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.
Highlights
Combined radiotherapy and hyperthermia is a well-established alternative to chemoradiotherapy for advanced stage cervical cancer patients with a contraindication for chemotherapy
The rationale for adding hyperthermia to radiotherapy is that hyperthermia suppresses DNA double strand break (DSB) repair, the most lethal type of DNA damage caused by radiation treatment [6, 7]
By examining the effect of time interval between external beam radiotherapy (EBRT) and hyperthermia on the prevalence of DSBs in patient biopsies we study a potential mechanism supporting the clinically observed relationship
Summary
Combined radiotherapy and hyperthermia is a well-established alternative to chemoradiotherapy for advanced stage cervical cancer patients with a contraindication for chemotherapy. 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. Thermoradiotherapy, i.e. radiotherapy combined with hyperthermia, is a well-established alternative for patients with a contraindication for chemotherapy and provides similar overall survival [3,4,5]. Hyperthermia sensitizes radioresistent (hypoxic) tumors by increasing oxygen delivery [8, 9] This radiosensitizing effect increases the efficacy of the radiation treatment [10,11,12,13]. An EBRT fraction and hyperthermia session are usually given sequentially rather than simultaneously, since preclinical studies suggest that this results in the best therapeutic ratio [10, 14]
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