The benefit of hyperthermia combined with radiotherapy is well-acknowledged for patients
with locally advanced cervical cancer (LACC) (1–3). However, recently a discussion
evolved on the optimal time interval between radiotherapy and hyperthermia. Kroesen
et al. (4) recently reported a retrospective analysis of factors influencing clinical
results of treatment with radiotherapy and hyperthermia in a large cohort of locally
advanced cervical cancer patients (LACC) at ErasmusMC in Rotterdam. They concluded
that there is no detrimental effect of prolonged intervals on clinical outcome within
a time frame of 4 h between radiotherapy and hyperthermia. Kroesen et al. thereby
explicitly dismissed the findings of Van Leeuwen et al. (5) in a smaller cohort of
LACC patients treated at the Academic Medical Center (AMC) of the University of Amsterdam.
In that study longer time intervals and lower tumor temperatures were both found to
have a highly negative effect on in-field tumor control (time interval: p = 0.021,
in multivariable analysis p = 0.007) and overall survival (idem: p = 0.015, in multivariable
analysis p = 0.012), where it is important to note that the median time intervals
between radiotherapy and hyperthermia were ~60 and ~90 min for the short and long
time interval subgroups of patients, respectively.
We feel that the conclusion of Kroesen et al. is presented with insufficient caution.
The absence of an impact of time interval may be true in their cohort, but that does
not mean that time interval never plays a role for LACC patients treated with radiotherapy
and hyperthermia. We are inclined to attribute that difference in outcome to a different
mix in working mechanisms and patient population in the ErasmusMC cohort and in the
AMC cohort.
Multiple working mechanisms contribute to the effectiveness of hyperthermia, as was
also nicely summarized by Kroesen et al. Relevant is that each of these mechanisms
require a different optimal temperature range. For instance, inhibition of DNA repair
is a very effective radiosensitizer, but requires at least 41°C (6–8), a significantly
higher temperature than required for many other mechanisms, such as the reperfusion
mechanism leading to sensitization through reoxygenation, which will occur at more
moderate temperatures starting at 39°C (9, 10). Thus, the tumor temperature achieved
should be sufficiently high for a significant contribution of inhibition of DNA repair
to the overall hyperthermia effect, and the question is whether this level was achieved
in the study of Kroesen et al. where the median temperature rise was 3.5°C, equivalent
to a median tumor temperature below 40.5°C (4), in line with the median vaginal lumen
temperature of 40.3°C reported for a similar large cohort of LACC patients from ErasmusMC
(11), which partly overlaps the present ErasmusMC cohort. Van Leeuwen did not report
the median vaginal lumen temperature, but instead a measure for the minimum temperature:
T90 = 40.2°C, with T90 the temperature exceeded in 90% of the volume, equivalent to
a median temperature close to 41°C. Kroesen et al. attribute the lack of impact of
time interval on clinical results to either no contribution of inhibition of DNA repair
to the hyperthermia treatment effect, or to a fairly time interval-independent contribution
by assuming the hyperthermic inhibition of repair involves very slow DNA damage repair
processes, up to 6 h. Much DNA damage is repaired by fast repair within an hour after
radiotherapy, repair of the residual damage can indeed take more hours (6, 12, 13).
Study of DNA damage repair kinetics in cervical cancer biopsies did suggest the majority
of DNA damage is repaired within 2 h though (5). But even if hyperthermia had contributed
in the cohort of Kroesen et al. by inhibiting very slow DNA repair processes taking
up to 6 h, then differences in effectiveness of hyperthermia should have been visible
when comparing the shortest (0.5–1 h) and longest (1.5–4 h) time interval subgroups
shown in Figure 2 of (4), as even for a very slow repair of 6 h at least half the
DNA damage should have been repaired in the longest time interval subgroup, vs. minimal
repair for the shortest time interval subgroup. This suggests near absence of DNA
repair inhibition is the most likely explanation for the lack of effect of time interval
found in the ErasmusMC cohort.
Overgaard (14, 15) found for hyperthermia combined with radiotherapy in an in vivo
murine model significant contributions of two clearly different working mechanisms:
one fairly independent of the time interval, which probably reflects the dominant
mechanisms also present in the LACC patients of Kroesen et al., and another mechanism
only active when the time interval is shorter than 4 h, the latter is probably associated
with inhibition of DNA damage repair, augmenting the effect of radiotherapy. The latter
mechanism also showed a significant increase in thermal enhancement when the time
interval was shortened from 4 to 1 h and even to 0.5 h, in agreement with the clinical
results at AMC. This rapid increase of the thermal radiosensitization with shorter
time intervals has been successfully used in a study using very low-dose hypofractionated
weekly re-irradiation sessions (5 x 4 Gy) immediately following hyperthermia treatment
for recurrent breast cancer patients (16). The temperature used by Overgaard was 42.5°C
and it is clear that the contribution of inhibition of DNA damage repair will eventually
drop to zero when the tumor temperature is gradually decreased to 41°C. A good hyperthermia
effect is of course still possible without inhibition of DNA damage repair. Tumor
hypoxia is a serious factor in treatment failure, particularly in LACC, and the reoxygenation
effect of hyperthermia may overcome this tumor hypoxia and thereby significantly enhance
the effect of radiation, as also noted by Dewhirst et al. (9). Direct cell kill of
hypoxic tumor cells by hyperthermia will also contribute to enhancing the effect of
radiation, an effect that also exhibits a clear dose-effect relationship (10). For
this purpose a 4 h time interval is acceptable, but one should bear in mind that only
part of the synergistic hyperthermia working mechanisms are utilized at these somewhat
milder temperatures.
Our conclusion would be that inhibition of DNA damage repair appeared to be exploited
less in the patients treated in the ErasmusMC cohort than in the AMC cohort. There
is sufficient evidence to conclude that time interval does play a role in the application
of radiotherapy and hyperthermia. Therefore, the conclusion of Kroesen et al. that
prolonged time intervals between radiotherapy and hyperthermia are not detrimental
to clinical outcome cannot be generalized.
Author Contributions
HC drafting the article, critically revising the article. HK, AO, NF and LS critically
revising the article.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.