Abstract
Regions of low oxygenation (hypoxia) are a characteristic feature of solid tumors, and cells existing in these regions are a major factor influencing radiation resistance as well as playing a significant role in malignant progression. Consequently, numerous pre-clinical and clinical attempts have been made to try and overcome this hypoxia. These approaches involve improving oxygen availability, radio-sensitizing or killing the hypoxic cells, or utilizing high LET (linear energy transfer) radiation leading to a lower OER (oxygen enhancement ratio). Interestingly, hyperthermia (heat treatments of 39–45 °C) induces many of these effects. Specifically, it increases blood flow thereby improving tissue oxygenation, radio-sensitizes via DNA repair inhibition, and can kill cells either directly or indirectly by causing vascular damage. Combining hyperthermia with low LET radiation can even result in anti-tumor effects equivalent to those seen with high LET. The various mechanisms depend on the time and sequence between radiation and hyperthermia, the heating temperature, and the time of heating. We will discuss the role these factors play in influencing the interaction between hyperthermia and radiation, and summarize the randomized clinical trials showing a benefit of such a combination as well as suggest the potential future clinical application of this combination.
Highlights
Hypoxia is a hallmark of solid tumors [1,2]
The authors showed the same effect for carbon ions. This taken together with other studies showing the benefit of combining hyperthermia with high LET radiation [112,113,114,115], and the fact that hypoxia is less of an issue with high
The analysis showed a significant improvement in local tumor control when hyperthermia was combined with radiation for all sites except lung
Summary
Hypoxia is a hallmark of solid tumors [1,2]. It occurs because the tumor neo-vasculature that develops from the host vascular supply via angiogenesis [3] is a primitive and chaotic system that is unable to meet the oxygen demands of the growing tumor mass [2,4]. Regardless of the type of hypoxia, both pre-clinical and clinical studies show that its presence in tumors is a major factor influencing malignant progression and response to treatment, especially radiation therapy [2,5] These observations have led to extensive pre-clinical and clinical attempts during the last 5 decades or so to try to target this hypoxia and thereby improve patient outcome [6,7]. We will discuss the different ways in which hyperthermia has been combined with radiation therapy, focusing on why this approach is selective for hypoxia, and suggest the clinical potential of this therapeutic combination to significantly improve patient outcome
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