The Relevance of High Temperatures and Short Time Intervals Between Radiation Therapy and Hyperthermia: Insights in Terms of Predicted Equivalent Enhanced Radiation Dose

Purpose: The radiosensitization effect of hyperthermia can be considered and quantified as an enhanced equivalent radiation dose (EQDRT), that is, the dose needed to achieve the same effect without hyperthermia. EQDRT can be predicted using an extended linear quadratic model, with temperature-dependent parameters. Clinical data show that both the achieved temperature and time interval between radiation therapy and hyperthermia correlate with clinical outcome, but their effect on expected EQDRT is unknown and was therefore evaluated in this study. Methods and Materials: Biological modeling was performed using our in-house developed software (X-Term), considering a 23- × 2-Gy external beam radiation scheme, as applied for patients with locally advanced cervical cancer. First, the EQDRT was calculated for homogeneous temperature levels, evaluating time intervals between 0 and 4 hours. Next, realistic heterogeneous hyperthermia treatment plans were combined with radiation therapy plans and the EQDRT was calculated for 10 patients. Furthermore, the effect of achieving 0.5°C to 1°C lower or higher temperatures was evaluated. Results: EQDRT increases substantially with both increasing temperature and decreasing time interval. The effect of the time interval is most pronounced at higher temperatures (>41°C). At a typical hyperthermic temperature level of 41.5°C, an enhancement of ∼10 Gy can be realized with a 0-hour time interval, which is decreased to only ∼4 Gy enhancement with a 4-hour time interval. Most enhancement is already lost after 1 hour. Evaluation in patients predicted an average additional EQDRT (D95%) of 2.2 and 6.3 Gy for 4- and 0-hour time intervals, respectively. The effect of 0.5°C to 1°C lower or higher temperatures is most pronounced at high temperature levels and short time intervals. The additional EQDRT (D95%) ranged between 1.5 and 3.3 Gy and between 4.5 and 8.5 Gy for 4- and 0-hour time intervals, respectively. Conclusions: Biological modeling provides relevant insight into the relationship between treatment parameters and expected EQDRT. Both high temperatures and short time intervals are essential to maximize EQDRT.