|Year : 2019 | Volume
| Issue : 1 | Page : 1-17
Thermal and nonthermal effects of radiofrequency on living state and applications as an adjuvant with radiation therapy
Department of Biotechnics, St. Istvan University, Budaörs, Hungary
|Date of Web Publication||22-May-2019|
Prof. Andras Szasz
Department of Biotechnics, St. Istvan University, Budaörs
Source of Support: None, Conflict of Interest: None
One of the most frequently applied bioelectromagnetic effects is the deep heating of living species with electromotive force energy. Despite its long history, hyperthermia is a rarely applied oncotherapy because of controversial results and complicated control. The challenge in clinical studies of oncological hyperthermia is the disharmony of the local response and local control with overall survival. Both whole-body (complete isothermia for the body) and local (isothermia for the chosen target) heating show excellent local effects; however, this is not followed with the expected elongation of survival time. A possible solution could be nonisothermal heating to the heterogeneity of the malignancy itself. The distinguishing parameters to select the target are the electromagnetic properties of the malignant tissue together with the physiological differences between malignant cells and their healthy counterparts. Selection could allow for cellular targeting, generating natural reactions, such as programmed cell death (apoptosis) followed by immunogenic cell death involving extended immune reactions. This complex method is a new kind of hyperthermia, named modulated electrohyperthermia (tradename oncothermia). The selective, nonequilibrium energy absorption is well synergized with modern radiation therapies, presenting a solution of an active and controllable tumor-specific immune reaction and subsequent abscopal effects.
Keywords: Abscopal effect, apoptosis, electromagnetic effects, immunogenic cell death, ionizing, modulated electrohyperthermia, oncothermia, radiofrequency current, radiotherapy
|How to cite this article:|
Szasz A. Thermal and nonthermal effects of radiofrequency on living state and applications as an adjuvant with radiation therapy. J Radiat Cancer Res 2019;10:1-17
|How to cite this URL:|
Szasz A. Thermal and nonthermal effects of radiofrequency on living state and applications as an adjuvant with radiation therapy. J Radiat Cancer Res [serial online] 2019 [cited 2019 Aug 21];10:1-17. Available from: http://www.journalrcr.org/text.asp?2019/10/1/1/258717
| Introduction|| |
Hyperthermia is an ancient treatment. Fire and the Sun, as the overall energy source of the Earth, had symbolic significance in ancient human cultures. As a consequence, heat delivery was naturally a medical possibility. Application of heat for tumors was used in ancient medicine, and the first description of this particular treatment was made by Hippocrates.
The original idea of hyperthermia was based on a simple principle: the heated tumor exhibits an accelerated metabolism without extra supply and the “starving” tumor destroys itself by acidosis. This approach is supported by the impoverishment of Adenosine triphosphate and enrichment of lactate in treated tumors, and furthermore, due to the change in energy consumption, the tumors are more sensitive to heating than their healthy counterparts.
Various heat deliveries were applied in the middle ages for tumors mainly for ablative intention. The birth of electromagnetic heating techniques at the end of the 19th century renewed medical heating methodology. Methods to heat up the whole body or specific regions were developed rapidly.
Two concepts of electromagnetic energy absorption as oncological treatment were developed in parallel by Carl D.W. Busch (1826–1881) in Germany and the French physician Arsene d'Arsonval (1851–1940), who worked out the temperature-based and electromagnetic field effects, respectively. In the first half of the 20th century, the market competition between the two methods was decided when Siemens, the largest producer of medical devices, launched heating devices with emphasis on temperature growth.
At the same time, oncological hyperthermia turned to electromagnetic direction, the birth of ionizing radiation by the discovery of X-rays by Wilhelm Conrad Rontgen (1845–1923) occurred at the end of the 19th century. The first textbook on radiotherapy (RT) was published in 1903, and publications continued afterward, building RT as one of the three “gold-standard columns” of monotherapies.
Oncological hyperthermia could not reach the status of the widely accepted “gold standard.” Despite the long history of the method, its medical applications are relatively rare; its recognition is similar to that of therapies at their infancy. Despite the statistical evidence in research and clinical applications, hyperthermia could not break through the limitations of the last alternative in late palliative care. Effects of oncological hyperthermia are mostly acknowledged, but the clinical evidence has many challenging problems.
The main success of hyperthermia lies in its complementary applications and mostly in combination with RT. Sensitizing classical ionizing radiation by hyperthermia is unambiguous,,,, and the synergy between methods is well known , and has been successfully applied.,, The success of complementary treatments with RT has a broad spectrum of evidence ,,,, and is well summarised by various review articles.,,, To characterize the gain, the thermal enhancement ratio was introduced.
The complementary effects exhibit three aspects that act in parallel:
- Radiation is most effective in M and G1 phases of the cell cycle in relatively alkaline, well-oxygenated regions, while hyperthermia predominantly acts in S phase  in moderately acidic, hypoxic regions, which complements the cell cycle arrest
- Various other molecular parameters increase to sensitizing effect, e.g., heat-induced decrease of DNA-dependent protein kinase 
- Hyperthermia physiologically increases the blood flow by vasodilatation to regulate thermal homeostasis, compensating for the increased temperature by cooling blood flow, which delivers extended oxygen supply for radio effects.,
The last point of synergy is contradictory. It naturally opposes the original “starvation” concept, because the higher metabolic rate of the proliferating mass compensates for the missing supply by nonlinearly increasing blood flow.,, The effects of higher radiosensitivity begin to compete with the number of nutrients by vasodilation and better perfusion through the vessel walls. On the other hand, in massive tumors the neo-angiogenic arteries do not vasodilate, as they lack musculature in their vessel wall. In this way, the healthy and malignant tissues differ in their reaction to heat. It has been shown that an increase in temperature can cause vasoconstriction in certain tumors, leading to decreased blood perfusion and heat conduction,,, while causing vasodilatation in healthy tissues leading to increased relative blood perfusion and heat conduction in this region., Blood perfusion of the tumor relative to the surrounding healthy tissue is always lower  and thus could provide an effective heat trap. The bloodstream compensates for the overheating by regulating the flow capacity of the vessels, and as a result of this physiological feedback, effective vascular response to heating is observed. The bloodstream has a central role in maintaining overall homeostasis, not only by temperature regulation but also by other parameters (e.g., acid-alkaline equilibrium, glucose delivery, and immune actions). The vascular response to heating differs in malignant tissues compared with healthy tissues over a tumor-specific threshold. Over the threshold, vasocontraction occurs instead of the vasodilatation, which downregulates the oxygenation and lowers the efficacy of RT. Furthermore, over the threshold downregulating natural killer cell cytotoxicity  and other immune actions  appears too. The tumor blood flow also exhibits tumor-specific changes from approximately 38°C. Substantial cellular damage has been observed at temperatures above 41°C–42°C. There is a limit with the cellular phase transition at approximately 42.5°C, which surprisingly fits the results of the Arrhenius plot.,
Reduced survival, despite local success, was observed in clinical studies at high-level evidence of oncological hyperthermia. One of the first phase III trials investigating thermo-RT compared with RT alone by extensive international cooperation for breast cancer showed clear and significant local remission, although the overall survival was unchanged. Another study observed that the local progression-free survival of breast cancer was improved by thermo-RT, although the survival time was better with RT alone. Additional development of distant metastases was shown when hyperthermia was combined with RT compared with earlier data. Interestingly, when local control was not successful, the survival rate was better by RT alone than in addition of thermal treatment. A similar study found evidence of toxicity.
Pelvic localizations were studied in one of the flagship trials of oncological hyperthermia. Local control for cervix tumors showed strongly significant results. Nevertheless, the local effects on bladder and rectum tumors were not significant, but were positive for thermal treatments. However, the change in survival time was significant only in the cervix cohort and was not favorable in rectum and bladder tumors. Later, the cervix results were questioned by a controlled study, which showed improvement of the local control but worsening of the survival time by hyperthermia in addition to RT.
