Hyperthermia: The Optimal Treatment to Overcome Radiation Resistant Hypoxia

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.

Hyperthermia with photon radiotherapy is thermoradiobiologically analogous to neutrons for tumors without enhanced normal tissue toxicity

“…In another meta-analysis of 779 patients of recurrent breast cancers from 16 studies who were re-irradiated with an additional mean RT dose of 36.7 Gy along with HT, none of the studies reported any significant increase in toxicities even with reirradiation and local HT [19]. Similar results also emerged from the use of HT with RT in pelvic tumors (bladder, rectum and cervix) [37], prostate [40] and from reviews of various clinical studies in other sites [10,12,15,27,38]. These indicate that photon HTRT is a safe, effective and well tolerated treatment modality in a wide range of malignancies.…”

“…In contrast, solid tumors have a coarse, elongated, dilated, tortuous capillary network with redundant bending and are devoid of smooth muscle and innervation. As tumor vessels are unable to physiologically auto regulate, they fail to 'wash out' heat when exposed to raised temperatures [24][25][26][27].…”

“…Mild to moderate HT initially leads to increased blood perfusion, an improved microcirculation and increased oxygen delivery in tumors. Higher temperatures could result in vascular damage resulting in greater hypoxia [25,27]. Over time, heat dissipates slowly from tumors compared with normal tissues resulting in a 'heat-trap' effect within the tumors [12,24,25].…”

“…The presence of hypoxic cells within solid tumors is a known limiting factor with low LET radiation (photons and protons). These are best treated with high LET radiation whereby the OER falls to 1.2 at around 200 keV/mm compared with 2.8-3.0 for protons or photons [13,27,35]. However, the lack of oxygen effect with HT offers additional thermoradiobiological advantages in clinical situations with low LET radiation similar to high LET radiation [29].…”

Combined wIRA-Hyperthermia and Hypofractionated Re-Irradiation in the Treatment of Locally Recurrent Breast Cancer: Evaluation of Therapeutic Outcome Based on a Novel Size Classification

“…Moreover, the option of systemic therapy (e.g., endocrine, cytostatic or targeted treatment) may often be excluded due to resistance or expected toxicity, as discussed by Oldenborg et al [3]. Hyperthermia has proven to be an effective radiosensitizer [4,5]. This is of high relevance in the treatment of locally recurrent breast cancers with significantly poorer vascularization and oxygenation status than in the respective primaries [6,7].…”