Hyperthermia In Oncology Research Articles

Thermal and nonthermal effects of radiofrequency on living state and applications as an adjuvant with radiation therapy

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.

Oncological hyperthermia: The correct dosing in clinical applications.

The problem with the application of conventional hyperthermia in oncology is firmly connected to the dose definition, which conventionally uses the concept of the homogeneous (isothermal) temperature of the target. Its imprecise control and complex evaluation is the primary barrier to the extensive clinical applications. The aim of this study was to show the basis of the problems of the misleading dose concept. A clear clarification of the proper dose concept must begin with the description of the limitations of the present doses in conventional hyperthermia applications. The surmounting of the limits the dose of oncologic hyperthermia has to be based on the applicability of the Eyring transition state theory on thermal effects. In order to avoid the countereffects of thermal homeostasis, the use of precise heating on the nanoscale with highly efficient energy delivery is recommended. The nano-scale heating allows for an energy-based dose to control the process. The main aspects of the method are the following: i) It is not isothermal (no homogeneous heating); ii) malignant cells are heated selectively; and iii) it employs high heating efficacy, with less energy loss. The applied rigorous thermodynamical considerations show the proper terminology and dose concept of hyperthermia, which is based on the energy-absorption (such as in the case of ionizing radiation) instead of the temperature-based ideas. On the whole, according to the present study, the appropriate dose in oncological hyperthermia must use an energy-based concept, as it is well-known in all the ionizing radiation therapies. We propose the use of Gy (J/kg) in cases of non-ionizing radiation (hyperthermia) as well.

Novel applications of magnetic materials and technologies for medicine

We analyze the applications of the magnetocaloric effect (MCE) achieved with advanced magnetic materials and technologies. New results such as the use of MCE-based composite material for ‘smart’ coating of implants, which allows for a controlled release of drugs over time. The material is comprised of two layers: the one manifesting a large MCE and the other made of a temperature-responsive polymer containing the drug. The latter is released by the polymer if the temperature induced by magnetic field (due to MCE) is changed. The polymer undergoes sharp phase transition in response to the slight temperature drop of ∼1–3 °C (down to 34–36 °C in the body). Local cooling is achieved with FeRh alloy, one of the most perspective MCE materials with the first order phase transition. It is critically important to take into account several peculiarities of phase transition and MCE behavior in these series of alloys. Recent studies on high-purity samples showed an ‘irreversible’ effect of MCE indicating that the temperature of FeRh does not return to its initial value after the full cycle of the magnetic field during dynamic MCE measurements. A theoretical explanation based on ab initio calculations has been provided. Magnetic hyperthermia in oncology is rapidly developing therapeutic modality. Recent experiments have shown that Mn-Zn ferrite emerges as a cost-effective material for this method compared with currently used magnetite nanoparticles. We present our achievements on magnetically guided capsule endoscopy. The advances in magnetically guided capsule endoscopy are also discussed. We provide the experimental setup for the computer-controlled system of magnetic field sources that create necessary forces to control the position of the capsule in five degrees of freedom in a given area. The system has the feedback on the position and is designed to monitor the endoscopic capsule during gastrointestinal tract examination.

What is on the Horizon for Hyperthermic Cancer Therapy?

Cancer is a complex disease. Malignancy can often obscure the localization of the original tumor, which can mislead the patient and clinicians. Cancer means that the tumor is not benign; rather, it is malignant and thus systemic, even when dissemination or micro-metastases have not been discovered yet. Conventional hyperthermia induces tumor cell necrosis, but with isothermal heating and poor depth selection, it has multiple drawbacks. The new trend is mild hyperthermia, with support from complementary treatments. Furthermore, the trend for loco-regional treatment is developing toward immune modulation, especially toward tumor-specific immune reactions. Our objective is to present a review and discuss the trends regarding hyperthermia in oncology.

Heating Preciosity—Trends in Modern Oncological Hyperthermia

The use of hyperthermia as a treatment in oncology is a common topic for debate. Some researchers expect a breakthrough in oncological treatments with hyperthermia, whereas others have disregarded the method. Serious questions concerning hyperthermia have arisen. Should homogeneous (isothermal) or heterogeneous (selective) heating being used? When we use selective heating (heterogeneity), should the entire tumour be targeted or should the malignant cells be individually selected? Does the mechanism involve thermal cell death or thermally-assisted cell death? Is the goal necrosis or apoptosis? Is hyperthermia safe as a monotherapy or does it have to be combined with conventional treatments? When the selection is local, how do we act on disseminated cells that represent a high risk of life threatening metastases? When local heating is the focus, how should it be carried out with measured and controlled? Our objective is to show how precise, selective heat transfer is necessary to remove malignant cells and, consequently, how hyperthermia as part of the immune-oncology can change the game in this promising field of oncological therapies.

