We thank the reviewer for this important question and would be happy to clarify. TTFields are alternating electric fields in the range of 100 to 500 kHz, with maximal efficacy seen at a different frequency for different tumor types. Since TTFields cannot be applied at several different frequencies simultaneously, one specific frequency needs to be selected, and so the first step in examination of a new tumor type is a frequency scan. The effect of TTFields is not dichotomic, such that only one frequency is effective while the other are not at all. From the frequencies showing efficacy the purpose is to select the most effective one. It should be clarified that higher frequencies of the alternating electric fields do not mean higher energy, and hence there is no disadvantage in working with higher frequencies and no added toxicity or increased side effects for higher frequencies within the TTFields frequency range. Of note, TTFields at 200 kHz is already approved and has been applied to more than 18,000 patients with glioblastoma, with skin irritation being the main treatment related adverse event. TTFields at 150 kHz is approved for treatment of unresectable malignant pleural mesothelioma. To address these issues, we have rephrased the discussion: “It has been previously shown that maximal effectivity of TTFields occurs at a different frequency for different cancer types, owing to the specific electrical properties of the cells [15, 28]. Hence, the first step in applying TTFields to a new tumor type includes frequency scans.” and “The lower TTFields intensity required for treatment of HepG2 relative to Huh-7D12 cells for achieving the same level of efficacy suggest higher sensitivity of the former to TTFields.” Point 2: What is the ‘n’ number of the samples and experiments in each group?
The manuscript is an interesting work related to a potential new therapy of hepatocellular carcinoma (HCC) by using TTFields in combination with a TKI (Sorafenib).