DISCUSSION
HCC, somnolence
ADVERSE EVENTS, ADVERSE EVENT
This feasibility trial confirmed the safety of EMF therapy with the AutEMdev in patients with advanced HCC, regardless of liver function (Child–Pugh class A–B), combination with systemic treatments and previous lines of therapy. No serious adverse events were reported in patients or healthy volunteers during any EMF exposure procedure. Quality of life was maintained among patients undergoing repeated exposures every 2–4 weeks. The extended OS compared with a historical control cohort indicated that AutEMdev EMF exposure was not harmful, and may suggest potential efficacy when combined with the radiological responses observed in a minority of patients.AutEMdev EMF exposure caused subtle but reproducible alterations in hemodynamic regulation, as assessed using beat‐to‐beat heart rate variability measurements.Mild, self‐limiting somnolence was a common adverse event in individuals receiving AutEMdev EMF, consistent with previous findings.OS was similar in patients receiving AutEMdev EMF monotherapy and combination therapy, including first‐line EMF. A trend toward increased duration of sorafenib treatment was observed among patients receiving combination therapy compared with pre‐enrolment. Furthermore, complete and partial RECIST v1.1 responses were observed in patients receiving EMF as a monotherapy and in combination with tyrosine kinase inhibitors. These exploratory findings warrant future investigation of the AutEMdev using personalized treatment frequencies in a prospective randomized‐controlled efficacy study.Limitations of this study include the open‐label, single‐site design, and lack of a sham exposure procedure. This spared patients from placebo interventions and ensured consistency. Safety was only monitored during procedures, and did not include liver function tests. Few patients received PD(L)‐1 inhibitors because these were not approved in Brazil when the study began. Sources of significant potential bias included: wide eligibility criteria, selection of patients willing and able to participate; patients' freedom to repeat exposures; systemic treatment flexibility; and heterogeneity in the historical control arm. Another limitation was that the study did not aim to investigate the potential relationship between hemodynamic signals of interest and clinical efficacy or somnolence side‐effects. Strengths of the study include the blinded independent radiographic review, the evaluation of OS and the use of a validated patient‐reported outcome.In conclusion, EMF treatment with the AutEMdev had an excellent safety profile in patients with advanced HCC, as both monotherapy and combination therapy. There was evidence for maintained quality of life among patients who remained on treatment. Hemodynamic variability during exposure may provide a biological surrogate for identification of optimal amplitude‐modulation frequencies in each patient. Whether these personalized frequencies are also optimal for potential anti‐tumor effects remains to be established. This study was not designed to assess efficacy, but the positive exploratory trends warrant further investigation.