HAMP quality assurance protocol of hyperthermia systems

Introduction Hyperthermia is an anticancer modality that uses non-ionizing radiation and performed in conjunction with radiotherapy or chemotherapy. The efficacy of hyperthermia depends on the controlled temperature increase of the tumor cells to 40– 45 °C. Treatment complications and side-effects are minimized when the temperature rise is maintained within the therapeutic range during the whole treatment session. Purpose To establish a protocol for quality assurance (QA) of Hyperthermia equipment in Greece in order to demonstrate the need of system performance evaluation by medical physicists assuring proper operation of such equipment. Materials and Methods The proposed protocol is the result of the Hyperthermia Committee of the Hellenic Association of Medical Physicists (HAMP) in an attempt to standardize the quality assurance procedures followed in hyperthermia applications in Greece. QA procedures proposed are based on national and international experience and on corresponding protocols of other national and international committees taking into account and incorporating the latest achievements and equipment currently used in hyperthermia applications. Results The protocol suggests QA procedures for all types of hyperthermia methods such as superficial, intracavitary, deep-tissue heating and whole-body Hyperthermia as well as frequency for each test. Basic quality control tests include performance evaluation and testing of the correct operation of the thermometry equipment, the generator, the power measurement device, and the applicators. Tests for electrical and radiation safety are also included. The proposed necessary equipment should be accordingly calibrated and consists of a thermometer, a heat insulated container, a muscle-equivalent phantom, a power meter, a 50-ohm load, a digital frequency counter and an isotropic radiation survey meter. Conclusion HAMP established a protocol for quality assurance of all types of Hyperthermia systems to be followed by medical physicists in Greece for efficient treatment delivery with patient and personnel safety. The protocol has been approved by the Hellenic Society of Oncologic Hyperthermia. Disclosure No disclosure.

Considering skin physiology in capacitive-coupled hyperthermia

Dominant technical solution for oncological hyperthermia devices is capacitive-coupling. However, it has the challenge of overheating the surface of adipose layers and burning cutaneous structures. The main technical solution of this is the intensive cooling of the surface. Our objective is studying the physiology and effect of the active cooling of the skin in capacitive-coupled hyperthermia technologies.

In Russian

In this paper, we present a theoretical analysis of heating spherical bimetallic nanoparticles with a silver core and a golden shell using laser radiation. The aim of the work is to prove a possibility for applying laser hyperthermia in oncology with use of these nanoparticles. At this, a power and distribution of heat sources in a nanoparticle should be found with subsequent estimation of the temperature in its environs. We investigated a spatial distribution of the field energy in a particle within the electrostatic approximation for homogeneous field acting along the sphere axis. In this case electrostatic energy keeps a stable value in the core but corresponding expression for the shell consists of two terms of the series in expansion on Legendre polynomials. We have constructed a solution of the heat transfer equation for a sphere in a capsule with internal heat sources which intensity is formed by energy distribution of the electrical field. The calculations made show that the temperature necessary for destruction of onco-cells in the nearest environment of the particle can be reached using the laser power that is safe enough for a body system.

Heating, Efficacy and Dose of Local Hyperthermia

Hyperthermia in oncology needs a definite dose which fixes well the clinical protocols. The temperature is far not a dose, it is mass independent. The half of the mass has the same temperature in equilibrium, so the basic criteria of the dose mass-dependence are lost. The energy could be a great option for dosing, (like it is in radiation therapies by Gy) but it has numerous drawbacks. These are discussed in this paper, trying to unify the dosing of ionizing and non-ionizing radiations.

