Enhancement of Tumor-Treating Field Efficacy by Time-Varying Frequency Sweeping

This study aimed to enhance the therapeutic efficacy of tumor-treating fields (TTFs) by replacing a single fixed frequency with a time-varying, frequency-swept electric field.

Human lung carcinoma A549 cells were exposed for 72 h to alternating electric fields (3 V_p-p/cm) generated between parallel electrodes. Fixed frequencies of 150 and 300 kHz were compared with continuously swept fields ranging from 100 to 400 kHz at modulation rates of 0.6-100 kHz/s. Cell proliferation was quantified using a tetrazolium-based viability assay, and intracellular electric-field nonuniformity around a dividing-cell geometry was analyzed by finite-element modeling.

Fixed-frequency exposure caused only minor, non-significant reductions in cell number, whereas frequency sweeping at 0.6-2.5 kHz/s reduced proliferation by more than 50%. Numerical analyses showed that the effective frequency range associated with pronounced electric-field redistribution near the cleavage furrow depends on cell diameter, ranging from 200 to 450 kHz for the observed size distribution. Frequency sweeping effectively encompassed multiple effective bands, suppressing heterogeneous cell populations without bias toward particular sizes. The most effective modulation rates coincided with the timescales of cell retraction and mitosis, suggesting that temporal synchronization between frequency variation and cellular events maximizes efficacy.

Frequency-swept TTFs provide a robust and practical strategy to overcome tumor heterogeneity, significantly improving treatment performance compared with fixed-frequency application.

Adjusting the time-dependent sweep of the applied electric-field frequency to match tumor-specific cellular characteristics may improve reproducibility and therapeutic outcomes in clinical TTF protocols.