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Effects of Modulated Electro-Hyperthermia (mEHT) on Two and Three Year Survival of Locally Advanced Cervical Cancer Patients.

ABSTRACT: (1) Background: Modulated electro-hyperthermia (mEHT) is a mild to moderate, capacitive-coupled heating technology that uses amplitude modulation to enhance the cell-killing effects of the treatment. We present three year survival results and a cost effectiveness analysis from an ongoing randomised controlled Phase III trial involving 210 participants evaluating chemoradiotherapy (CRT) with/without mEHT, for the management of locally advanced cervical cancer (LACC) in a resource constrained setting (Ethics Approval: M120477/M704133; ClinicalTrials.gov ID: NCT033320690). (2) Methods: We report hazard ratios (HR); odds ratio (OR), and 95% confidence intervals (CI) for overall survival and disease free survival (DFS) at two and three years in the ongoing study. Late toxicity, quality of life (QoL), and a cost effectiveness analysis (CEA) using a Markov model are also reported. (3) Results: Disease recurrence at two and three years was significantly reduced by mEHT (HR: 0.67, 95%CI: 0.48-0.93, p = 0.017; and HR: 0.70, 95%CI: 0.51-0.98, p = 0.035; respectively). There were no significant differences in late toxicity between the groups, and QoL was significantly improved in the mEHT group. In the CEA, mEHT + CRT dominated the model over CRT alone. (4) Conclusions: CRT combined with mEHT improves QoL and DFS rates, and lowers treatment costs, without increasing toxicity in LACC patients, even in resource-constrained settings.

SUBMITTER: Minnaar CA

PROVIDER: S-EPMC8833695 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Effects of Modulated Electro-Hyperthermia (mEHT) on Two and Three Year Survival of Locally Advanced Cervical Cancer Patients.

Minnaar Carrie Anne CA Maposa Innocent I Kotzen Jeffrey Allan JA Baeyens Ans A

Cancers 20220127 3

(1) Background: Modulated electro-hyperthermia (mEHT) is a mild to moderate, capacitive-coupled heating technology that uses amplitude modulation to enhance the cell-killing effects of the treatment. We present three year survival results and a cost effectiveness analysis from an ongoing randomised controlled Phase III trial involving 210 participants evaluating chemoradiotherapy (CRT) with/without mEHT, for the management of locally advanced cervical cancer (LACC) in a resource constrained sett ...[more]

PMID: 35158924

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Project description:The benefits of high-fever range hyperthermia have been utilized in medicine from the Ancient Greek culture to the present day. Amplitude-modulated electro-hyperthermia, induced by a 13.56 MHz radiofrequency current (mEHT, or Oncothermia), has been an emerging means of delivering loco-regional clinical hyperthermia as a complementary of radiation-, chemo-, and molecular targeted oncotherapy. This unique treatment exploits the metabolic shift in cancer, resulting in elevated oxidative glycolysis (Warburg effect), ion concentration, and electric conductivity. These promote the enrichment of electric fields and induce heat (controlled at 42 °C), as well as ion fluxes and disequilibrium through tumor cell membrane channels. By now, accumulating preclinical studies using in vitro and in vivo models of different cancer types have revealed details of the mechanism and molecular background of the oncoreductive effects of mEHT monotherapy. These include the induction of DNA double-strand breaks, irreversible heath and cell stress, and programmed cells death; the upregulation of molecular chaperones and damage (DAMP) signaling, which may contribute to a secondary immunogenic tumor cell death. In combination therapies, mEHT proved to be a good chemosensitizer through increasing drug uptake and tumor reductive effects, as well as a good radiosensitizer by downregulating hypoxia-related target genes. Recently, immune stimulation or intratumoral antigen-presenting dendritic cell injection have been able to extend the impact of local mEHT into a systemic "abscopal" effect. The complex network of pathways emerging from the published mEHT experiments has not been overviewed and arranged yet into a framework to reveal links between the pieces of the "puzzle". In this paper, we review the mEHT-related damage mechanisms published in tumor models, which may allow some geno-/phenotype treatment efficiency correlations to be exploited both in further research and for more rational clinical treatment planning when mEHT is involved in combination therapies.

Project description:Modulated electro-hyperthermia (mEHT) is a form of mild hyperthermia (HT) used for cancer treatment. The principle utility of HT is the ability not only to increase cell temperature, but also to increase blood flow and associated pO2 to the microenvironment. While investigational evidence has shown the unique ability of mEHT to elicit apoptosis in cancer cells, in vivo and in vitro, the same trait has not been observed with conventional HT. There is dissension as to what allows mEHT to elicit apoptosis despite heating to only mild temperatures, with the predominant opinion in favor of increased temperature at a cellular level as the driving force. For this study, we hypothesized that in addition to temperature, the amount of electrical energy delivered is a major factor in induction of apoptosis by mEHT. To evaluate the impact of electrical energy on apoptosis, we divided generally practiced mEHT treatment into 3 phases: Phase I (treatment start to 10?min. mark): escalation from 25?°C to 37?°C Phase II (10?min. mark to 15?min. mark): escalation from 37?°C to 42?°C Phase III (15?min. mark to 45?min. mark): maintenance at 42?°C Combinations of mEHT at 18?W power, mEHT at 7.5?W power, water bath, and incubator were applied to each of the three phases. Power output was recorded per second and calculated as average power per second. Total number of corresponding Joules emitted per each experiment was also recorded. The biological effect of apoptotic cell death was assayed by annexin-V assay. In group where mEHT was applied for all three phases, apoptosis rate was measured at 31.18?±?1.47%. In group where mEHT was only applied in Phases II and III, apoptosis rate dropped to 20.2?±?2.1%. Where mEHT was only applied in Phase III, apoptosis was 6.4?±?1.7%. Interestingly, when mEHT was applied in Phases I and II, whether Phase III was conducted in either water bath at 42?°C or incubator at 37?°C, resulted in nearly identical apoptosis rates, 26?±?4.4% and 25.9?±?3.1%, respectively. These results showed that accumulation of mEHT at high-powered setting (18?W/sec) during temperature escalation (Phase I and Phase II), significantly increased apoptosis of tested cancer cells. The data also showed that whereas apoptosis rate was significantly increased during temperature escalation by higher power (18?W/sec), apoptosis was limited during temperature maintenance with lower power (7.5?W/sec). This presents that neither maintenance of 42?°C nor accumulation of Joules by mEHT has immediate correlating effect on apoptosis rate. These findings may offer a basis for direction of clinical application of mEHT treatment.

Dataset Information

Effects of Modulated Electro-Hyperthermia (mEHT) on Two and Three Year Survival of Locally Advanced Cervical Cancer Patients.

Publications

Effects of Modulated Electro-Hyperthermia (mEHT) on Two and Three Year Survival of Locally Advanced Cervical Cancer Patients.

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