The Rationale for Combining Hypofractionated Radiation and Hyperthermia

Abstract

The conventional radiation treatment of cancer patients has typically involved a large number of daily treatments with relatively low doses of radiation. However, improved technology has now resulted in the increased use of fewer radiation fractions at a high dose per fraction. This latter approach is often referred to as hypofractionated irradiation. While conventional radiation typically kills tumor cells through the production of DNA damage, treatments with higher doses per fraction have been suggested to also kill cells via the induction of vascular damage. Such vascular effects will also increase the level of adverse microenvironmental conditions, such as hypoxia and acidity, that already exist in tumors. Cells existing in these adverse microenvironmental conditions are resistant to radiation but actually sensitive to hyperthermia (heating at 40-45 °C) treatment. This suggests that the combination of hypofractionated radiation and heat may be a viable treatment approach. While there are preliminary pre-clinical and even clinical studies investigating this option, there are actually no data on the optimal application for the greatest therapeutic benefit. In this critical review, we will present the rationale for combining hypofractionated radiation with hyperthermia and discuss what has been done and what should be done to establish this combination as an effective cancer therapy option.

Keywords: heat; hyperthermia; hypofractionated radiation; pre-clinical and clinical studies; stereotactic radiation.

Figure 1

Summary of the effects of single radiation (RT) and hyperthermia (HT) treatments in tumors. When tumors are irradiated (RT-1), it causes DNA strand breaks (RT-2). Tumor cells either repair (RT-3) that damage and survive or not (RT-4), the latter resulting in cell killing when measured immediately (day 0) after irradiating. With higher doses, radiation can also damage tumor vasculature (RT-5), which can result in additional cell killing (RT-6) at later times (day 5). When tumors are heated (HT-1), there is also direct cell killing (HT-2) in a time–temperature relationship. This will influence tumor growth delay (HT-3) in a similar fashion. At higher temperatures, heat also induces vascular damage (HT-4), which can indirectly affect tumor growth delay (HT-5) and increase the poor microenvironmental conditions (low pH and hypoxia) within tumors, and cells under such conditions are more sensitive to heat-induced cell killing (HT-6). Heat also transiently increases tumor oxygenation (HT-7), which can enhance radiation-induced DNA damage (HT-8). It can also cause protein denaturation (HT-9), which, by affecting the proteins involved in DNA repair, will also give rise to additional radiation-induced cell killing (HT-10). Based on published data [9,10,11,12,13,14,15,16,17]. Tumor image adapted from biorender.

Figure 2

The effect of sequence and interval on the interaction between radiation and heat. In all panels, radiation (RT) was applied at time 0, with heat (HT) given at different times before (HT-RT) or after (RT-HT) irradiating. (Left) panel: shows in vitro survival for the various cell lines indicated on the insert following the stated radiation and heat treatments. Data redrawn from [48,49,50,51]. (Middle) panel: shows the level of enhancement of the radiation response by heat in tumors. The various tumor types are indicated on the insert; all tumors were heated at 42.5 °C for 60 min. Data redrawn from [52,53,54,55]. (Right) panel: shows the level of enhancement of the radiation response by heat in normal tissues. The different normal tissues are indicated on the insert; all were heated for 60 min at the various temperatures shown. Data redrawn from [53,54,56,57,58,59].