Clinical trial NCT05318612: Effectiveness of MR-guided LITT Therapy in Irresectable Glioblastoma (EMITT)
Official title: (Cost)Effectiveness of MR-guided LITT Therapy in Patients With Primary Irresectable Glioblastoma: a Prospective Multicenter Randomized Controlled Trial (EMITT)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Primary Glioblastoma
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Dutch National Health Care Institute
name: ZonMw: The Netherlands Organisation for Health Research and Development
name: UMC Utrecht
First posted: 2022-04-08
Enrollment: 238
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, multicenter, open-label randomized controlled trial
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall survival
timeFrame: Depending on which event occurs first: either when a study participant dies or at the end of the trial (61 months).
measure: Health Related Quality of Life (HR-QoL)
timeFrame: At 5 months after randomization
Secondary outcomes:
measure: Costs
timeFrame: At 1, 2, 3, 4, 5, 6, 12, 18, 30, 42 and 54 months after randomization.
measure: Ablation rate
timeFrame: Using the MRI made right after LITT procedure
measure: Progression Free Survival (PFS)
timeFrame: During the entire study period, estimated 18 months for each patient
measure: Disease Specific Survival (DSS)
timeFrame: During the entire study period, estimated 18 months for each patient
measure: Complication rate
timeFrame: During the entire study period, estimated 18 months for each patient
measure: Overall survival since intervention
timeFrame: During the entire study period, estimated 18 months for each patient
measure: Tumor volume response
timeFrame: Using the MRI made right after LITT procedure
measure: Effects of LITT on adjuvant treatment
timeFrame: During the entire study period, estimated 18 months for each patient
measure: General Quality of Life
timeFrame: At randomization, 72 hours after surgery, 1, 2, 3, 4, 5, 6, 12, 18, 30, 42 and 54 months after randomization.
measure: Longitudinal effects
timeFrame: During the entire study period, estimated 18 months for each patient.
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam Medical Center
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Tilburg
country: Netherlands
facility: Elisabeth Tweesteden Ziekenhuis
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: Radboud University Medical Center
name: Mark ter Laan, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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