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      Safety and Efficacy of amplitude-modulated radiofrequency electromagnetic fields in advanced hepatocellular carcinoma


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          Importance: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Despite the recent approval of several new agents, long-term disease control remains elusive for most patients. Administration of 27.12 MHz radiofrequency (RF) electromagnetic fields (EMF) by means of a spoon-shaped antenna (TheraBionic P1 device) placed on the anterior part of the tongue results in systemic delivery of low and safe levels of RF EMF from head to toe.

          Objective: To report treatment outcomes and adverse events associated with treatment with the TheraBionic P1 device in comparison to suitable historical placebo and actively treated controls.

          Design: Pooled case series with comparison to historical controls.

          Participants: Patients with advanced HCC receiving this treatment, 18 real-world patients and 41 patients from a previously reported phase II study. Historical controls from previously conducted clinical trials.

          Interventions: Three hours daily treatment with the TheraBionic P1 device compared with standard of care as received by historical controls in the previously conducted trials.

          Main outcomes and measures: Overall survival (OS), time to progression, response rate, and adverse events in the combined pooled patients and in appropriate subgroups comparable to the historical control groups.

          Results: In the pooled treatment group, median OS of patients with Child-Pugh A disease ( n = 32) was 10.36 (95% CI 5.42–14.07) months, 4.44 (95% CI 1.64–7.13) months for patients with Child-Pugh B disease ( n = 25), and 1.99 (95% CI 0.76–3.22) months for patients with Child-Pugh C disease ( n = 2). Median OS for Child-Pugh A patients was 2.62 (33.9%) months longer than the 7.74 months OS of comparable historical controls ( p = 0.036). The 4.73 (95% CI 1.18–8.28) months median OS for Child-Pugh B patients receiving TheraBionic P1 device as first line therapy is slightly higher than the 4.6 months median OS of historical controls receiving Sorafenib as first line therapy. Only grade 1 mucositis and fatigue were reported by patients using the device, even among Child-Pugh B and C patients. No patients discontinued treatment because of adverse events.

          Conclusions and Relevance: Treatment of advanced HCC with the TheraBionic P1 device is well tolerated, even in patients with severely impaired liver function, and results in improved overall survival compared to historical controls without any significant adverse events, even after many years of continuous treatment. This treatment modality appears to be well suited for patients who have failed or are intolerant to currently approved therapies.

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          Most cited references 24

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          Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.
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              No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.) 2008 Massachusetts Medical Society

                Author and article information

                EDP Sciences
                21 July 2021
                21 July 2021
                : 4
                : ( publisher-idID: fopen/2021/01 )
                [1 ] Department of Radiation Oncology, Wake Forest Baptist Medical Center, , Winston-Salem, NC 27157, USA,
                [2 ] Wake Forest Baptist Comprehensive Cancer Center, , Winston-Salem, NC 27157, USA,
                [3 ] Division of Hematology/Oncology, Northwestern Medical Group, , Chicago, IL 60611, USA,
                [4 ] Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, , Osaka 577-8502, Japan,
                [5 ] Department of Cancer Biology, Wake Forest Baptist Medical Center, , Winston-Salem, NC 27157, USA,
                [6 ] Genolier Cancer Center, , Genolier 1272, Switzerland,
                [7 ] Department of Social Sciences and Health Policy, Wake Forest University Health Service, , Winston-Salem, NC 27157, USA,
                [8 ] Department of Biostatistics and Data Science, Wake Forest Baptist Medical Center, , Winston-Salem, NC 27157, USA,
                [9 ] TheraBionic Inc., , Winston-Salem, NC 27106, USA,
                [10 ] TheraBionic GmbH, , Ettlingen 76275, Germany,
                Author notes
                [* ]Corresponding author: bpasche@ 123456wakehealth.edu
                © A.W. Blackstock et al., Published by EDP Sciences, 2021

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 1, Tables: 8, Equations: 0, References: 24, Pages: 13
                Self URI (journal page): https://www.4open-sciences.org/
                Research Article
                Life Sciences - Medicine
                Custom metadata
                4open 2021, 4, 3


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