Personalised Dosing of Hyperthermia

Objective: Our objective is to show the superiority of the membrane selection and connected energy dose fixed via personal sensing. Method: Hyperthermia in oncology involves heating malignant cells and causing thermal damage in an attempt to destroy them. This could be immediate (necrotic) cell-distortion and ignite natural cell elimination, like apoptosis or autophagy. Two concepts determine the dose of hyperthermia: (1) isothermal tumour heating, homogeneous tumour temperature, which is used for necrosis based cumulative equivalent minutes (CEM), and (2) inhomogeneous heating of the tumour following the heterogeneity of the lesion itself. The personalized dosing used by oncothermia is heterogenic, it selects the membrane rafts of malignant cells that sense temperature on a cellular level targeting the nano-clusters of transmembrane proteins. The method uses the standard specific energy dosing controlled by personal sensing of the treated patient maintaining homeostatic control through gradual step-up heating process. Results: The nano excitation is thermal (fits to Arrhenius plot), and acts directly on the membrane of malignant cells. The homeostatic physiology reactions do not suppress the effective hyperthermia action with this heating. The stress reactions could be more regulated, the vasocontraction and vasodilatation effects roughly compensate each other. This allows a clear measurability of the dose of the treatment: instead of the temperature based cumulative equivalent minutes (CEM) it uses absorbed energy controlled by the RF-circuit. Due to the small mass of targets the applied power is low, the energy-sink surface cooling is fixed to homeostasis ensuring the accuracy of the energydose and improving the safety of the hyperthermia method. Conclusion: The nanoselection of malignant cells via oncothermia allows us to return to the dosing “gold standard,” which is also applied in radiotherapy. This energy-based dose is personalised with accurate step-up heating taking the wash-out time and the personal sensing of the patient into account.

Nanoheating without Artificial Nanoparticles Part II. Experimental Support of the Nanoheating Concept of the Modulated Electro-Hyperthermia Method, Using U937 Cell Suspension Model

There are intensive debates about the effects and mechanisms of radiofrequency (RF) hyperthermia in oncology. We theoretically modelled the mechanism of the nanoheating effect of the RF current at the cellular and subcellular level. Then, we experimentally investigated the mechanism of heating in comparison with selective modulated electrohyperthermia and water-bath heating conventional hyperthermia (WHT) using the U937 suspension cell line model. The two heating-processes resulted in different distributions of energy-absorption, causing different mechanisms of the thermal processes. Both of the mechanisms are thermal (fit to Arrhenius plot) but the selectively absorbed energy by the plasma membrane rafts and the cell-cell contacts of the cells results in earlier cell-destruction than in case of unselective homogeneous heating. This thermal effect is used for the characterisation of selective heating. The experimental results clearly support the previous theoretical considerations; the cell killing effect can be realised at lower temperature ranges in the case of the modulated electro-hyperthermia (mEHT, trade-name: oncothermia) method than with WHT.

Generalization of the Thermal Dose of Hyperthermia in Oncology

Hyperthermia has been a modality to treat cancer for thousands of years. During this time, intensive efforts are concentrated on determining the dose of the proper treatment, but the dominantly in vitro induced cellular death does not provide enough confidence for the clinical dosing. The cell-death by heat-monotherapy applications in laboratory experiments is difficult to apply in the complementary therapies in clinical applications. The newly developed nanotechnologies offer completely new possibilities in this field as well. Modulated electro-hyperthermia (mEHT, trade-name Oncothermia) is a nanoheating technology that has selective effects on membrane rafts and on the transmembrane proteins. This effect is thermal. The thermal action is in nanoscopic range which makes the phenomenon special. Our objective is to show the dose concept on this emerging method.

117 Ankara Oncology Hospital Department of Radiation Oncology hyperthermia experience

117 Ankara Oncology Hospital Department of Radiation Oncology hyperthermia experience

“Quo Vadis” Oncologic Hyperthermia?

Hyperthermia was the very first oncotherapy in human medicine based directly on sacral and philosophical roots in ancient cultures. The discovery of electromagnetism gave new hopes a century ago; however, up to now it has been suffering from lack of wide applications. Oncological hyperthermia struggles with multiple technical and medical problems which are far from the complete solution. Technically, the deep heating, the precise focusing, the technical control, and repeatability are challenging. The missing medical explanation of the phenomenon, together with the he missing measurable dose hinders the acceptance of hyperthermia. The contra-feedback of physiology mechanisms makes this method hardly controllable. Multiple, most promising results and studies are mixed together with some negatives and controversial consequences, causing huge fluctuations of its applications. There are positive and negative “believers” of the method, but the decisional facts are missing. A new way gives shape to the development: heating in nanorange, which could solve most of the open problems in oncological hyperthermia.