Further study of uterine cervix carcinomas showed a benefit in terms of survival, but newer critics have questioned this result., Other high-level evidence, a phase III trial of cervical carcinomas with complementary hyperthermia and brachytherapy, registered the same controversies between survival time and local control involving 224 patients. A recent study of cervical carcinomas  was also inconclusive in the comparison of RT-based differences of complementary chemotherapy (CT) or hyperthermia, and thus, the study was terminated. The interim results showed, however, that the event-free survival was slightly worse in the thermo-RT group than in the chemo-RT group, but the difference was not statistically significant.
It is not only the cervical carcinoma studies that suffer from controversy between survival time and local control. A study on locally advanced nonsmall cell lung cancer (NSCLC) also showed significant improvement of the overall response rate in local measures, although there was no change in overall survival. Later, a multicenter phase III trial for NSCLC showed no improvements in overall survival in the hyperthermia cohort. The cause was directly shown: the appearance of distant metastases was five-times higher (10/2; P = 0.07) in the thermo-RT group compared with RT alone.
Other recent findings in heatable surface tumors show the same contradiction between the local control and survival rate. A recent study found that the local control was better when less energy was administered than prescribed.
The dissemination of malignant cells most likely causes the poor results of the survival rate, forming micro- and later macro-metastases. These controversial data are questioning the successful applicability of heat therapy in oncology and the hope of a promising approach  could be lost.
However, the data showing highly significant improvement of local control obtained with hyperthermia and RT represent facts that we must consider as the basis for further development of oncological hyperthermia and to correct the problems with overall survival. To overcome the issues, we must concentrate on blocking invasion and reducing dissemination. The task is to prevent formation of metastases caused by heating. Furthermore, we may eliminate the metastases formed earlier, before thermal treatment with local hyperthermia of the primary tumor.
To overcome this problem, we have modified the isothermal concept of oncological hyperthermia to heterogenic, selective heating by bioelectromagnetic selection and excitation of apoptotic pathways of malignant cells by the absorbed energy. The method is a new kind of hyperthermia, introduced as modulated electrohyperthermia (mEHT; tradename, oncothermia).
| Methods|| |
The applied hyperthermia technique was the mEHT method, which uses capacitively coupled energy-transfer [Figure 1]. Capacitive coupling technique (CCT) is a relatively old technical solution. The first CCT device was marketed under the name “Universal Thermoflux” by Siemens. It was later further developed and launched to market by the name of Radiotherm in the early 1930s. The first modern medically oriented CCT was published in 1976 by H.H. LeVeen  and has been widely applied since.,,,,
The capacitor in CCT is formed by the approximately plane-parallel electrodes and ensures a homogeneous temperature in the deep-seated target by regulating the applied size ratios of the electrodes. However, living structures form very heterogeneous impedances and well-controlled heat-sinks by physiological regulatory signals. Due to these conditions, the CCT technique has drawbacks when the task request is localized isothermal heating in depth.
The concept of heating by mEHT differs from conventional heat therapies. Technically, it uses CCT but in a redesigned form, taking a well-compensated resonant circuit to maximize the RF current and at the same time minimize the voltage on the electrodes at a given output power. The patient is an electric part of the preciously tuned system, representing active electrical impedance, so it is not simply an “energy absorbent.” Approaching the proper impedance matching the solution has negligible reflected power (order of 1 W), mimicking the galvanic contact with the skin as much as possible.
While the goal of conventional hyperthermia treatment is to heat the tumor mass homogeneously, mEHT is genuinely breaking the isothermal approach. Instead of homogenous heating of the target, mEHT uses excellent selection to force absorption of energy on the malignant cells, heating them locally to the hyperthermia temperature to induce cellular changes in the targeted cells [Figure 2].
|Figure 2: mEHT uses the heterogeneous selective heating (a), instead of the homogeneous, isothermal one (b)|
Click here to view
The biophysical differences of the malignant cells compared with their healthy counterparts allow proper selection of targeted cells. The biophysical alterations of malignant cells are connected to their intensive proliferative behavior with lack of apoptotic activity. The energy source building new structure is accelerated glycolysis, which is measurable by positron-emission tomography (PET). The consequence of the metabolic differences allows for the development of a high ionic concentration in the tumor mass; thus, cells can be distinguished by the flow of the current.
The other distinguishable characteristic of malignant cells is their autonomy. These cells are individual, breaking intercellular bonds  and junctions, and “fighting” with all other cells for metabolic energy. This autonomy is recognized by differences in the increased dielectric constant of the extracellular electrolyte in the near vicinity of malignant cells (Szent-Gyorgyi effect). The high dielectric constants around the malignant cells channelizes the RF current.
The RF current exhibits a characteristic dispersion in the MHz frequency range (β/δ dispersion  and the Schwan effect ), which concentrates the action on lipid–protein interactions, and selects water-bound states  at the membrane, using it effectively for appropriate targeting. The concentration of lipid rafts on the membranes of malignant cells is significantly higher than on the membrane of nonmalignant cells. Consequently, the dense lipid rafts of the selected malignant cells by the above biophysical differences become an easy target of the energy absorption. Due to the electric properties of the clusters of transmembrane proteins, their selection for absorption is automatic.
| Results|| |
The synergy of the electric field with temperature-induced changes on malignant cells is tracked from the laboratory to the patient's bed. This complex interaction is more effective than conventional hyperthermia. The temperature gradient changes membrane processes and promotes signaling pathways for natural apoptosis  instead of thermal necrosis.
The absolute differences between mEHT and conventional isothermal hyperthermia with the same temperature have been studied in vitro and in vivo. The temperature of the malignant cells acts as if they are at least 3°C higher than the environmental average. The selective targeting of mEHT appears as mild conventional hyperthermia in the tumor mass, averaging the overheated rafts. Consequently, the blood flow remains in the optimal fever-range level,,, avoiding additional adverse processes such as increased glucose delivery, increased invasion, and high risk of dissemination. The proliferation marker Ki67 has been shown to be significantly suppressed by mEHT compared with its untreated counterpart. The formation of new E-cadherin-β-catenin complexes to bond the cells intercellularly helps block invasion, “gluing” the cells to the location.
Experimental studies have clearly shown the excellent synergy of mEHT with RT. The advantage of the application of oncothermia is significant. Interestingly, comparison with water-bath isothermal heating shows an optimum ratio at an average medium temperature of 42°C [Figure 3].
|Figure 3: (a) Surviving fraction after 60 min heat treatment by conventional hyperthermia (HT; water-bath) and mEHT, for SCCVII (SCC7), a mouse head and neck carcinoma cell line in vitro. (b) Ratio of mEHT/HT survival|
Click here to view
The same study  showed significant improvement of the apoptotic ratio by mEHT in combination with RT compared with the water-bath combined with RT. There was also a large increase in autophagy with the mEHT combinations [Figure 4]. The fingerprint of the extrinsic apoptotic pathway, caspase-8, was significantly higher in the RT + mEHT combination, as has been shown previously., Cell cycle arrest of malignant cells has also been clearly demonstrated. Another radiation study was performed in vivo and showed significantly less hypoxia in FSall tumors 3 days after treatment with 15 Gy combined with mEHT at 41°C for 30 min. A significant decrease in vascular endothelial growth factor has also been shown when mEHT is applied alone or in combination with RT.
|Figure 4: (a) Apoptosis and (b) autophagy induced by HT and mEHT in combination with RT for SCCVII (SCC7), a mouse head and neck carcinoma cell in vitro. Apoptosis is expressed as a percentage, while autophagy is expressed as folding rate|
Click here to view
Clinical studies of mEHT are consistent with the experimental data. Enhancement of oxygen in the target for sensitizing RT has been shown in a blood flow trial, and increased permeability of blood vessels has been shown by a pharmacokinetic trial. Sensitive organs, such as the brain, can also be treated safely, as shown by a dose escalation study.
