A short time interval between radiotherapy and hyperthermia reduces in-field recurrence and mortality in women with advanced cervical cancer

Abstract

BackgroundCombined radiotherapy and hyperthermia is a well-established alternative to chemoradiotherapy for advanced stage cervical cancer patients with a contraindication for chemotherapy. Pre-clinical evidence suggests that the radiosensitizing effect of hyperthermia decreases substantially for time intervals between radiotherapy and hyperthermia as short as 1–2 h, but clinical evidence is limited. The purpose of this study is to determine the effect of the time interval between external beam radiotherapy (EBRT) and same-day hyperthermia on in-field recurrence rate, overall survival and late toxicity in women with advanced stage cervical cancer.MethodsPatients with advanced stage cervical cancer who underwent a full-course of curative daily EBRT and (4–5) weekly hyperthermia sessions between 1999 and 2014 were included for retrospective analysis. The mean time interval between EBRT fractions and same-day hyperthermia was calculated for each patient; the median thereof was used to divide the cohort in a ‘short’ and ‘long’ time-interval group. Kaplan-Meier analysis and stepwise Cox regression were used to compare the in-field recurrence and overall survival. Finally, high-grade (≥3) late toxicity was compared across time-interval groups. DNA repair suppression is an important hyperthermia mechanism, DNA damage repair kinetics were therefore studied in patient biopsies to support clinical findings.ResultsIncluded were 58 patients. The 3-year in field recurrence rate was 18% and 53% in the short (≤79.2 min) and long (>79.2 min) time-interval group, respectively (p = 0.021); the 5-year overall survival was 52% and 17% respectively (p = 0.015). Differences between time-interval groups remained significant for both in-field recurrence (HR = 7.7, p = 0.007) and overall survival (HR = 2.3, p = 0.012) in multivariable Cox regression. No difference in toxicity was observed (p = 1.00), with only 6 and 5 events in the short and long group, respectively. The majority of DNA damage was repaired within 2 h, potentially explaining a reduced effectiveness of hyperthermia for long time intervals.ConclusionsA short time interval between EBRT and hyperthermia is associated with a lower risk of in-field recurrence and a better overall survival. There was no evidence for difference in late toxicity.

Measurement and analysis of the impact of time-interval, temperature and radiation dose on tumour cell survival and its application in thermoradiotherapy plan evaluation

“…RT: radiotherapy; HT: hyperthermia. intervals, with time intervals for the included patients varying from 0.5 to 2 h [42], also suggesting a faster decay of hyperthermic radiosensitisation. The cause for the substantial difference in dynamic behaviour of the radiosensitisation remains unclear.…”

Commentary: The Impact of the Time Interval Between Radiation and Hyperthermia on Clinical Outcome in Patients With Locally Advanced Cervical Cancer

“…It was to our honest surprise that we found an absolute null effect of the time interval with Hazard Ratio's of a perfect 1.0 in 400 patients. In our discussion we thought of potential explanations for the different findings between the two studies, including the potential difference in temperatures achieved, as also pointed out by Crezee et al (7).A limitation of both our studies, besides the retrospective nature, is the long inclusion period; 1999-2014 for van Leeuwen et al and 1996-2016 for our cohort. This makes both our analyses subject to confounding factors, because of changes in interval times in different time periods.…”

“…We share the common opinion of Crezee et al that the important clinical consequence of hyperthermia and radiotherapy in the same center should not be based on a single institutions' experience. Hence, our decision to investigate the issue of the time interval in our patient population (6). It was to our honest surprise that we found an absolute null effect of the time interval with Hazard Ratio's of a perfect 1.0 in 400 patients.…”

“…A limitation of both our studies, besides the retrospective nature, is the long inclusion period; 1999-2014 for van Leeuwen et al and 1996-2016 for our cohort. This makes both our analyses subject to confounding factors, because of changes in interval times in different time periods.…”

Predictive value of SAR based quality indicators for head and neck hyperthermia treatment quality

“…However, temperature is difficult to predict, due to large thermal tissue property uncertainties and hence cannot be prescribed. Establishing a prescriptive quality parameter prognostic for the treatment outcome would help in the development of new devices or techniques and for a further spread of hyperthermia adoption as an addition to first line radio-and chemo-therapy [8,9]. Although a single unique thermal dose parameter has not been established, the need for such a parameter is widely accepted by the hyperthermia community [10][11][12][13][14].…”