Forcing the Antitumor Effects of HSPs Using a Modulated Electric Field.

The role of Heat Shock Proteins (HSPs) is a "double-edged sword" with regards to tumors. The location and interactions of HSPs determine their pro- or antitumor activity. The present review includes an overview of the relevant functions of HSPs, which could improve their antitumor activity. Promoting the antitumor processes could assist in the local and systemic management of cancer. We explore the possibility of achieving this by manipulating the electromagnetic interactions within the tumor microenvironment. An appropriate electric field may select and affect the cancer cells using the electric heterogeneity of the tumor tissue. This review describes the method proposed to effect such changes: amplitude-modulated radiofrequency (amRF) applied with a 13.56 MHz carrier frequency. We summarize the preclinical investigations of the amRF on the HSPs in malignant cells. The preclinical studies show the promotion of the expression of HSP70 on the plasma membrane, participating in the immunogenic cell death (ICD) pathway. The sequence of guided molecular changes triggers innate and adaptive immune reactions. The amRF promotes the secretion of HSP70 also in the extracellular matrix. The extracellular HSP70 accompanied by free HMGB1 and membrane-expressed calreticulin (CRT) form damage-associated molecular patterns encouraging the dendritic cells' maturing for antigen presentation. The process promotes CD8+ killer T-cells. Clinical results demonstrate the potential of this immune process to trigger a systemic effect. We conclude that the properly applied amRF promotes antitumor HSP activity, and in situ, it could support the tumor-specific immune effects produced locally but acting systemically for disseminated cells and metastatic lesions.

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

(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.

Quo Vadis Oncological Hyperthermia (2020)?

Heating as a medical intervention in cancer treatment is an ancient approach, but effective deep heating techniques are lacking in modern practice. The use of electromagnetic interactions has enabled the development of more reliable local-regional hyperthermia (LRHT) techniques whole-body hyperthermia (WBH) techniques. Contrary to the relatively simple physical-physiological concepts behind hyperthermia, its development was not steady, and it has gone through periods of failures and renewals with mixed views on the benefits of heating seen in the medical community over the decades. In this review we study in detail the various techniques currently available and describe challenges and trends of oncological hyperthermia from a new perspective. Our aim is to describe what we believe to be a new and effective approach to oncologic hyperthermia, and a change in the paradigm of dosing. Physiological limits restrict the application of WBH which has moved toward the mild temperature range, targeting immune support. LRHT does not have a temperature limit in the tumor (which can be burned out in extreme conditions) but a trend has started toward milder temperatures with immune-oriented goals, developing toward immune modulation, and especially toward tumor-specific immune reactions by which LRHT seeks to target the malignancy systemically. The emerging research of bystander and abscopal effects, in both laboratory investigations and clinical applications, has been intensified. Our present review summarizes the methods and results, and discusses the trends of hyperthermia in oncology.

Relationship between Energy Dosage and Apoptotic Cell Death by Modulated Electro-Hyperthermia.

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.

Potentiation of the Abscopal Effect by Modulated Electro-Hyperthermia in Locally Advanced Cervical Cancer Patients.

Background: A Phase III randomized controlled trial investigating the addition of modulated electro-hyperthermia (mEHT) to chemoradiotherapy for locally advanced cervical cancer patients is being conducted in South Africa (Human Research Ethics Committee approval: M1704133; ClincialTrials.gov ID: NCT03332069). Two hundred and ten participants were randomized and 202 participants were eligible for six month local disease control evaluation. Screening 18F-FDG PET/CT scans were conducted and repeated at six months post-treatment. Significant improvement in local control was reported in the mEHT group and complete metabolic resolution (CMR) of extra-pelvic disease was noted in some participants. We report on an analysis of the participants with CMR of disease inside and outside the radiation field. Method: Participants were included in this analysis if nodes outside the treatment field (FDG-uptake SUV>2.5) were visualized on pre-treatment scans and if participants were evaluated by 18F-FDG PET/CT scans at six months post-treatment. Results: One hundred and eight participants (mEHT: HIV-positive n = 25, HIV-negative n = 29; Control Group: HIV-positive n = 26, HIV-negative n = 28) were eligible for analysis. There was a higher CMR of all disease inside and outside the radiation field in the mEHT Group: n = 13 [24.1%] than the control group: n = 3 [5.6%] (Chi squared, Fisher's exact: p = 0.013) with no significant difference in the extra-pelvic response to treatment between the HIV-positive and -negative participants of each group. Conclusion: The CMR of disease outside the radiation field at six months post-treatment provides evidence of an abscopal effect which was significantly associated with the addition of mEHT to treatment protocols. This finding is important as the combined synergistic use of radiotherapy with mEHT could broaden the scope of radiotherapy to include systemic disease.