This method has been applied successfully in various cancer types, mostly complimentary with various chemotherapies. Remarkable results were achieved with gliomas,,,, colorectal cancers,, lung cancers,, uterine cervix carcinomas, malignant ascites, sarcomas,, pancreas carcinomas,, and prostate cancer.,
A successful case of definitive RT with concurrent mEHT for stage IIIB NSCLC  projects the feasibility of mEHT combined with RT. Another case, the treatment of advanced cervical cancer with complex trimodal (mEHT + CT + RT), supports the possibility of combined therapy. A large number of case reports were published with complementary RT + mEHT, which may be followed in the open-access Oncothermia Journal.
Two examples of representative case reports for mEHT + RT combined with CT (mEHT + RT + CT) for inoperable advanced metastatic esophagus cancer are shown in [Figure 5] and [Figure 6].
|Figure 5: Treatment of relapsed, inoperable esophagus cancer (a) before mEHT therapy, (b) after mEHT therapy, (c) trimodal protocol, (d) placement of electrodes|
Click here to view
|Figure 6: Treatment of relapsed, inoperable esophagus cancer (a) before mEHT therapy; (b) after mEHT therapy, (c) trimodal protocol, (d) placement of electrodes|
Click here to view
Together with the extended number of studies in a combination of mEHT with CT, only some pilot studies were performed with a combination of RT. Some exciting results have been shown in pilot studies. In a small study [Figure 7], the superiority of RT + mEHT was observed, but the small number of patients does not allow for conclusive results.
|Figure 7: Advanced liver metastases of various types of primary tumors. Investigator: Prof. H. Aydin; Institute: Clinic and Institute of radio-oncology, zentralkrankenhus reinkenheide, Bremerhaven, Germany; oncothermia: ×2/week; concomitant chemotherapy; vinorelbine (20 mg/m2/week); concomitant radiotherapy: 10 MV, 1.5–1.8 Gy fractional radiation × 5/week, overall dose; 21–24 GY. (a) Protocols and response rates; (b) Successful case before RT + mHET combined therapy; and (c) after therapy|
Click here to view
Quality of life (QoL) of the patient is the integrative goal of mEHT combined with elongation of overall survival. Bone metastases frequently reduce QoL by intense pain. The mEHT method is helpful in these cases as well [Figure 8].
|Figure 8: Bone metastasis treatment by 18–20 Gy, fractionally 1.8–2 Gy/day, 5x/week, plus mEHT every second day|
Click here to view
Preoperative application of mEHT for liver metastases was performed by Prof. H. Renner  [Klinikum Nord, Nürnberg, Germany; [Figure 9]. The primary tumors were inoperable (R2) rectal carcinomas (n = 7). Trimodal therapy was applied: RT, 45 + 5 Gy (fractional); CT, 5-FU/Mitomicine-C (×2); oncothermia, 60 min, diameter 30 cm (8–×10). Following oncothermia, all patients were eligible for operation. The results of the operations were excellent: 71% of patients exhibited complete resection (R0) while one was partially resected (R1) and one was not successfully operated (remained R2).
|Figure 9: Results of the operations performed postoncothermia on previously inoperable patients|
Click here to view
The successful application of mEHT in combination with CT  has demonstrated the feasibility of mEHT in uterus cervix carcinomas. A phase III randomized clinical trial using trimodal (mEHT + CT + RT) therapy is currently ongoing ,, for this localization. Interim results of 160 patients after the PET control before and after therapy shows promising results after 6 months of local disease control [Figure 10]. The trimodal protocol was as follows: radiation, 25 × 2 Gy external and 3 × 8 Gy brachytherapy; CT, 3 × 80 mg/m 2 cisplatin, and mEHT 2 × 55 min/week (4 weeks).
|Figure 10: Interim of Phase III trial of participants with FIGO stage IIB (initial distal parametrium involvement) to IIIB cervical cancer. (a) Response rates. (b) Overall survival rates 6 months after the trimodal combined theraby. (c) Overall survival by HIV infections|
Click here to view
Both therapies, RT and mEHT, are local treatments that target the tumor. Circulating tumor cells (CTCs) are present even in early stages of cancer, which can form micro- and macro-metastases by extravasation in sensitive organs, reducing the possibility of patient survival. Intercellular signal transduction and molecular transport between cells allow RT to act on neighboring cells, resulting in a bystander effect. Systemic effect of local RT was first observed by R.H. Mole, who named it the “abscopal effect.” Bystander mechanisms using other messengers extends its effective influence and could be abscopal,, active on distant metastases or on CTCs. Discovering its controversies  and hunting for bystander and abscopal effects is a hot topic in cancer therapies., The abscopal effect was first observed in hyperthermia applications 40 years after it was demonstrated in RT.
Although mEHT is a local treatment, it could also act systemically via the abscopal effect, which was shown in vivo,,, and a possible mechanism is discussed below. This vaccination-like mechanism, which has been proven in experimental studies, has been observed in human case reports.,,, The abscopal effect induced by mEHT is a new strategy.
The abscopal effect observed in a patient with multiple metastatic stage IIIB NSCLC is an excellent example  [Figure 11]. Despite the advanced stage, the patient refused CT and requested other possible treatment options. RT in combination with mEHT and additional immune-stimulating granulocyte-monocyte colony stimulation factor (GM-CSF) was performed to induce the abscopal effect. Local field RT directed at the lung mass was delivered at a dose of 1.7 cGy in 28 daily fractions, 5–6 times per week. This was followed by oncothermia after radiation three times per week. After 2 weeks of treatment, GM-CSF (250 μg, Leukine ®, USA) was administered subcutaneously daily for 10 days. A complete abscopal effect was observed on distant metastases with partial response of the primary tumor.
|Figure 11: Metastatic non-small cell lung cancer; (cT2 cN2 Mx stage IIIB); (a) Before therapy. (b) After therapy. The distant metastases disappeared while the primary tumor showed a partial response|
Click here to view
The abscopal effect has also been investigated in an ongoing trimodal phase III clinical study. One patient in the study had neck and thorax nodes, bone, and lung metastases on pretreatment scan. This patient was HIV negative, stage IIIB, and aged 34 years. Following complex trimodal therapy including two rounds of CT, a complete abscopal effect was measured without further evidence of disease. Overall, 24.1% of the patients (13 of 54 patients) showed a complete abscopal effect; the therapy eliminated the active cancer in the cervix, and metastases in pelvic and extra-pelvic areas disappeared, as observed by PET [Figure 12].
|Figure 12: (a) Observed local and abscopal effects by PET scan. (b) Participants with abscopal effect by HIV status. Applied protocol: radiation, 25 × 2 Gy external and 3 × 8 Gy brachytherapy; chemotherapy: 3 × 80 mg/m2 cisplatin; mHET (oncothmia): 2 × 55 min/week (4 weeks) (n = 54)|
Click here to view
| Discussion|| |
Synergy of RT and mEHT is the common goal, to restore apoptosis in malignant cells as much as possible. The common root of these methods is energy absorption by micro/nano parts of the malignant cells selected by precise focusing and biophysical differences in RT and mEHT, respectively. DNA nano-targeting in RT harmonizes well with the nano-targeting of mEHT. The premise of both treatments is similar. The expected effects of ionizing radiation, where the target is DNA, and energy, which heats up its environment is useless, and can result in adverse effects. RT is an exemplary method for selective targeting of chemical bonds to arrest the cell cycle in malignant cells and induce apoptosis instead of proliferation. The goal of mEHT is to selectively kill malignant cells in a natural way, by inducing apoptotic cell death. The goals of mEHT and RT are not identical only in the local action, but expected to be nonlocal by the various mechanisms of bystander and abscopal effects, which extend the local therapy systemic and allowing for successful action against systemic malignancy.
RT and mEHT differ in the targets of energy-absorption and the selection of treatable cells. The relatively easy focusing of high energetic ionizing radiation by the beam size and shielding windows differs from the biophysical targeting mechanism of mEHT, which could be automatic with a well-chosen modulated RF current through the target. The major mechanisms of cell death induced by RT  include apoptosis, senescence, autophagy, and necrosis, which could be promoted by mEHT as well.,,, The well-known DNA fragmentation-driven process in RT is also common with mEHT. A portion of the RT effect occurs via the extrinsic apoptotic pathway of death-receptor ligands in the FADD complex, producing Caspase-8/10 and culminating with apoptosis by cleaved Caspase-3. This mechanism is strongly activated by mEHT as well.
