivariate Imputation by Chained Equations in R. Journal of Statistical Software 2011; Volume 45(issue 3)

Reference Type: BACKGROUND

S vB. Flexible imputation of missing data, second edition: Boca Raton; 2008.

Reference Type: BACKGROUND

Carreras G, Miccinesi G, Wilcock A, Preston N, Nieboer D, Deliens L, Groenvold M, Lunder U, van der Heide A, Baccini M; ACTION consortium. Missing not at random in end of life care studies: multiple imputation and sensitivity analysis on data from the ACTION study. BMC Med Res Methodol. 2021 Jan 9;21(1):13. doi: 10.1186/s12874-020-01180-y.

Reference Type: BACKGROUND

PMID: 33422019 (View on PubMed)

Kamath AA, Friedman DD, Hacker CD, Smyth MD, Limbrick DD Jr, Kim AH, Hawasli AH, Leuthardt EC. MRI-Guided Interstitial Laser Ablation for Intracranial Lesions: A Large Single-Institution Experience of 133 Cases. Stereotact Funct Neurosurg. 2017;95(6):417-428. doi: 10.1159/000485387. Epub 2018 Jan 17.

Reference Type: BACKGROUND

PMID: 29339639 (View on PubMed)

Riche M, Amelot A, Peyre M, Capelle L, Carpentier A, Mathon B. Complications after frame-based stereotactic brain biopsy: a systematic review. Neurosurg Rev. 2021 Feb;44(1):301-307. doi: 10.1007/s10143-019-01234-w. Epub 2020 Jan 4.

Reference Type: BACKGROUND

PMID: 31900737 (View on PubMed)

Jackson C, Westphal M, Quinones-Hinojosa A. Complications of glioma surgery. Handb Clin Neurol. 2016;134:201-18. doi: 10.1016/B978-0-12-802997-8.00012-8.

Reference Type: BACKGROUND

PMID: 26948356 (View on PubMed)

Rahmathulla G, Recinos PF, Kamian K, Mohammadi AM, Ahluwalia MS, Barnett GH. MRI-guided laser interstitial thermal therapy in neuro-oncology: a review of its current clinical applications. Oncology. 2014;87(2):67-82. doi: 10.1159/000362817. Epub 2014 Jul 3.

Reference Type: BACKGROUND

PMID: 24994550 (View on PubMed)

Franck P, Henderson PW, Rothaus KO. Basics of Lasers: History, Physics, and Clinical Applications. Clin Plast Surg. 2016 Jul;43(3):505-13. doi: 10.1016/j.cps.2016.03.007.

Reference Type: BACKGROUND

PMID: 27363764 (View on PubMed)

Di L, Wang CP, Shah AH, Eichberg DG, Semonche AM, Sanjurjo AD, Luther EM, Jermakowicz WJ, Komotar RJ, Ivan ME. A Cohort Study on Prognostic Factors for Laser Interstitial Thermal Therapy Success in Newly Diagnosed Glioblastoma. Neurosurgery. 2021 Aug 16;89(3):496-503. doi: 10.1093/neuros/nyab193.

Reference Type: BACKGROUND

PMID: 34156076 (View on PubMed)

Patel NV, Jethwa PR, Shetty A, Danish SF. Does the real-time thermal damage estimate allow for estimation of tumor control after MRI-guided laser-induced thermal therapy? Initial experience with recurrent intracranial ependymomas. J Neurosurg Pediatr. 2015 Apr;15(4):363-71. doi: 10.3171/2014.10.PEDS13698. Epub 2015 Jan 16.

Reference Type: BACKGROUND

PMID: 25580512 (View on PubMed)

Nakagawa M, Matsumoto K, Higashi H, Furuta T, Ohmoto T. Acute effects of interstitial hyperthermia on normal monkey brain--magnetic resonance imaging appearance and effects on blood-brain barrier. Neurol Med Chir (Tokyo). 1994 Oct;34(10):668-75. doi: 10.2176/nmc.34.668.

Reference Type: BACKGROUND

PMID: 7529367 (View on PubMed)

Rieke V, Butts Pauly K. MR thermometry. J Magn Reson Imaging. 2008 Feb;27(2):376-90. doi: 10.1002/jmri.21265.

Reference Type: BACKGROUND

PMID: 18219673 (View on PubMed)

Neutel CLG, Viozzi I, Overduin CG, Rijpma A, Grutters JPC, Hannink G, van Eijsden P, Robe PA, Rovers MM, Ter Laan M. Study protocol for a multicenter randomised controlled trial on the (cost)effectiveness of biopsy combined with same-session MR-guided LITT versus biopsy alone in patients with primary irresectable glioblastoma (EMITT trial). BMC Cancer. 2023 Aug 23;23(1):788. doi: 10.1186/s12885-023-11282-7.

Reference Type: DERIVED

PMID: 37612610 (View on PubMed)

Other Identifiers

NL79202.091.21

Identifier Type: -

Identifier Source: org_study_id