Radiotherapy for prostate cancer could be more effective if preceded by mild hyperthermia. This is the finding of researchers at the University of Maryland School of Medicine, who used radiofrequency (RF) fields to heat tumours in mice before administering a single dose of X-rays. Treatments that combine the two techniques could spare surrounding tissue by using a smaller overall dose to achieve outcomes similar to those of conventional radiotherapy (Br. J. Radiol. 10.1259/bjr.20180759).

Long-term survival rates for patients receiving radiotherapy for prostate cancer are relatively high, so a focus of current research is on minimizing the secondary effects of treatment. These effects arise because irradiation of deep-seated tumours inevitably involves damage to healthy adjacent tissue, which in prostate cancer can result in quality-of-life-lowering conditions like erectile, urinary and bowel dysfunction.

One way of limiting such complications is to make the tumour especially susceptible to radiation damage while preserving the surrounding tissue’s natural level of radioresistance. Various chemical means exist to increase radiosensitivity, but the difficulty of applying these selectively to the tumour means that healthy cells can be sensitized too.

Previous work has shown that applying mild hyperthermia — producing temperature increases too small to kill cancer cells directly — could be a more targeted way to specifically sensitize tumours. Now, Justin Cohen and colleagues have demonstrated in a preclinical study that such radiosensitivity can be induced even in deep tumours by externally applied RF fields.

To test the approach, the researchers cultured human prostate cancer cells and modified their DNA to express a luminescent protein. The cancer cells were introduced by surgery into the prostates of mice, and left to develop into tumours; the presence of a bioluminescent signal confirmed that cancers had become established. The researchers then monitored the growth of the tumours using ultrasound.

Splitting the 40 test animals into four groups, the researchers applied either radiotherapy alone, radiotherapy preceded by hyperthermia, or hyperthermia alone. A quarter of the subjects were left untreated as a control group.

The hyperthermia procedure involved using electrodes on the animal’s skin to produce an RF field in the prostate, heating the organ to 41°C. In comparison, ablative hyperthermia — a commonly used technique to kill cancer cells directly — requires temperatures above around 54°C.

After the interventions, tumours were allowed to continue growing, with the time taken for the volume to double serving as a measure of treatment’s effectiveness. In animals in the control and hyperthermia-only groups, the tumours doubled in volume after four days, with the hyperthermia procedure slowing growth by just a few hours on average. In animals that received just radiotherapy, and hyperthermia followed by radiotherapy, the average doubling times were 30 and 33 days, respectively. These findings indicate that the combination of hyperthermia and RT has a synergistic effect.

There are many possible mechanisms behind the radiosensitivity enhancement, but in this case, the effect can probably be attributed to denatured DNA-repair proteins, which hamper recovery of damaged cancer cells, and dilated local blood vessels, which raise oxygen levels in the tumour.

Clinical potential

Next, the team hopes to show that sensitizing the tumour using hyperthermia means that a smaller radiation dose can be used without compromising treatment efficacy. “Half of all prostate cancer patients receiving radiotherapy experience erectile dysfunction post-treatment. If we can achieve the same level of tumour kill at a lower dose, we hope to reduce this toxicity significantly,” says principal investigator Amit Sawant.

If the results are promising, it should be straightforward to translate the research into clinical practice, as previous studies have already demonstrated mild prostate hyperthermia in human patients. “Those trials were done a couple of decades ago and the main barrier to the widespread clinical adoption of hyperthermia was that, back then, there were no accurate and non-invasive in vivo thermometry techniques to validate the temperature distribution,” says Sawant. “Now, with the availability of modern modalities like MR thermometry, this is no longer a barrier.”