To improve the apoptotic signal, mEHT repairs intercellular connections. New connections also make the missing signal transmissions possible. The restored intercellular bonds of E-cadherin  bridge cells, forming a β-catenin complex and allowing for signal transduction. Intercellular connections do not only transmit signals; they can also block the invasion of cells by bonding malignant cells to their neighbors.
Targeting of lipid rafts is similar to nano-particle heating, but no artificial nanoparticles are involved; all are naturally present on the membrane of malignant cells. The active energy absorption on the rafts combined with the various selection mechanisms ensures that the lipid rafts are induced to trigger apoptosis. The general principles of cellular distortion are similar in mEHT and RT. Both target a part of the malignant cell (rafts in mEHT and DNA in RT) to induce chemical reactions, which lead to apoptosis [Figure 13]. Naturally, both processes have additional effects (e.g., mEHT acts on the membrane potential of mitochondria, while RT can induce membrane damage), but the major reactions are localized.
|Figure 13: The principles of mEHT and RT are similar: a nano-range excitation initiates apoptosis|
Click here to view
The conceptual difference in mEHT and RT is the temperature. The energy absorption produces heat and causes thermal effects. Certain thermal effects are conditional for mEHT. However, the thermal effect is not identical to the temperature increase. Thermal effects are often mixed with temperature development and sometimes equalize the thermal reactions with temperature changes. This is an incorrect approach, because thermal effects of phase changes of the materials or molecular excitations by absorbed heat energy are usually independent of the change in temperature. The temperature in these cases is a conditional factor, but its change is not necessary. An obvious example is boiling water, which absorbs a lot of heat (thermal effect) until the water evaporates without changing temperature. The thermal effect is not equal to the temperature change; however, the consequence of heat absorption usually changes the temperature. Distinguishing heat absorption from the temperature change is mandatory in the case of oncological hyperthermia when our task is to change the chemical reactions and the chemical bonds involved in the cellular signals to eliminate malignant cells from the system. The desired effects are the molecular changes where the temperature is only a condition, and its change is not requested.
The thermal effect is limited to nanoscopic local “points,” which are most sensitive to any lethal attack on malignant cells. For this, a broad spectrum of biophysical and technical achievements are used. The first is the well-chosen radiofrequency current, which constructs a thermal gradient between extra-and intracellular electrolytes. The RF carrier frequency was chosen according to the medical standards of 13.56 MHz with appropriate time-fractal modulated current, which is essential to have the proper effect (a technical description can be found elsewhere ,). The temperature gradient is one of the driving forces of the signal propagation that starts at the outer membrane of the cell as extrinsic excitation. The excitation requires energy absorption and changes the molecular structure, and thus these are thermal, but not temperature dependent., The action is like a first-order phase transition with latent energy exchange at constant (transition) temperature.
The dose of the thermal effect is not the temperature. The temperature is not a dose! (It does not change by the volume/mass.) This can lead to controversial results, as has been demonstrated with the clinical study described earlier., This challenge requests a reference point., This challenge could be solved by mEHT, which uses the well-known gold standards, with an energy-dose concept in the protocol. The energy is controlled to apply the largest tolerable energy-dose (J/kg).,,, The efficacy is measured by the absorbed energy (J/kg), and the safe limit is determined by energy transfer through the skin (J/m 2). The control of this last point makes safe and complication-free mEHT possible.
The new strategy of tumor treatment with local therapies is tightly connected to the abscopal mechanism, which allows cellular distortion to extend to bystander cells and distant malignant lesions. One of the mechanisms is considerably investigated by mEHT and the starting point of the mechanism is likely apoptosis. mEHT induces an extrinsic signal for apoptosis [Figure 14], and produces damage-associated molecular pattern (DAMP) and immunogenic cell death (ICD).
|Figure 14: (a) Extrinsic excitation of trail death receptor and other molecules in lipid rafts. (b) immunohistochemistry detection of TRAIL R2 in the treated sample (HT29 × enograft) following 8 h of mEHT treatment. (c) Membrane expression of TRAIL-R2, FAS, and FADD following mEHT|
Click here to view
This type of apoptosis induces ICD with DAMP [Figure 15] and is a novel type of “cancer vaccination” that has been patented in the US  and EU  with the application of mEHT.
|Figure 15: (a) Mechanism of immunogenic cell death induction (CRT calreticulin) (adapted from). (b) Immunohistochemistry registration of CRT, HMGB1, and HSP70 as factors of DAMP (HT29 × enograft experiment). (c) T-cell characteristics by CDs following concomitant application of DC + mEHT|
Click here to view
| Conclusions|| |
Oncological hyperthermia is recently at a crossroads, facing a challenge by immune oncology: how to target the sensitive bonds by energy-absorption producing apoptosis and its immunological consequences. A recognized specialist of hyperthermia formulated a long time ago : “The mistakes made by the hyperthermia community may serve as lessons, not to be repeated by investigators in other novel fields of cancer treatment.”
mEHT offers a new paradigm with nanoscopic heating, providing an adequate answer to the present challenges. mEHT breaks the long-term dominance of the isothermal heating approach. It uses nano-heating technology to select and heat the membrane of malignant cells effectively. The heating is concentrated mostly on the cell membrane, thus nano-range energy liberation can be precisely controlled without considerable wasted energy and without disadvantages that result from heating the tumor environment. The results and general benefits of mEHT open a new kind of local heating and destroy primary and metastatic tumor lesions by apoptosis-inducing ICD by DAMP. The selective, nonequilibrium energy absorption is well synergized with modern RT, presenting an effective and controllable tumor-specific immune reaction and in consequence abscopal effects. Due to the highly precise and effective energy delivery, the actual dose of mEHT is the same as the dose of RT: The Gy (J/kg).
Author is thankful for Dr. Oliver Szasz for critical reading and for Ms. Adrienn Dovala for editing of the manuscript.
Financial support and sponsorship
This work was supported by the Hungarian Competitiveness and Excellence Program grant (NVKP_16-1-2016-0042).
Conflicts of interest
The author is Chief Scientific Officer of Oncotherm GmbH.
| References|| |
Vaupel PW, Kelleher DK. Metabolic status and reaction to heat of normal and tumour tissue. In: Seegenschmiedt MH, Fessenden P, Vernon CC, editors. Thermo-Radiotherapy and Thermo-Chemiotherapy. Biology, Physiology and Physics. Vol. 1. Springer Verlag, Berlin Heidelberg; 1996. p. 157-76.
Freund L. Elements of General Radio-Therapy for Practitioners. Berlin: Arzte, Urban and Schwarzenberg; 1903.
Roussakow SV. Critical analysis of electromagnetic hyperthermia randomized trials: Dubious effect and multiple biases. Hindawi Publishing Corporation Conference Papers in Medicine. Vol. 2013 2013. p. 412186.
Streffer C, vanBeuningen D, Dietzel F, Röttinger E, Robinson JE, Scherer E, et al
. Cancer Therapy by Hyperthermia and Radiation. Baltimore, Munich: Urban and Schwarzenberg; 1978.
Seegenschmiedt MH, Fessenden P, Vernon CC, editors. Thermo-Radiotherapy and Thermo-Chemotherapy. Clinical Applications. Vol. 2. Springer Verlag, Berlin Heidelberg; 1996.
Kosaka M, Sugahara T, Schmidt KL, Simon E, editors. Thermotherapy for Neoplasia, Inflammation, and Pain. Tokyo: Springer Verlag; 2001.
Matsuda T, editor. Cancer Treatment by Hyperthermia, Radiation and Drugs. London, Washington DC: Taylor & Francis; 1993.
Urano M, Douple E, editors. Hyperthermia and Oncology: Biology of Thermal Potentiation of Radiotherapy. Vol. 2. The Netherlands: VSP BV Utrecht; 1992.
