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

Study Overview
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Brief Summary
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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
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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.

Official Title
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(Cost)Effectiveness of MR-guided LITT Therapy in Patients With Primary Irresectable Glioblastoma: a Prospective Multicenter Randomized Controlled Trial (EMITT)

Conditions
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Primary Glioblastoma

Intervention / Treatment
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* Procedure: Laser Interstitial Thermal Therapy (LITT)
* Procedure: Biopsy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Prospective, multicenter, open-label randomized controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Control group (biopsy group)<br>Standard of care: biopsy + adjuvant treatment | Procedure: Biopsy<br>* A sample of tissue from the tumor is obtained to confirm the diagnosis.<br>|
| Experimental: Intervention group (LITT group)<br>Biopsy + LITT + adjuvant treatment | Procedure: Laser Interstitial Thermal Therapy (LITT)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Percentage of patients still alive for a given period of time after randomization. | Depending on which event occurs first: either when a study participant dies or at the end of the trial (61 months). | 
| Health Related Quality of Life (HR-QoL) | QoL measured with the QLQ-C30BN20 at 5 months after randomization. | At 5 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Costs | Use of care and health-related costs measured using costs questionnaires. | At 1, 2, 3, 4, 5, 6, 12, 18, 30, 42 and 54 months after randomization. | 
| Ablation rate | Measuring the expected ablation rate. | Using the MRI made right after LITT procedure | 
| Progression Free Survival (PFS) | The length of time during and after the treatment of the disease that a patient lives with the disease but it does not get worse. | During the entire study period, estimated 18 months for each patient | 
| Disease Specific Survival (DSS) | The percentage of patients who have not died from glioblastoma. | During the entire study period, estimated 18 months for each patient | 
| Complication rate | Registration of complications in both study groups. | During the entire study period, estimated 18 months for each patient | 
| Overall survival since intervention | Percentage of patients still alive for a given period of time after surgery. | During the entire study period, estimated 18 months for each patient | 
| Tumor volume response | Response of tumor tissue to LITT. | Using the MRI made right after LITT procedure | 
| Effects of LITT on adjuvant treatment | Effects of LITT on the effect of adjuvant treatment assessed by tumor response to chemotherapy and radiotherapy on follow-up MRI. | During the entire study period, estimated 18 months for each patient | 
| General Quality of Life | QoL measured with the QoL questionnaires. | At randomization, 72 hours after surgery, 1, 2, 3, 4, 5, 6, 12, 18, 30, 42 and 54 months after randomization. | 
| Longitudinal effects | Changes attributable to aging during the study period. Longitudinal effects will be assessed using mixed model analysis. | During the entire study period, estimated 18 months for each patient. |