Abstract
Studies indicate that increasing the electric field intensity of Tumor Treating Fields therapy (TTFields) may prolong survival for glioblastoma (GBM) patients. Skull remodeling surgery (SR-surgery) aims to increase electric field intensity by 30-100% by removing the poorly conductive skull, and OptimalTTF-1 (pilot trial) concluded that SR-surgery was safe with a median overall survival (mOS) of 15.5 months for first recurrence GBM (rGBM). OptimalTTF-2 is a 1:1 randomized, comparative, multi-center, investigator-initiated, interventional clinical phase 2 trial investigating the efficacy and safety of TTFields and standard of care with or without SR-surgery for 84 rGBM subjects, with a planned interim analysis after enrollment of the first 52. Randomization is solely for SR-surgery and involves five burr holes of 15mm each in diameter, located in the skull between the tumor and the transducer arrays. The trial was nationwide in Denmark and active from 2020-2024. Major eligibility criteria include age ≥18 years, histopathological confirmed first recurrence of supratentorial GBM, and KPS ≥70. The primary endpoint is OS after 12 months (OS12), while secondary endpoints include PFS, QoL, ORR, QoL, KPS, steroid dose, and toxicity. The trial recruited 58 subjects and 52 had follow-up of 12-months or longer. Randomization was balanced and both arms had a median age of 59 years and no statistical difference in prognostic markers. Intent-to-treat analysis revealed the following for the intervention and control respectively, OS12 55% [95%CI 37-74%] vs. 45% [95%CI 27-64%](p=0.4), mOS 12.2 [7.9-19.1,95%CI] vs. 11 [6.5-17.1, 95%CI] months, and PFS 4.5 [3.4-9.5,95%CI] vs. 3.5 [3-6.4,95%CI] months. All the secondary outcomes were statistically insignificant. The trial was terminated early after interim analysis indicated no survival benefit from SR-surgery and a conditional power calculation that showed a low expected survival benefit for the planned cohort of 84 subjects. Post hoc analysis examining potential negative outcome modifiers is needed.