Hehr T, Wust P, Bamberg M, Budach W. Current and potential role of thermoradiotherapy for solid tumours. Onkologie 2003;26:295-302.
van der Zee J, González González D, van Rhoon GC, van Dijk JD, van Putten WL, Hart AA, et al.
Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: A prospective, randomised, multicentre trial. Dutch deep hyperthermia group. Lancet 2000;355:1119-25.
Wust P, Hildebrandt B, Sreenivasa G, Rau B, Gellermann J, Riess H, et al.
Hyperthermia in combined treatment of cancer. Lancet Oncol 2002;3:487-97.
Overgaard J, Gonzalez Gonzalez D, Hulshof MC, Arcangeli G, Dahl O, Mella O, et al.
Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European society for hyperthermic oncology. Lancet 1995;345:540-3.
van der Zee J, Treurniet-Donker AD, The SK, Helle PA, Seldenrath JJ, Meerwaldt JH, et al.
Low dose reirradiation in combination with hyperthermia: A palliative treatment for patients with breast cancer recurring in previously irradiated areas. Int J Radiat Oncol Biol Phys 1988;15:1407-13.
Vernon CC, Harrison M. Hyperthermia with low-dose radiotherapy for recurrent breast carcinoma. Lancet 1990;336:1383.
Bicher JI, Al-Bussam N, Wolfstein RS. Thermotherapy with curative intent – Breast, head, and neck, and prostate tumours. Deutsc Z Oncol 2006;38:116-22.
Peeken JC, Vaupel P, Combs SE. Integrating hyperthermia into modern radiation oncology: What evidence is necessary? Front Oncol 2017;7:132.
Horsman MR, Overgaard J. Hyperthermia: A potent enhancer of radiotherapy. Clin Oncol (R Coll Radiol) 2007;19:418-26.
Molls M. Hyperthermia – The actual role in radiation oncology and future prospects. Part I. Strahlenther Onkol 1992;168:183-90.
Seegenschmiedt MH, Feldmann HJ, Wust P. Hyperthermia – Its actual role is radiation oncology. Strahlentherapie Oncol 1995;171:560-72.
Emami B, Scott C, Perez CA, Asbell S, Swift P, Grigsby P, et al.
Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors. A prospectively controlled randomized study by the radiation therapy group. Int J Radiat Oncol Biol Phys 1996;34:1097-104.
Wust P, Rau B, Gemmler M, Schlag P, Jordan A, Löffel J, et al
. Radio-thermotherapy in multimodal surgical treatment concepts. Onkologie 1995;18:110-21.
Overgaard J. The current and potential role of hyperthermia in radiotherapy. Int J Radiat Oncol Biol Phys 1989;16:535-49.
Roti JL, Laszlo A. The effects of hyperthermia on cellular macromolecules. In: Urano M, Douple E, editors. Hyperthermia and Oncology. Thermal Effects on Cells and Tissues. Vol. 1. The Netherlands: VSP Utrecht; 1988. p. 13-56.
Pandita TK, Pandita S, Bhaumik SR. Molecular parameters of hyperthermia for radiosensitization. Crit Rev Eukaryot Gene Expr 2009;19:235-51.
Okumura Y, Ihara M, Shimasaki T, Takeshita S, Okiachi K. Heat inactivation of DNA-dependent protein kinase: Possible mechanism of hyperthermic radio-sensitization. In: Kosaka M, Sugahara T, Schmidt KL, Kosaka M, Sugahara T, Simon E. editors. Thermotherapy for Neoplasia, Inflammation, and Pain. Tokyo: Springer Verlag; 2001. p. 420-3.
Vujaskovic Z, Song CW. Physiological mechanisms underlying heat-induced radiosensitization. Int J Hyperthermia 2004;20:163-74.
Song CW, Shakil A, Osborn JL, Iwata K. Tumour oxygenation is increased by hyperthermia at mild temperatures 1996. Int J Hyperthermia 2009;25:91-5.
Dudar TE, Jain RK. Differential response of normal and tumor microcirculation to hyperthermia. Cancer Res 1984;44:605-12.
Song CW, Lokshina A, Rhee JG, Patten M, Levitt SH. Implication of blood flow in hyperthermic treatment of tumors. IEEE Trans Biomed Eng 1984;31:9-16.
Pence DM, Song CW. Effect of heat on blood-flow. In: Anghileri LJ, Robert J, editors. Hyperthermia in Cancer Treatment. Vol. 2. Boca Raton Florida, US: CRC Press, Inc.; 1986. p. 1-17.
Vaupel P. Pathophysiological mechanism of hyperthermia in cancer therapy. In: Gautherie M, editor. Methods of Hyperthermia Control, Clinical Thermology. New York, London, Paris, Tokyo, Hong Kong: Springer Verlag, Berlin, Heidelberg; 1990. p. 73-134.
Erdmann B, Lang J, Seebass M. Optimization of temperature distributions for regional hyperthermia based on a nonlinear heat transfer model. Ann N
Y Acad Sci 1998;858:36-46.
Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: A review. Cancer Res 1989;49:6449-65.
Song CW, Choi IB, Nah BS, Sahu SK, Osborn JL. Microvasculature and perfusion in normal tissues and tumours. In: Seegenschmiedt MH, Fessenden P, Vernon CC, editors. Thermoradiometry and Thermochemotherapy. Vol. 1. Springer-Verlag, Berlin Heidelberg; 1995. p. 139-56.
Song CW, Park H, Griffin RJ. Theoretical and experimental basis of hyperthermia. In: Kosaka M, Sugahara T, Schmidt KL, Simon E. editors. Thermotherapy for Neoplasia, Inflammation, and Pain. Tokyo: Springer Verlag; 2001. p. 394-407.
Takana Y. Thermal responses of microcirculation and modification of tumour blood flow in treating the tumours. In: Kosaka M, Sugahara T, Schmidt KL, Simon E. editors. Theoretical and Experimental Basis of Hyperthermia. Thermotherapy for Neoplasia, Inflammation, and Pain. Tokyo: Springer Verlag; 2001. p. 408-19.
Hietanen T, Kapanen M, Kellokumpu-Lehtinen PL. Restoring natural killer cell cytotoxicity after hyperthermia alone or combined with radiotherapy. Anticancer Res 2016;36:555-63.
Beachy SH, Repasky EA. Toward establishment of temperature thresholds for immunological impact of heat exposure in humans. Int J Hyperthermia 2011;27:344-52.
Repasky E, Issels R. Physiological consequences of hyperthermia: Heat, heat shock proteins and the immune response. Int J Hyperthermia 2002;18:486-9.
Dewey WC, Hopwood LE, Sapareto SA, Gerweck LE. Cellular responses to combinations of hyperthermia and radiation. Radiology 1977;123:463-74.
Lindholm CE. Hyperthermia and Radiotherapy. Ph.D. Thesis, Lund University, Malmo, Sweden; 1992.
Hafström L, Rudenstam CM, Blomquist E, Ingvar C, Jönsson PE, Lagerlöf B, et al.
Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities. Swedish Melanoma Study Group. J Clin Oncol 1991;9:2091-4.
Vernon CC, Hand JW, Field SB, Machin D, Whaley JB, van der Zee J, et al.
Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: Results from five randomized controlled trials. International collaborative hyperthermia group. Int J Radiat Oncol Biol Phys 1996;35:731-44.
Sherar M, Liu FF, Pintilie M, Levin W, Hunt J, Hill R, et al.
Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: Data from a phase III trial. Int J Radiat Oncol Biol Phys 1997;39:371-80.
Sharma S, Patel FD, Sandhu AP, Gupta BD, Yadav NS. A prospective randomized study of local hyperthermia as a supplement and radiosensitiser in the treatment of carcinoma of the cervix with radiotherapy. Endocurietherapy Hypertherm Oncol 1989;5:151-9.
Vasanthan A, Mitsumori M, Park JH, Zhi-Fan Z, Yu-Bin Z, Oliynychenko P, et al.
