- Hyperthermia + Radiotherapy
- Hyperthermia + Chemotherapy
- Hyperthermia + Radiochemotherapy
- The Future
Hyperthermia and radiotherapy
Hyperthermia is a potent radiosensitizer (Van der Zee, 2002).
In vivo studies have demonstrated that the effect of radiotherapy can be enhanced by a factor of 1.2 to 5 (Marino et al., 1992; Overgaard 1996).
Substantial radiosensitization may also be obtained at low (41°C-43°C) hyperthermia doses (Myerson et al., 2004; Kampinga et al., 2004).
RT+HT Biological rationale: mechanisms of radiosensitization by hyperthermia
Repair inhibition of ionizing radiation damaged DNA by hyperthermia at a temperature of 43°C seems to explain the mechanism by which HT represents a valid auxiliary treatment in anticancer therapy (Kampinga et al., 2004; Dewey et al., 1978). Horsman and Overgaard in 2008 have shown that the interaction between radiotherapy and hyperthermia results in a reduction of survival fraction cells, according to several factors such as heating temperature and time. (figure 1).
It has also been observed that HT can induce reduction of tumor hypoxia at 41°C, as result of changes in tumor blood flow (figure 2) and/or oxyhaemoglobin saturation (Vaupel et al., 1987). At that temperature, improvement of oxygenation status seems to play an important role in enhancing RT efficacy (Horsman et al., 2007).
Radiotherapy effect is based on the tumor DNA damage through two mechanisms: direct and indirect, by mean of the creation of oxygen free radicals. Heat can enhance both mechanism: on one hand it hampers the action of the DNA Repair and, on the other, increasing perfusion, increases the presence of oxygen for the creation of free radicals (figure 3).
At the same temperature, damage of tumor vasculature seems to occur. Hyperthermia, in fact, can inhibit in vitro and in vivo angiogenesis (Roca et al.,2003). ). Moreover, according to Iliakis et al. 2004, we can assess that also other heat-induced effects contribute to the inhibition of DNA replication in vivo, such as protein accretion of nuclear matrix and other alterations of chromatin structure (Roti Roti et al., 1994; Warters et al., 1988; Higashikubo et al., 1993; Vanderwaal et al., 2004).
RT+HT Clinical rationale: thermal enhancement for tumor control
The combined use of hyperthermia and radiotherapy has important advantages.
The tumor control is determined by the Radiotherapy dose.
When combining radiotherapy with hyperthermia, there has been observed a shift of the tumor control with a reduced radiotherapy dose.
. This allows for both increased tumor control at equal RT dose, in the treatment of a primary tumor, and an equal tumor control at lower RT dose, which is a key aspect in the re-irradiation of recurrent tumor in which the RT dose has to be as little as possible (figure 1).
Defining the Thermal Enhancement Ratio as
It has been found by Horsman and Overgaard in 2007 that the Thermal Enhancement Ratio is greatest when radiation and heat are administered within 2 hours (figure 2) from one another. With respect to the question if the radiation and heat have to be given simultaneously or sequentially, they found that (figure 3):
- for a simultaneous treatment, both in tumor (closed symbols) and in normal tissues (open symbols), higher temperature and longer heating time produce a larger TER;
- in a sequential treatment the TER reaches a plateau, although, since there is a little or no effect in normal tissues, there is a substantial therapeutic benefit.
Many randomized clinical trials have shown important results comparing the effect of radiotherapy alone and radiotherapy plus hyperthermia. They are summarized in the following histogram.