Quo Vadis Oncological Hyperthermia (2020)?

Abstract

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

Keywords: abscopal effect; bystander-effect; hyperthermia; immune effects; oncology; trend.

FIGURE 1

The most frequently used WBH methods. The first three examples do not generate a significant increase in body temperature, however infrared water-window (IR-A) and the extra-corporeal variations of techniques are widely used and have proven to increase the body temperature.

FIGURE 2

The various frequencies and the associated dispersion. Frequencies have different excitation mechanisms. The energy absorbed at various frequencies (called dielectric loss), is represented graphically for the α, β, δ, and γ absorption range. The 13.56 MHz, which is the carrier frequency of the mEHT, is shown. The distributions are only approximate and depend on the real conditions and heterogeneity of the material, which absorbs the energy. The overlapping of the β/δ ranges has multiple interactions, the effects of which are used for the excitation of membrane rafts, mainly the water-binding transmembrane proteins with their lipid environment.

FIGURE 3

The interaction strengths of the bio-electromagnetic interactions. The “strength” refers to the ability of the energy to be absorbed by the living system.

FIGURE 4

Basic division of loco-regional hyperthermia categories (112). There are technical solutions in each categories, and each product has its own unique technical details, but all have the end goal to heat, either resulting in either temperature homogeneity or heterogeneity.

FIGURE 5

Illustrative representation of the two heating principles. (A) Isothermal (homogeneous) heating causes energy-absorption in the complete target, while in (B) non-isothermal heating only selected parts are heated in a heterogenic manner. The selected parts that are heated are either unique characteristics of the tumor which respond to a stimulation by heating up, or nano-particles which are introduced into the tumor and which respond to a stimulus by heating up. These heated targets then heat up the target volume by heat conduction.

FIGURE 6

Radiative and capacitive heating with plane-waves. (A) The radiative situation causes an artificial focusing. The target is independent from the source. (B) Capacitive with impedance matching: the source and the target are coupled; they are in a common electric circuit.

FIGURE 7

The challenge of electrode cooling. The figure shows the capacitive solution, but the situation is the same with the radiative solution, only with three-dimensional cooling (water bolus typically wraps around the patient) instead of in the two dimensions of the parallel pads. (A) The forwarded energy dose is compromised by the energy removed by cooling mechanisms. (B) The situation starts a physiological reaction which results in a positive feedback cycle: the cooling causes are reduction in blood flow to the skin, causes electrical isolation in the superficial tissues, requiring an increase in the power (voltage). This in turn increases the burn risk, so more cooling is needed, further decreasing the blood flow. And the cycle continues in a positive, non-linear loop.

FIGURE 8

A representation of the effects of two electrodes with opposite charges. (A) Two opposite charges, (B) two plan-parallel electrodes in a capacitive coupling forming a virtual zero field in the center between each electrode, (C) a one-side grounded capacitor, with one electrode and the bed base acting as the second, grounded capacitor, as applied in the impedance matched coupling technique.

FIGURE 9

The five steps of the energy-selective mechanism causing apoptotic cell-destruction. The energy-absorption step (the 3rd one) is hyperthermic, proven by Arrhenius plot. The 4th step belongs to fractal-physiology. Extrinsic excitation and the apoptotic pathways to kill the cell with the mEHT method. Three variants of apoptotic signal pathway are used, and the blocker (XIAP) is blocked, preventing its action from limiting the signal transfer.

FIGURE 10

Immunogenic treatment with mEHT. The induced immunogenic cell-death presents the genetic information to DCs forming antigen presenting cells (APCs) and tumor-specific killer cells which are active all over the system. It is an in situ, real-time process.

FIGURE 11

The molecular details of the immunogenic action of mEHT. The set of damage associated molecules (DAMP) has an important messenger role. The HSP is liberated from the cytosol, and becomes a game-changer: instead of protecting the tumor-cell, it helps to destroy it.

FIGURE 12

Development of the locoregional hyperthermia methods in oncology. The trend is in the direction of immune effects, demanding a new paradigm in hyperthermia.