Regional hyperthermia combined with radiotherapy for uterine cervical cancers: A multi-institutional prospective randomized trial of the international atomic energy agency. Int J Radiat Oncol Biol Phys 2005;61:145-53.
Harima Y, Nagata K, Harima K, Ostapenko VV, Tanaka Y, Sawada S, et al.
Arandomized clinical trial of radiation therapy versus thermoradiotherapy in stage IIIB cervical carcinoma. Int J Hyperthermia 2001;17:97-105.
Roussakow SV. “A randomized clinical trial of radiation therapy versus thermoradiotherapy in stage IIIB cervical carcinoma” of Yoko Harima et al
. (2001): Multiple biases and no advantage of hyperthermia. Int J Hyperthermia 2018;34:1400.
Harima Y. “A randomised clinical trial of radiation therapy versus thermoradiotherapy in stage IIIB cervical carcinoma” of Yoko Harima et al
. (2001): A response letter to the editor of comments from Dr. Roussakow. Int J Hyperthermia 2018;34:1401.
Zolciak-Siwinska A, Piotrkowicz N, Jonska-Gmyrek J, Nicke-Psikuta M, Michalski W, Kawczyńska M, et al.
HDR brachytherapy combined with interstitial hyperthermia in locally advanced cervical cancer patients initially treated with concomitant radiochemotherapy – A phase III study. Radiother Oncol 2013;109:194-9.
Lutgens LC, Koper PC, Jobsen JJ, van der Steen-Banasik EM, Creutzberg CL, van den Berg HA, et al.
Radiation therapy combined with hyperthermia versus cisplatin for locally advanced cervical cancer: Results of the randomized RADCHOC trial. Radiother Oncol 2016;120:378-82.
Kay CS, Choi IB, Jang JY, Choi BO, Kim IA, Shinn KS. Thermoradiotherapy in the treatment of locally advanced nonsmall cell lung cancer. J Korean Soc Ther Radiol Oncol 1996;14:115-22.
Mitsumori M, Zeng ZF, Oliynychenko P, Park JH, Choi IB, Tatsuzaki H, et al.
Regional hyperthermia combined with radiotherapy for locally advanced non-small cell lung cancers: A multi-institutional prospective randomized trial of the international atomic energy agency. Int J Clin Oncol 2007;12:192-8.
Jones EL, Oleson JR, Prosnitz LR, Samulski TV, Vujaskovic Z, Yu D, et al.
Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol 2005;23:3079-85.
Shoji H, Motegi M, Osawa K, Okonogi N. Does standardization of radiofrequency hyperthermia benefit patients with malignancies? Ann Cancer Res Ther 2014;22:28-35.
van der Zee J. Heating the patient: A promising approach? Ann Oncol 2002;13:1173-84.
Szasz A, Szasz O, Szasz N. Oncothermia – Principles and Practices. Dordrecht, Heidelberg: Springer Verlag; 2010.
Hegyi G, Szasz O, Szasz A. Oncothermia: A new paradigm and promising method in cancer therapies. Acupuncture and Electro-Therapeutics Res Int J 2013;38:161-197.
LeVeen HH, Wapnick S, Piccone V, Falk G, Nafis A. Tumor eradication by radiofrequency therapy. Responses in 21 patients. JAMA 1976;235:2198-200.
Short JG, Turner PF. Physical hyperthermia and cancer therapy. Proc IEEE 1980;68:133-42.
Storm FK, Morton DL, Kaiser LR, Harrison WH, Elliott RS, Weisenburger TH, et al.
Clinical radiofrequency hyperthermia: A review. Natl Cancer Inst Monogr 1982;61:343-50.
Abe M, Hiraoka M, Takahashi M, Egawa S, Matsuda C, Onoyama Y, et al.
Multi-institutional studies on hyperthermia using an 8-MHz radiofrequency capacitive heating device (thermotron RF-8) in combination with radiation for cancer therapy. Cancer 1986;58:1589-95.
Song CW, Rhee JG, Lee CK, Levitt SH. Capacitive heating of phantom and human tumors with an 8 MHz radiofrequency applicator (Thermotron RF-8). Int J Radiat Oncol Biol Phys 1986;12:365-72.
Takahashi M, Hiraoka M, Nishimura Y, Jo S, Akuta K, Abe M. Clinical results of thermoradiotherapy for deep-seated tumours. In: Matsuda T, editor. Cancer Treatment by Hyperthermia, Radiation and Drugs. London: Taylor & Francis; 1993. p. 227-39.
Szigeti GP, Szasz O, Hegyi G. Connections between Warburg's and Szentgyorgyi's approach about the causes of cancer. J Neoplasm 2017;1:1-13.
Wong SHM, Fang CM, Chuah LH, Leong CO, Ngai SC. E-cadherin: Its dysregulation in carcinogenesis and clinical implications. Crit Rev Oncol Hematol 2018;121:11-22.
Knights AJ, Funnell AP, Crossley M, Pearson RC. Holding tight: Cell junctions and cancer spread. Trends Cancer Res 2012;8:61-9.
Szentgyorgyi A. Bioelectronics, a Study on Cellular Regulations, Defense and Cancer. New York, London: Academy Press; 1968.
Szasz A, Vincze GY, Szasz O, Szasz N. An energy analysis of extracellular hyperthermia. Magneto Electro Biol 2003;22:103-15.
Caduff A, Talary MS, Zakharov P. Cutaneous blood perfusion as a perturbing factor for noninvasive glucose monitoring. Diabetes Technol Ther 2010;12:1-9.
Schwan HP. Nonthermal cellular effects of electromagnetic fields AC-field induced ponderomotoric forces. Br J Cancer Suppl 1982;5:220-4.
Pething R. Dielectric and Electronic Properties of Biological Materials. New York, John Wiley and Sons; 1979.
Szasz O, Andocs G, Kondo T, Rehman MU, Papp E, Vancsik T. Heating of membrane raft of cancer-cells. ASCO annual meeting. J Clin Oncol 2015;33 Suppl 15:abstre22176.
Physical Sciences – Oncology Centers Network, Agus DB, Alexander JF, Arap W, Ashili S, Aslan JE, et al.
Aphysical sciences network characterization of non-tumorigenic and metastatic cells. Sci Rep 2013;3:1449.
Papp E, Vancsik T, Kiss E, Szasz O. Energy absorption by the membrane rafts in the modulated electro-hyperthermia (mEHT). Open J Biophys 2017;7:216-29.
Andocs G, Szasz O, Szasz A. Oncothermia treatment of cancer: From the laboratory to clinic. Electromagn Biol Med 2009;28:148-65.
Andocs G, Renner H, Balogh L, Fonyad L, Jakab C, Szasz A, et al.
Strong synergy of heat and modulated electromagnetic field in tumor cell killing. Strahlenther Onkol 2009;185:120-6.
Meggyeshazi N, Andocs G, Szasz A. Possible Immune-Reactions with Oncothermia. Aarhus, Denmark: ESHO; 2011. p. 26-8.
Yang KL, Huang CC, Chi MS, Chiang HC, Wang YS, Hsia CC, et al
. In vitro
comparison of conventional hyperthermia and modulated electro-hyperthermia. Oncotarget 2016;7:84082-92.
Andocs G, Renner H, Balogh L, Fonyad L, Jakab C, Szasz A, et al
. Strong synergy of heat and modulated electromagnetic field in tumor cell killing. Strahlenther Onkol 2009;185:120-6.
Andocs G, Rehman MU, Zhao QL, Papp E, Kondo T, Szasz A. Nanoheating without artificial nanoparticles Part II. Experimental support of the nanoheating concept of the modulated electro-hyperthermia method, using U937 cell suspension model. Biol Med 2015;7:1-9.
Balogh L, Polyak A, Postenyi Z, Kovacs-Haasz V, Gyongy M, Thuroczy J. Temperature increase induced by modulated electrohyperthermia (oncothermia®) in the anesthetized pig liver. J Cancer Res Ther 2016;12:1153-9.