Analysis of the effects of mEHT on the treatment-related toxicity and quality of life of HIV-positive cervical cancer patients.

Introduction: HIV infection is associated with increased treatment-related toxicity and worse outcomes in locally advanced cervical cancer patients (LACC), especially in resource-constrained settings. Local control (LC) in a phase III randomized, controlled trial investigating modulated electro-hyperthermia (mEHT) on LACC patients in South Africa (ethics registration: M120477/M190295), was significantly higher in participants randomized to receive chemoradiotherapy (CRT) with mEHT compared to CRT alone (stratum: HIV status, accounting for age and stage). This analysis investigates whether mEHT adds to the toxicity profile of CRT in HIV-positive LACC participants.Methods: Inclusion criteria: signed informed consent; International Federation of Gynecology and Obstetrics stages IIB to IIIB squamous cell carcinoma of the cervix; HIV-positive patients: CD4 count >200 cell/µL/on antiretroviral treatment for >6 months; eligible for CRT with radical intent. Recruitment: January 2014 to November 2017 (ClinicalTrials.gov: NCT03332069). Acute toxicity (evaluated using CTCAE v4 criteria) and quality of life (according to EORTC forms) in 206 participants randomized for treatment were evaluated alongside the LC results to determine safety and efficacy in HIV-positive participants.Results: Compliance to mEHT treatment was high (97% completed ≥8 treatments) with no significant differences in CRT-related toxicity between treatment groups or between HIV-positive and -negative participants. Adverse events attributed to mEHT were minor, even in obese patients, and did not affect CRT compliance. Participants treated with mEHT reported improved fatigue, pain, emotional and cognitive functioning.Conclusion: mEHT did not cause unexpected CRT-related toxicities and is a safe treatment modality for HIV-positive patients, with minor limitations regarding body weight, even in a low-resource setting.

Review of the Clinical Evidences of Modulated Electro-Hyperthermia (mEHT) Method: An Update for the Practicing Oncologist.

Background: Modulated electro-hyperthermia (mEHT) is a variation of the conventional hyperthermia which selectively targets the malignant cell membranes in order to heat the malignant tissue and sensitize the tissue to oncology treatments. Although widely applied, the formulation of guidelines for the use thereof is still in progress for many tumors. Aim: In this paper we review the literature on the effects of mEHT in cancer patients on local disease control and survival. Methodology: Our review on data presents the collected experience with capacitive hyperthermia treatments with the EHY-2000+ device (OncoTherm Ltd., Germany). A literature search was conducted in Pubmed and articles were grouped and discussed according to: trial type, animal studies, in vitro studies, and reviews. Search results from Conference Abstracts; Trial Registries; Thesis and Dissertations and the Oncothermia Journal were included in the discussions. Results: Modulated electro-hyperthermia is a safe form of hyperthermia which has shown to effectively sensitizes deep tumors, regardless of the thickness of the adipose layers. The technology has demonstrated equal benefits compared to other forms of hyperthermia for a variety of tumors. Given the effective heating ability to moderate temperatures, the improved tumor perfusion, and ability to increase drug absorption, mEHT is a safe and effective heating technology which can be easily applied to sensitize tumors which have demonstrated benefits with the addition of hyperthermia. Modulated electro-hyperthermia also appears to improve local control and survival rates and appears to induce an abscopal (systemic) response to ionizing radiation. Conclusion: Based on clinical studies, the method mEHT is a feasible hyperthermia technology for oncological applications. Concomitant utilization of mEHT is supported by the preclinical and clinical data.

