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; ID: NCT03332069). Two hundred and ten participants were randomized and 202 participants were eligible for six month local disease control evaluation. Screening F-18-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 F-18-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

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 F-18-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 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. F-18-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/mL, 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

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/mu L 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 F-18-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

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

Possible potentiation of the abscopal effect of ionising radiation by modulated electro-hyperthermia in locally advanced cervical cancer patients

INTRODUCTION: Literature has shown that the local application of ionising radiation is able to induce a response at distant sites of disease. This effect, known as the abscopal effect, is generally accepted to be mediated by the triggering of an immune response by ionising radiation. The application of hyperthermia has also been suggested to enhance the abscopal effect. Our ongoing phase III, randomised clinical study investigates the effects of the addition of modulated electro-hyperthermia (mEHT) on chemoradiotherapy in locally advanced cervical patients. We assess the response of the tumour and lymph nodes inside and outside of the radiation treatment field based on PET/CT images and report on the potential abscopal effect mediated by mEHT. METHODS: Participants enrolled in the study had FIGO stage IIb (distal parametrium involvement) to IIIb (bilateral hydronephrosis excluded) cervical cancer. HIV positive participants were included if their CD4 count was >200cells/mL or they had been on antiretroviral therapy for more than 6 months. Participants were randomised into a mEHT arm or a control arm. All participants were prescribed 50Gy external beam radiation to the pelvis in 25 fractions, plus 3 fractions of 8Gy High Dose Rate (HDR) Brachytherapy. Participants in the mEHT arm were prescribed 2 mEHT treatments per week during external beam radiation using modulated 13.56MHz capacitive heating (55 minutes; 130W). 155 pre-treatment and 155 post-treatment 18F-FDG PET/CT scans were analysed. Each region (head and neck; thorax; abdomen; pelvis) was scored according to the nodes visualised on 18F-FDG PET/CT: no change in the number of visualised nodes; resolution of all nodes; new nodes; no nodes in either pre- or post-treatment scans. Tumour response was reported based on PERCIST version 1.0 criteria. RESULTS: 56% and 62% of the participants in the mEHT and control arm respectively had nodes with an 18F-FDG Standard Uptake Value of more than 2.5 visualised on PET/CT before treatment. A complete metabolic response of the tumour was significantly higher in the participants in the mEHT group than in the participants in the control group (58% versus 37% respectively). The number of participants with a complete metabolic response of the tumour and extra-pelvic nodes was also significantly higher in the mEHT group versus in the control group (27.7% vs 6.8%; Chi2: p=0.009). CONCLUSIONS: In our study, the addition of mEHT may be contributing to an enhanced abscopal effect with a significantly higher increase in the complete metabolic response of nodal disease outside of the treated area observed in the mEHT group

Effects of modulated electro-hyperthermia on disease control and disease-free survival in locally advanced cervical cancer patients : preliminary results

INTRODUCTION: Modulated electro-hyperthermia (mEHT) proposes an alternative, feasible, method to the conventional thermo-monitoring techniques currently applied in HT. Literature also suggests that mEHT induces immunological processes which can be harnessed for the management of malignancies. For these reasons mEHT was selected for investigation in a resource-constrained setting with high-risk patients in South Africa. We present preliminary results on the effects of mEHT in our ongoing phase III randomised controlled trial on disease control disease-free survival (DFS) in locally advanced cervical cancer (LACC) patients. METHODS: Participants were randomised to receive mEHT with/without chemoradiotherapy (CRT). mEHT was administered 2/week using 13.56MHz capacitive heating (planned power of 130W; 55 minutes) before external beam radiation. Disease control and disease pattern were assessed by 18F-FGD PET/CT at six months post-treatment. Participants were followed up every three months in the first year and every six months thereafter. Regression models were used to assess DFS. RESULTS: 165 participants have reached two years post-treatment (mEHT=68; Control=97), of whom 66 mEHT and 94 Control group participants were eligible for six month local DFS analysis. Six month local DFS was significantly higher in the mEHT group: 25[38%] than in the control group: 20[21%] (p=0.21). In participants eligible for analysis at two years, two year DFS was significantly higher in the mEHT group (52% [33 out of 64]) than in the Control Group (34% [31 out of 91])(HR: 1.60; p=0.033). In the participants who have reached three years post-treatment, three year DFS is also significantly higher in the mEHT group: 58% [18 out of 31] versus 35% [16 out of 46] (HR: 1.97; p=0.042). A subgroup analysis of participants with extra-pelvic disease visualised on pre-treatment scans showed complete metabolic response of all disease was higher in the mEHT group (13 out of 54; [24.1%]) than in the Control Group (3 out of 54 [5.6%]) (p=0.013). CONCLUSION: Preliminary results continue to show a positive trend in local control and disease free survival benefit in the participants treated with mEHT combined with CRT versus participants treated with CRT alone. The significant reduction in disease outside the radiation field in the mEHT Group suggests the potentiation of the abscopal effect by mEHT which motivates future investigations into the use of mEHT and immune checkpoint inhibitors

Interim statistical analysis on a phase III randomised trial investigating the addition of modulated electro-hyperthermia to chemoradiation for cervical cancer in HIV positive and negative women in South Africa

BACKGROUND: Cervical cancer is the second most common cancer in South Africa where funding and resources for treatment are limited and HIV infection rates are high. A Cochrane review (2010) on pooled data from six randomised trials showed a potential benefit to the addition of hyperthermia (HT) to radiotherapy (RT) protocols for cervical cancer. The Dutch Deep Hyperthermia trial (2010) reported a cost saving per quality adjusted life year when HT was added to RT protocols. The potential cost-saving resulting from the addition of HT to cervical cancer treatment protocols may lower the burden on healthcare facilities in South Africa and improve treatment options in HIV positive patients. AIM: To determine the clinical effects of the addition of modulated electro-hyperthermia (EHT) on the standard treatment protocols for locally advanced cervical cancer patients in state healthcare in South Africa. OBJECTIVES: To assess the effects of the addition of EHT on local disease control, quality of life, acute and late toxicity and survival. DESIGN AND METHOD: This is an ongoing phase III randomised clinical trial conducted at the Charlotte Maxeke Johannesburg Academic Hospital. The study aims to enrol 236 female participants with FIGO stage IIB to IIIB cervical cancer. Participants are being randomised into a “Hyperthermia” group (EHT plus chemoradiation) and a “Control” group (chemoradiation alone), based on HIV status, age and stage of disease. All participants are receiving 25 fractions of 2Gy external beam radiation, 3 doses of high dose rate brachytherapy (8Gy) and up to 3 doses of cisplatin (80mg/m2). The Hyperthermia group is receiving two 55 minute local EHT treatments per week during radiation therapy. Local disease control is being assessed by Positron Emission Tomography (PET) scans. Adverse events, quality of life and overall survival are being recorded and the data is being analysed. Ethics was obtained by the Human Research and Ethics Council (clearance number: M120477