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.

Keywords: hyperthermia; hypoxia; radiation therapy.

Figure 1

(A) Influence of time interval and sequence between radiation and hyperthermia (42.5 °C; 60 min) on tumor control in C3H mammary carcinomas (●) or moist desquamation in normal skin (○). (B) Effect of heating time and temperature on the thermal enhancement ratio (TER) for tumor control in a C3H mammary carcinoma when radiation and hyperthermia were given either simultaneously (solid symbols) or tumors irradiated and then heated 4 h later (open symbols); the heat temperatures are indicated. For both figures the TERs were determined from full radiation dose-response curves and represent the ratio of the radiation dose for radiation alone to that for radiation + heat to produce a response in 50% of animals. (Modified from [18,19]).

Figure 2

The radio-sensitizing effect of nitro-aromatic drugs and hyperthermia in a C3H mammary carcinoma. The sensitizer enhancement ratios (SERs) were calculated from full radiation dose-response curves of tumor control and represent the ratio of the radiation dose for radiation alone to that for radiation + sensitizer to produce a response in 50% of animals. The drug treatments were misonidazole (○), nimorazole (□), and doranidazole (△), with different drug doses administered as a single intraperitoneal (misonidazole and nimorazole) or intravenous (doranidazole) injection 30 min prior to irradiating (Modified from [24]). The dashed lines represent the SER levels when tumors were irradiated in the middle of a 60-min heating period at the indicated temperatures and are taken from Figure 1B.

Figure 3

Effect of heating on perfusion in RIF-1 fibrosarcomas (A) or C3H mammary carcinomas (B). Tumors were heated for 1 h (shown by the black bars) at the indicated temperatures and blood perfusion in the tumors measured at different times before, during, or after heating by intravenously injecting radioactive rubidium chloride; tumors were excised 90–120 min later and tracer uptake measured on a gamma counter. Points are means (±1 S.E.) with the pre-treatment control values shown by the open symbols (Modified from [38,88]).

Figure 4

Meta-analysis of all trials in which patients were randomized to receive radiation alone (RAD) or radiation + hyperthermia (RAD + HEAT). The endpoint in each trial was complete response (CR) measured by loco-regional control and shows the calculated Odds ratio with 95% confidence intervals (95% CI). Data from [116,117,118,119,120,121,122,123,124,125,126,127,128,129] and observations from Overgaard, J. [130].

Figure 5

Hypoxia in tumors causes resistance to conventional treatments (i.e., radiotherapy of chemotherapy) and enhanced malignant progression (i.e., more aggressive growth of primary tumors or metastatic spread). Attempts to decrease hypoxia, and thereby improve tumor response to therapy as well as decrease the formation of metastases, have utilized a variety of different “traditional” approaches, as listed in Table 1. Hyperthermia can also decrease tumor hypoxia by a variety of mechanisms equivalent to all those seen with the more traditional methods.