The effect of modulated electro-hyperthermia on local disease control in HIV-positive and -negative cervical cancer women in South Africa: Early results from a phase III randomised controlled trial.

BACKGROUND: The global burden of cervical cancer remains high with the highest morbidity and mortality rates reported in developing countries. Hyperthermia as a chemo- and radiosensitiser has shown to improve treatment outcomes. This is an analysis of the local control results at six months post-treatment of patients enrolled in an ongoing study investigating the effects of the addition of modulated electro-hyperthermia (mEHT) to chemoradiotherapy for the treatment of HIV-positive and -negative cervical cancer patients in a low-resource setting. METHODS: This ongoing Phase III randomised controlled trial, conducted at a state hospital in Johannesburg, South Africa, was registered with the appropriate ethics committee. After signing an informed consent, participants with FIGO stages IIB to IIIB squamous cell carcinoma of the cervix were randomised to receive chemoradiotherapy with/without mEHT using a secure online random-sampling tool (stratum: HIV status) accounting for age and stage. Reporting physicians were blind to treatment allocation. HIV-positive participants on antiretroviral treatment, or with a CD4 count >200cell/µL were included. mEHT was administered 2/weekly immediately before external beam radiation. The primary end point is local disease control (LDC) and secondary endpoints are toxicity; quality of life analysis; and two year survival. We report on six month LDC, including nodes visualised in the radiation field on 18F-FDG PET/CT (censored for six month survival), and six month local disease free survival (LDFS) (based on intention to treat). Trial status: Recruitment closed (ClinicalTrials.gov: NCT03332069). RESULTS: 271 participants were recruited between January 2014 and November 2017, of which 210 were randomised for trial and 202 were available for analysis at six months post-treatment (mEHT: n = 101; Control: n = 101). Six month LDFS was higher in the mEHT Group (n = 39[38.6%]), than in the Control Group (n = 20[19.8%]); p = 0.003). LDC was also higher in the mEHT Group (n = 40[45.5%]) than the Control Group (n = 20[24.1%]); (p = 0.003). CONCLUSION: Our results show that mEHT is effective as a chemo-radiosensitiser for cervical cancer, even in high risk a patients and resource-constrained settings.

Defining Characteristics of Nodal Disease on PET/CT Scans in Patients With HIV-Positive and -Negative Locally Advanced Cervical Cancer in South Africa.

Literature reports increased FDG nodal uptake in HIV-positive patients. Our aim is to identify differences in presentation and characteristics of FDG-avid lymph nodes between HIV-positive and HIV-negative locally advanced cervical cancer (LACC) patients in our clinical setting. We evaluated 250 pre-treatment 18F-FDG PET/CT imaging studies from women screened for a phase III randomised controlled trial investigating modulated electro-hyperthermia as a radiosensitiser (Ethics approval: M120477). The number of nodes; size; maximum standardised uptake value (SUVmax); symmetry; and relationship between nodal size and SUVmax uptake, were assessed by region and by HIV status. In total, 1314 nodes with a SUVmax ≥ 2.5 were visualised. Of 128(51%) HIV-positive participants, 82% were on antiretroviral therapy (ART) and 10 had a CD4 count <200 cells/µL. Overall pattern of presentation and nodal characteristics were similar between HIV-positive and -negative groups and the uniformity in presentation of the nodes draining the cervix strongly suggests these nodes may be attributed to malignancy rather than HIV infection. Novel findings: HIV infection is associated with: >four nodes visualised in the neck, symmetrical inguinal lymph nodes, increased rates of supraclavicular node visualisation; FDG-avid axillary nodes were more common, but not exclusive, in HIV-positive participants. 18F-FDG PET/CT is a reliable staging method for LACC in HIV-positive patients who are not in acute stages of HIV infection, have a CD4 count >200 cells/µL, and/or are on ART and there is a potential risk of underestimating metastatic spread by attributing increased nodal metabolic activity to HIV infection in these patients.