Kim JK, Prasad B, Kim S. Temperature mapping and thermal dose calculation in combined radiation therapy and 13.56 MHz radiofrequency hyperthermia for tumour treatment. Proc SPIE 10047, Optical Methods for Tumour Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXVI, 1004718; 2017.
Nagy G, Meggyeshazi N, Szasz O. Deep temperature measurements in oncothermia processes. Corporation Conference Papers Med 2013;2013:685264.
Szasz A, Szasz O, Szasz N. Local hyperthermia in oncology - To choose or not to choose. In: Huilgol N, editor. Local Hyperthermia in Oncology, a Chapter in Book: Hyperthermia. London: InTech; 2013.
Ota A, Matsumuto Y, Sakurai H. Anti-Tumour Effects of a New low-Energy Thermal Therapy, Oncothermia; Tsukuba University, Japan; Presented on Conferences of Japan Hyperthermia Association and International Association for the Sensitization of Cancer Treatment; 2017.
Andocs G, Rehman MU, Zhao QL, Tabuchi Y, Kanamori M, Kondo T. Comparison of Biological Effects of Modulated Electro-Hyperthermia and Conventional Heat Treatment in Human Lymphoma U937 Cell. Cell Death Discovery (Nature Publishing Group), 2, 16039; 2016.
Matsumoto Y, Hayshi J, Sekino Y, Fukumitsu N, Saito T, Ishikawa H, et al
. Radio-sensitization effect of novel cancer therapy, oncothermia ~ Toward overcoming treatment resistance; 2018 Annual Conference of Japanese Hyperthermia Society, Fukui, Japan; 2018.
Kim W, Kim MS, Kim HJ, Lee E, Jeong JH, Park I, et al.
Role of HIF-1α in response of tumors to a combination of hyperthermia and radiation in vivo
. Int J Hyperthermia 2018;34:276-83.
Lee SY, Kim JH, Han YH, Cho DH. The effect of modulated electro-hyperthermia on temperature and blood flow in human cervical carcinoma. Int J Hyperthermia 2018;21:1-8.
Lee SY, Kim MG. The effect of modulated electro-hyperthermia on the pharmacokinetic properties of nefopam in healthy volunteers: A randomised, single-dose, crossover open-label study. Int J Hyperthermia 2015;28:1-6.
Wismeth C, Dudel C, Pascher C, Ramm P, Pietsch T, Hirschmann B, et al.
Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsed high-grade gliomas: Phase I clinical results. J Neurooncol 2010;98:395-405.
Sahinbas H, Groenemeyer DH, Boecher E, Szasz A. Retrospective clinical study of adjuvant electro-hyperthermia treatment for advanced brain-gliomas. Deutsc Z Onkol 2007;39:154-60.
Fiorentini G, Giovanis P, Rossi S, Dentico P, Paola R, Turrisi G, et al.
Aphase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia. In Vivo
Hager ED, Sahinbas H, Groenemeyer DH, Migeod F. Prospective phase II trial for recurrent high-grade malignant gliomas with capacitive coupled low radiofrequency (LRF) deep hyperthermia. ASCO J Clin Oncol 2008;26:2047.
Roussakow SV. Clinical and economic evaluation of modulated electrohyperthermia concurrent to dose-dense temozolomide 21/28 days regimen in the treatment of recurrent glioblastoma: A retrospective analysis of a two-centre german cohort trial with systematic comparison and effect-to-treatment analysis. BMJ Open 2017;7:e017387.
Hager ED, Dziambor H, Höhmann D, Gallenbeck D, Stephan M, Popa C, et al.
Deep hyperthermia with radiofrequencies in patients with liver metastases from colorectal cancer. Anticancer Res 1999;19:3403-8.
Gadaleta-Caldarola G, Infusino S, Galise I, Ranieri G, Vinciarelli G, Fazio V, et al.
Sorafenib and locoregional deep electro-hyperthermia in advanced hepatocellular carcinoma: A phase II study. Oncol Lett 2014;8:1783-7.
Szasz A. Current status of oncothermia therapy for lung cancer. Korean J Thorac Cardiovasc Surg 2014;47:77-93.
Lee DY, Haam SJ, Kim TH, Lim JY, Kim EJ, Kim NY. Oncothermia with chemotherapy in the patients with small cell lung cancer. Corporation Conference Papers Med 2013;2013:910363. Available from: http://www.hindawi.com/archive/2013/910363/
. [Last accessed on 2018 Nov 06].
Lee SY, Lee NR, Cho DH, Kim JS. Treatment outcome analysis of chemotherapy combined with modulated electro-hyperthermia compared with chemotherapy alone for recurrent cervical cancer, following irradiation. Oncol Lett 2017;14:73-8.
LPang CL, Zhang X, Wang Z, Ou J, Lu Y, Chen P, et al.
Local modulated electro-hyperthermia in combination with traditional chinese medicine vs. intraperitoneal chemoinfusion for the treatment of peritoneal carcinomatosis with malignant ascites: A phase II randomized trial. Mol Clin Oncol 2017;6:723-32.
Jeung TS, Ma SY, Choi J, Yu J, Lee SY, Lim S. Results of oncothermia combined with operation, chemotherapy and radiation therapy for primary, recurrent and metastatic sarcoma. Case Rep Clin Med 2015;4:157-68. Available from: http://www.scirp.org/journal/PaperInformation.aspx?PaperID=56280
. [Last accessed on 2018 Nov 05].
Volovat C, Volovat SR, Scripcaru V, Miron L. Second-line chemotherapy with gemcitabine and oxaliplatin in combination with loco-regional hyperthermia (EHY-2000) in patients with refractory metastatic pancreatic cancer – Preliminary results of a prospective trial. Rom Rep Phys 2014;66:166-74. Available from: http://www.rrp.infim.ro/2014_66_1/A18.pdf
. [Last accessed on 2018 Nov 04].
Douwes FR. Transurethral hyperthermia in early stage prostate cancer. Focus Alternat Complement Ther 2001;6:77-8.
Yeo SG. Definitive radiotherapy with concurrent oncothermia for stage IIIB non-small-cell lung cancer: A case report. Exp Ther Med 2015;10:769-72.
Pesti L, Dankovics Z, Lorencz P, Csejtei A. Treatment of advanced cervical cancer with complex chemoradio – Hyperthermia. Corporation Conference Papers Med 2013;2013:192435.
Aydin H. Radiotherapy for liver-metastases and therapy-resistant bone-metastases. Hyperthermia Seminaries. Cologne; 2003. p. 24-5.
Szasz A, Szasz O. Case reports made with oncothermia. Oncothermia J 2014;11:9-70.
Aydin H. Strahlen-Hyperthermie bei Lebermetastasen und bei therapieresistenten Knochenmetastasen; Hyperthermia Symposium. Cologne, Germany; 2003. p. 25-6.
Renner H. Simultane Radio Thermo Therapie bzw. RadioChemoThermoTherapie, Hyperthermia Symposium. Cologne, Germany; 2003.
Strauss C, Kotzen J, Baeyens A, Maré I. Oncothermia in HIV positive and negative locally advanced cervical cancer patients in South Africa. Corporation Conference Papers Med 2013;2013:293968.
Minnaar C, Baeyens A, Kotzen J. Update on phase III randomized clinical trial investigating the effects of the addition of electro-hyperthermia to chemora-diotherapy for cervical cancer patients in South Africa. Phys Med 2016;32:151-2.
Minnaar C, Kotzen JA. Cervical cancer and modulated electro-hyperthermia: What we have learnt from our clinical trial so far. European Society for Hyperthermic Oncology. Athens, Greece; 2017. p. 21-3.
MOLE RH. Whole body irradiation; radiobiology or medicine? Br J Radiol 1953;26:234-41.
Wang R, Zhou T, Liu W, Zuo L. Molecular mechanism of bystander effects and related abscopal/cohort effects in cancer therapy. Oncotarget 2018;9:18637-47.
Pouget JP, Georgakilas AG, Ravanat JL. Targeted and off-target (Bystander and abscopal) effects of radiation therapy: Redox mechanisms and risk/Benefit analysis. Antioxid Redox Signal 2018;29:1447-87.
