LITT for Ultra-early GBM Recurrence

Background:

GBM is frequent and still has a poor prognosis. Standard therapy consists of complete resection of enhancing tumor (CRET) followed by RT and CT. At the institution, patients planned for RT undergo a pre-radiotherapy planning MRI. As recently published, \>40% of patients exhibit contrast-enhancing tumor recurrence in the short interval between early postoperative MRI and pre-RT MRI, despite CRET in the initial surgery. This ultra-early recurrence is strongly associated with shorter OS: in the cohort, median overall survival (OS) was 13.3m and 24.4m for patients with and without recurrence in pre-RT MRI, respectively. Hence, pre-radiation GBM recurrence is a frequent event with detrimental consequences for patients.

Reoperation in this setting is rarely performed as it delays adjuvant treatment, which worsen prognosis further. LITT is an established, minimally invasive treatment form for brain lesions such as glioblastoma recurrences and metastases. LITT may offer a solution to this dilemma as its minimal invasiveness enables to ablate the recurrent tumor without delaying treatment. As an additional benefit, LITT may work as a potent sensitizer to subsequent RT and CT.

A key challenge in the implementation of LITT in this setting is the tight scheduling window (maximum 1 week) between pre-radiotherapy planning MRI and start of radiotherapy. In order not to delay adjuvant treatment, LITT should optimally be performed within this time window. To be feasible, both planning and execution of LITT, including coordination of intraoperative MRI and engineering support, must occur within this short timeframe. This feasibility study aims to prospectively investigate whether LITT can be integrated into the existing care pathway without postponing of adjuvant treatment. This may lay the groundwork for future clinical trials.

Objective:

The aim is to test feasibility of integrating scheduling, planning and execution of LITT into the standard treatment course of patients with CRET-resected glioblastoma scheduled to receive concomitant radio-chemotherapy. The primary objective of this feasibility study is to evaluate the feasibility of performing LITT for ultra-early recurrence following GBM resection without delaying adjuvant radio-chemotherapy.

Secondary objectives are collected to estimate the effect size of pre-RT LITT on median overall survival compared to patients with ultra-early recurrence who do not receive LITT, and to historic controls; the purpose of these endpoints is to guide power calculations of a subsequent phase II trial.

Methods:

This is a prospective, single-arm, monocentric feasibility study conducted at the University Department of Neurosurgery, Inselspital, Bern. The study is exploratory in nature and aims to generate foundational data for a larger, multi-centric phase II trial. At the University Hospital of Bern, all patients are presented to the tumor board after surgery for brain tumors. All patients with histologically confirmed glioblastoma and without residual contrast enhancement (CRET) meeting the inclusion criteria for study participation will be asked for consent and, where applicable, included in the trial. All patients showing ultra-early recurrence on planning MRI and meeting the inclusion criteria for LITT will be considered to undergo LITT before the beginning of radiotherapy. Patients without recurrence ("no recurrence" group) and patients with recurrence who do not undergo LITT ("recurrence/no LITT" group) will serve as internal control groups.

• Complications of LITT [Time frame: from enrollment to the end of radiotherapy, an average of 8 weeks]
• Delay of Radiotherapy [Time frame: assessed the day of radiation start, ranging from 3 to 6 weeks after GBM resection]
• Use of steroids [Time frame: from enrollment to the end of radiotherapy, an average of 8 weeks]
• Evolution of radiation necrosis [Time frame: from enrollment to the end of radiotherapy, an average of 8 weeks]
• Evolution of target lesion [Time frame: from enrollment to the end of radiotherapy, an average of 8 weeks]
• Evolution of pseudoprogression [Time frame: from enrollment to the end of radiotherapy, an average of 8 weeks]
• Time to local recurrence [Time frame: from enrollment to the end of radiotherapy, an average of 8 weeks]
• Time to distant recurrence [Time frame: from enrollment to the end of radiotherapy, an average of 8 weeks]
• Median overall survival [Time frame: from enrollment to date of death, assessed up to the end of the study period (end of ratiotherapy for the last included patient)]
• Site of recurrence [Time frame: assessed the day of radiation start, ranging from 3 to 6 weeks after GBM resection]
• Recruitment rate [Time frame: at study completion (date of end of radiotherapy for the last included patient, approximately 2 years after enrollment of the first participant]
• Progression rate [Time frame: pre RT-MRI]