Critical Analysis of Electromagnetic Hyperthermia Randomized Trials: Dubious Effect and Multiple Biases

Hyperthermia in oncology still remains an experimental treatment with no realistic future in clinical cancer therapy, though declaration of the undisputed efficacy of hyperthermia is a common place in every hyperthermia paper. We have studied the available randomized trials on hyperthermia from the position of “null hypothesis” to confirm or refuse the efficacy and safety of clinical hyperthermia, taking into account also the possible biases. Unfortunately, careful analysis of 14 randomized clinical trials has not confirmed a clinical benefit of hyperthermia independently of its type: superficial, deep or whole-body. We have not found any positive trial not affected with biases. With correction to the distortions, there is no trial with obvious long-term positive effect of hyperthermia. Effect of hyperthermia could be shown in experimentally designed clinical trial or versus inadequate comparator. In clinical setting and provided that study design is correct, hyperthermia is not effective at all or not effective enough to justify its obvious disadvantages: toxicity and labor intensity. Thermal concept of hyperthermia seems to be irrelevant. Nevertheless, multiple publications of positive trials, reviews, and meta-analyses create an impression of hyperthermia renaissance.

Essentials of Oncothermia

Oncothermia is a method of hyperthermia in oncology, controlling the locally applied deep heat by selectively targeting the cellular membrane of the malignant cells. The selection of the method is based on various biophysical and biochemical achievements. There are various differences between the malignant and healthy cells, which could be used for their selection by heat targeting. The primary selection factor is a different metabolic activity which creates distinguishable environments of the malignant cells. The other factor is the clear difference of dielectric properties of the membrane and near-membrane extracellular electrolytes, marking off the malignancies. There is also a structural factor, which is clear in the different pathological patterns of the malignancy from their healthy counterparts. This last is described by fractal pattern evaluation technique, in which dynamic time-fractal transformation is used for further discernment of the malignancy. My objective is to show a new heating method, which makes oncological hyperthermia controllable and effective.

Cases That Respond to Oncothermia Monotherapy

There is a long history of hyperthermia in oncology, but its wide range acceptance and application are missing even today. A new approach of oncological hyperthermia, oncothermia, looks promising modality of the complementary treatment of advanced malignant cases. Our present paper is targeting this method, trying to answer the question of its feasibility to treat various advanced cases in monotherapy process, as well as its applicability for a long, large number of treatment sessions protocols.

Hyperthermia versus Oncothermia: Cellular Effects in Cancer Therapy

Hyperthermia means overheating of the living object completely or partly. Hyperthermia, the procedure of raising the temperature of a part of or the whole body above the normal for a defined period of time, is applied alone or as an adjunctive with various established cancer treatment modalities such as radiotherapy and chemotherapy. The fact that is the hyperthermia is not generally accepted as conventional therapy. The problem is its controversial performance. The controversy is originated from the complications of the deep heating and the focusing of the heat effect. The idea of oncothermia solves the selective deep action on nearly cellular resolution. We would like to demonstrate the force and perspectives of oncothermia as a highly specialized hyperthermia in clinical oncology. Our aim is to prove the ability of oncothermia to be a candidate to become a widely accepted modality of the standard cancer care. We would like to show the proofs and the challenges of the hyperthermia and oncothermia applications to provide the presently available data and summarize the knowledge in the topic. Like many early-stage therapies, oncothermia lacks adequate treatment experience and long-range, comprehensive statistics that can help us optimize its use for all indications.

Burden of Oncothermia: Why Is It Special?

There are many contradictory opinions about conventional hyperthermia in oncology. The main points are the physical and technical imperfection of classical heating, as well as the limits of the natural physiological feedback of the organism. We would like to present the definitive differences between oncothermia and conventional hyperthermia, explaining the new line of problem solving in this important field of oncology.

オンコサーミアにおける挑戦と問題

腫瘍治療のハイパーサーミアは数千年の歴史をもつ古い治療法の一つであるが, それはいまだ初期の発展段階にある. 他の治療法と同様に, この治療法にも適切な治療経験が欠けており, 治療法の適用を最適化できるような長期的かつ包括的統計が不足している. その理由は, 局所加熱の適用において, 生理学, 熱力学, 技術的解決法の三つに十分な調和が達成されていないことから説明される. 悪性細胞と健康細胞の選択的加熱は, ナノレベルの細胞領域でエネルギーを解放し, 悪性腫瘍のもっとも敏感な部分を感応させるものでなければならない. 本論文は腫瘍学における加熱のメカニズムと効果について論じるものであり, オンコサーミア (ナノサーミア) こそが悪性細胞に効果的に作用する解決法であることを提示する.