Shiraishi K. Abscopal effect of radiation therapy: Current concepts and future applications. In: Natanasabapathi G, editor. Modern Practices in Radiation Therapy. Ch. 15. Rijeka, Croatia: InTech; 2012.
Kaminski JM, Shinohara E, Summers JB, Niermann KJ, Morimoto A, Brousal J, et al.
The controversial abscopal effect. Cancer Treat Rev 2005;31:159-72.
Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol 2009;10:718-26.
Tubin S, Raunik W. Hunting for abscopal and bystander effects: Clinical exploitation of non-targeted effects induced by partial high-single-dose irradiation of the hypoxic tumour segment in oligometastatic patients. Acta Oncol 2017;56:1333-9.
Vartak S, George KC, Singh BB. Antitumor effects of local hyperthermia on a mouse fibrosarcoma. Anticancer Res 1993;13:727-9.
Vancsik T, Kovago C, Kiss E, Papp E, Forika G, Benyo Z, et al.
Modulated electro-hyperthermia induced loco-regional and systemic tumor destruction in colorectal cancer allografts. J Cancer 2018;9:41-53.
Qin W, Akutsu Y, Andocs G, Suganami A, Hu X, Yusup G, et al.
Modulated electro-hyperthermia enhances dendritic cell therapy through an abscopal effect in mice. Oncol Rep 2014;32:2373-9.
Tsang YW, Huang CC, Yang KL, Chi MS, Chiang HC, Wang YS, et al.
Improving immunological tumor microenvironment using electro-hyperthermia followed by dendritic cell immunotherapy. BMC Cancer 2015;15:708.
Lee D, Kim SS, Seong S, Cho W, Yu H. Stage IV Wilms tumor treated by Korean medicine, hyperthermia and thymosin-α1: A case report. Case Rep Oncol 2016;9:119-25.
Schirrmacher V. Oncolytic newcastle disease virus as a prospective anti-cancer therapy. A biologic agent with potential to break therapy resistance. Expert Opin Biol Ther 2015;15:1757-71.
Schirrmacher V, Stücker W, Lulei M, Bihari AS, Sprenger T. Long-term survival of a breast cancer patient with extensive liver metastases upon immune and virotherapy: A case report. Immunotherapy 2015;7:855-60.
Schirrmacher V, Bihari AS, Stücker W, Sprenger T. Long-term remission of prostate cancer with extensive bone metastases upon immuno- and virotherapy: A case report. Oncol Lett 2014;8:2403-6.
Yoon SM, Lee JS. Case of abscopal effect with metastatic non-small-cell lung cancer. Oncothermia J 2012;5:53-7.
Minnaar CA, Kotzen JA, Baeyens A. Possible potentiation of the abscopal effect of ionising radiation by modulated electro-hyperthermia in locally advanced cervical cancer patients. 36th
Annual Conference of International Clinical Hyperthermia Society. Budapest, Hungary; 28-29 September, 2018.
Szasz O, Szasz A. Oncothermia – Nano-heating paradigm. J Cancer Sci Ther 2014;6:4.
Cha J, Jeon TW, Lee CG, Oh ST, Yang HB, Choi KJ, et al.
Electro-hyperthermia inhibits glioma tumorigenicity through the induction of E2F1-mediated apoptosis. Int J Hyperthermia 2015;31:784-92.
Eriksson D, Stigbrand T. Radiation-induced cell death mechanisms. Tumour Biol 2010;31:363-72.
Meggyeshazi N, Andocs G, Krenacs T. Programmed cell death induced by modulated electro-hyperthermia. Hindawi Publishing Corporation Conference Papers Med 2013;2013:187835.
Jeon TW, Yang H, Lee CG, Oh ST, Seo D, Baik IH, et al
. Electro-hyperthermia up-regulates tumour suppressor Septin 4 to induce apoptotic cell death in hepatocellular carcinoma. Int J Hyperthermia 2016;7:1-9.
Meggyeshazi N, Andocs G, Balogh L, Krenacs T. DNA fragmentation-driven tumour cell degradation induced by modulated electro-hyperthermia. Virchows Arch 2011;459 Suppl 1:S204-5.
Gy V, Gy S, Andocs G, Szasz A. Nanoheating without artificial nanoparticles. Biol Med 2015;7:249.
Szasz A. Electromagnetic effects in nanoscale range. In: Shimizu T, Kondo T, editors. Cellular Response to Physical Stress and Therapeutic Applications. Ch. 4. New York: Nova Science Publishers, Inc.; 2013.
Szasz A, Szasz O, Szasz N. Electro-hyperthermia: A new paradigm in cancer therapy. Deutsc Z Onkol 2001;33:91-9.
Szasz O, Szasz A. Burden of oncothermia: Why is it special? Hindawi Publishing Corporation Conference Papers Med 2013;2013:938689.
Szasz A. Bioelectromagnetic paradigm of cancer treatment oncothermia. In: Rosch PJ, editor. Bioelectromagnetic and Subtle Energy Medicine. New York: CRC Press, Taylor and Francis Group; 2015. p. 323-36,
Szasz A. Oncothermia: Complex Therapy by EM and Fractal Physiology. IEEE General Assembly and Scientific Symposium (URSI GASS). 2014 21th
URSI. Beijing, China; 16-23 August. 2014. p. 1-4.
zasz A, Vincze G. Dose concept of oncological hyperthermia: Heat-equation considering the cell destruction. J Cancer Res Ther 2006;2:171-81.
Szasz A. Hyperthermia, a modality in the wings. J Cancer Res Ther 2007;3:56-66.
Fatehi D, van der Zee J, van der Wal E, Van Wieringen WN, Van Rhoon GC. Temperature data analysis for 22 patients with advanced cervical carcinoma treated in Rotterdam using radiotherapy, hyperthermia and chemotherapy: A reference point is needed. Int J Hyperthermia 2006;22:353-63.
Szasz O, Szasz A. Heating, efficacy and dose of local hyperthermia. Open J Biophys 2016;6:10-8.
Gy V, Szasz O, Szasz A. Generalization of the thermal dose of hyperthermia in oncology. Open J Biophys 2015;5:97-114.
Szasz O, Szigeti GY, Vancsik T, Szasz A. Hyperthermia dosing and depth of effect. Open J Biophys 2018;8:31-48.
Schirrmacher V, Lorenzen D, vanGool SW, Stücker W. A new strategy of cancer immunotherapy combining hyperthermia/oncolytic virus pretreatment with specific autologous anti-tumour vaccination – A review. Austin Oncol Case Rep 2017;2:1-8.
Meggyeshazi N, Andocs G, Balogh L, Balla P, Kiszner G, Teleki I, et al.
DNA fragmentation and caspase-independent programmed cell death by modulated electrohyperthermia. Strahlenther Onkol 2014;190:815-22.
Meggyeshazi N. Studies on Modulated Electrohyperthermia Induced Tumour Cell Death in a Colorectal Carcinoma Model. PhD Thesis, Pathological Sciences Doctoral School, Semmelweis University; 2015.
Andocs G, Meggyeshazi N, Balogh L, Spisak S, Maros ME, Balla P, et al.
Upregulation of heat shock proteins and the promotion of damage-associated molecular pattern signals in a colorectal cancer model by modulated electrohyperthermia. Cell Stress Chaperones 2015;20:37-46.
Montico B, Nigro A, Casolaro V, Dal Col J. Immunogenic apoptosis as a novel tool for anticancer vaccine development. Int J Mol Sci 2018;19. pii: E594.
Andocs G, Szasz A, Iluri N, Szasz O. Tumour Vaccination US Patent. US 2015/0217099 A1; 2015.
Andocs G, Szasz A, Iluri N, Szasz O. Tumour Vaccination EU Patent, EP 2703001 A1; 2014.
Storm FK. What happened to hyperthermia and what is its current status in cancer treatment? J Surg Oncol 1993;53:141-3.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15]