Oncological hyperthermia: The correct dosing in clinical applications

Abstract

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.

Keywords: hyperthermia dose; CEM43Tx; TRISE; specific absorption rate; modulated electro-hyperthermia.

Figure 1

Change in free energy by jumping through an energy barrier (activation energy). The reaction coordinate represents the progress of the chemical reaction pathway. Usually, it describes the geometric changes when a transition happens between particle entities (molecules, atoms, clusters).

Figure 2

The set of the multiple barriers allowing subsequent small steps of energy-liberation. The ‘liberated’ energy can provide mechanical work (change height or pressure by lifting, dropping, pumping, etc.), electrical work (change the voltage by ion exchange) or chemical work (change the chemical free energy by the concentration of reactants).

Figure 3

Three processes to go over an energy-barrier: (A) tunneling effect (quantum mechanical), (B) lowering the barrier (catalytic), and (C) reaching the appropriate energy.

Figure 4

The Arrhenius plot at the transition temperature. The slope of the transition temperature is usually less than that below it, meaning that the new phase at a higher temperature has smaller activation energy. arb.u, arbitrary units.

Figure 5

The Arrhenius activation energy can be measured using different methods such as impedance (14).

Figure 6

Change in free energy by jumping through an energy barrier (activation energy). ‘A’ and ‘B’ are the reactants, ‘P’ is the product, and the reaction has an intermediate active complex [AB] which has a two-directional probability of proceeding, as most chemical reactions.

Figure 7

(A) Arrhenius and (B) Eyring plots. The slopes are E_a and ΔH^‡ while the y-intercepts are A and ΔS^‡, respectively.

Figure 8

Energy delivery can be well focused, but the heat and the temperature spread. This initiates competitive processes: whether the thermal cell killing, or the tumor-supporting effects are stronger. The control is indefinite. The main risk is compounded by increased tumor cell dissemination, leading to distant micro- and macrometastases.

Figure 9

The extrinsic apoptotic pathway induced by mEHT (HT29 human colorectal cell-line in a murine xenograft model) (116,148).

Figure 10

The extrinsic apoptotic pathway induced by mEHT (HT29 human colorectal cell-line in murine xenograft model) (116,121).