Modeling the influence of Tumor Treating Fields (TTFields) treatment usage time and break patterns on therapeutic outcomes

Introduction: Tumor Treating Fields (TTFields) therapy delivers low-intensity, alternating electric fields that disrupt cancer cell division and tumor growth. Clinical evidence indicates that device usage is directly correlated with patient outcomes. While the clinical recommendation for patients is to aim for maximal average monthly usage, there are no clear guidelines on how to manage treatment interruptions within the month. The aim of the current study was to examine the impact of treatment breaks, including their timing and duration, on TTFields efficacy in vitro. Methods: Human NSCLC (A549) and GBM (U87 MG) cell lines were exposed to TTFields (150 and 200 kHz, respectively; 1 V/cm RMS) under varying treatment schedules incorporating intentional interruptions. Initially, continuous TTFields exposure for 48 or 72 hours was compared to a 48-hour cumulative exposure delivered within a 72-hour experimental window, including either a single 24-hour interruption at mid-treatment or three distributed 8-hour daily breaks. The effect of break timing was then evaluated by positioning a 24-hour interruption at the beginning, middle, or end of the 72-hour treatment period. Subsequently, the duration of the mid-treatment break was extended to 24, 48, or 72 hours (total experimental duration of 72, 96, and 120 hours, respectively), followed by an assessment of fractionating the 72-hour break across the 120-hour period. Treatment efficacy across all conditions was determined by measuring cell counts at experiment completion, expressed as a percentage relative to untreated time-matched controls. Results: Implementing treatment breaks totaling up to 24 hours within a 72-hour experimental window yielded similar efficacy to uninterrupted TTFields exposure with the same cumulative treatment duration of 48 hours. Comparable results were observed whether the 24-hour interruption was delivered as a single continuous break or fractionated into three 8-hour intervals. Varying the timing of the 24-hour break - at the beginning, middle, or end - did not significantly influence efficacy. Extending the mid-treatment break from 24 (of 72) to 48 (of 96) to 72 (of 120) hours had little effect on TTFields response in U87 MG cells but markedly reduced efficacy in A549 cells when the interruption lasted 72 hours. Fractionating the 72-hour break for the A549 cells across the 120-hour total experimental duration partially restored efficacy. Conclusions: These results indicate that TTFields efficacy is preserved under short or fractionated 24-hour interruptions but declines with extended continuous treatment breaks. Optimizing treatment adherence and defining tolerable interruption patterns may help sustain clinical efficacy while reducing device burden and improving patient quality-of-life.