OptimalTTF-1: Enhancing tumor treating fields therapy with skull remodeling surgery. A clinical phase I trial in adult recurrent glioblastoma

Abstract

Background Preclinical studies suggest that skull remodeling surgery (SR-surgery) increases the dose of tumor treating fields (TTFields) in glioblastoma (GBM) and prevents wasteful current shunting through the skin. SR-surgery introduces minor skull defects to focus the cancer-inhibiting currents towards the tumor and increase the treatment dose. This study aimed to test the safety and feasibility of this concept in a phase 1 setting. Methods 15 adult patients with first recurrence of GBM were treated with personalized SR-surgery, TTFields and physician’s choice oncological therapy. The primary endpoint was toxicity and secondary endpoints included standard efficacy outcomes. Results SR-surgery resulted in a mean skull defect area of 10.6 cm 2 producing a median TTFields enhancement of 32% (range 25-59%). The median TTFields treatment duration was 6.8 months and the median compliance rate 90%. Patients received either bevacizumab, bevacizumab/irinotecan, or temozolomide rechallenge. We observed 71 adverse events (AEs) of grades 1 (52%), 2 (35%), and 3 (13%). There were no grade 4 or 5 AEs or intervention-related serious AEs. Six patients experienced minor TTFields-induced skin rash. The median progression-free survival (PFS) was 4.6 months and the PFS rate at 6 months was 36%. The median overall survival (OS) was 15.5 months and the OS rate at 12 months was 55%. Conclusions TTFields therapy combined with SR-surgery and medical oncological treatment is safe and non-toxic and holds potential to improve the outcome for GBM patients through focal dose enhancement in the tumor.

The Routine Application of Tumor-Treating Fields in the Treatment of Glioblastoma WHO° IV

“…For superficial tumors, removal of a standard craniotomy bone flap increased the electrical field strength by up to 70% ( 51 ). A phase 1 safety study on 15 patients with recurrent GBM confirmed the safety of this approach ( 52 ) and a phase 2 study was announced ( 53 ).…”

Skull Modulated Strategy to Intensify Tumor Treating Fields on Brain Tumor: a Finite Element Study

“…The tumors were all near the surface of the brain and 4 patients did not receive TTFields due to personal reasons. Three drilling patterns were applied with signi cantly prolonged median progression free survival (mPFS) and mOS (mPFS, 4.6 months; 6-month PFS rate, 36%; mOS, 15.5 months) 29 . To clarify the exact augmentation of SR surgery to TTFields, one phase II clinical trial (NCT04223999) is ongoing.…”

“…Korshoej AR et al conducted in vitro simulation studies to prove that the skull remodeling (SR) by drilling, thinning, and craniectomy could intensify the local dosage. And they recently published the results of their phase I trial entitled OptimalTTF-1, in which SR surgery combined with TTFields and the physicians' choice of cancer treatment could elongate the survival of recurrent GBM patients, compared to historical cohorts 29 . Nevertheless, more detailed research on the modulations of SR surgery is required.…”

Guidelines for Burr Hole Surgery in Combination With Tumor Treating Fields for Glioblastoma: A Computational Study on Dose Optimization and Array Layout Planning

“…Recently, it was proposed to introduce holes at strategic positions in the skull (skull-remodeling surgery, SR-surgery) to facilitate current flow into the tumor, and thereby enhance the anti-neoplastic dose of TTFields focally in the region of interest (Korshoej et al, 2016 ). The principle has been described and analyzed in preclinical modeling studies (Korshoej et al, 2018 ; Mikic and Korshoej, 2021 ) and the concept translated into a phase 1 clinical trial demonstrating safety in 15 patients with recurrent GBM (Korshoej et al, 2020 ). Furthermore, the trial indicated prolonged overall survival (15.5 months) relative to 6–11 months in comparable first recurrence GBM trial population (Taal et al, 2014 ) and showed that an average of 32% (range 25–59%) field enhancement could be obtained with an mean skull defect area of 10.5 cm 2 (range 7–48 cm 2 ).…”