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. 2017 Apr 27;12(1):75.
doi: 10.1186/s13014-017-0813-0.

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

Caspar M van Leeuwen  1 , Arlene L Oei  2   3 , Kenneth W T K Chin  4 , Johannes Crezee  4 , Arjan Bel  4 , Anneke M Westermann  5 , Marrije R Buist  6 , Nicolaas A P Franken  4   7 , Lukas J A Stalpers  4 , H Petra Kok  4
Affiliations

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

Caspar M van Leeuwen et al. Radiat Oncol. .

Abstract

Background: Combined 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.

Methods: Patients 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.

Results: Included 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.

Conclusions: A 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.

Keywords: Cervical cancer; Clinical outcome; Hyperthermia; Radiotherapy; Time interval.

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Figures

Fig 1
Fig 1
Kaplan-Meier survival analysis for in-field recurrence (left) and overall survival (right) for the short time-interval group (black) and the long time-interval group (red). Shaded area represents the 95% confidence interval
Fig 2
Fig 2
γ-H2AX staining showing unrepaired DNA double strand breaks (in red) in patient biopsies at 15 min (a) and 2 h (b) after 4 Gy irradiation (RT) compared to control (ctrl). Roman numerals identify individual biopsies
See this image and copyright information in PMC

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