Download Review of radiotherapy and hyperthermia in primary cervical cancer

Int. J. Hyperthermia, September 2012; 28(6): 543–548
RESEARCH ARTICLE
Review of radiotherapy and hyperthermia in primary cervical cancer
MARTINE FRANCKENA
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Department of Radiation Oncology, Erasmus MC, Rotterdam, Netherlands
(Received 16 January 2012; Revised 20 February 2012; Accepted 24 February 2012)
Abstract
This review focuses on combined radiotherapy and hyperthermia for the primary treatment of cervical cancer compared to
the current international standard of chemoradiation. Practical considerations, biological effects and clinical results are
discussed.
Keywords: clinical trials, deep, cervix cancer
A decade ago the introduction of chemoradiation
instead of radiotherapy alone as the standard treatment approach for cervical cancer led to significant
improvements in local control and progression-free
survival, especially for the lower stages of cervical
cancer (FIGO stage I/II) [1–3]. For the more
advanced stages however, achieving local control
still remains a challenge [4].
This review focuses on combined radiotherapy and
hyperthermia for the treatment of locally advanced
cervical cancer compared to the current international
standard of chemoradiation.
Deep locoregional hyperthermia
Hyperthermia, the elevation of tissue temperature
above physiological level, is an evolving oncological
treatment modality for sensitisation of chemotherapy
and/or radiotherapy effects. The elevation of temperature is achieved by applying electromagnetic
energy to the treatment area. For the pelvic region,
several commercial and custom-made appliances are
available. When interpreting treatment results of
hyperthermia, it is important to keep in mind that the
technology used to heat up the patient plays a
decisive role in adequate treatment delivery and
treatment results [5–6]. For treatment of the pelvic
area, several radiative and capacitive systems are
commercially available (Figures 1 and 2). As the
technology used plays such a decisive role, the
introduction of hyperthermia treatment planning in
clinical practice constitutes an important step forward. Until recently, the clinical application of
hyperthermia was experience-based. And although
this experience-based approach proved to be successful in several clinical trials, it did make treatment
results susceptible to variations in expertise and
experience of the hyperthermia staff. Three recent
developments will allow for a more objective and
reproducible treatment strategy in the future, as well
as facilitate the large scale delivery of high quality
hyperthermia. First, the introduction of online 3D
hyperthermia treatment planning should enable a
more uniform and standardised treatment delivery
[7–8]. Moreover, more tumour-selective and patientspecific heating should improve hyperthermia treatment results, as higher tumour temperatures
Correspondence: Martine Franckena, MD PhD, Department of Radiation Oncology, Erasmus MC, Groene Hilledijk 301, Rotterdam, 3075 EA, Netherlands.
Tel: +31107041421. Fax: +31107041022. E-mail: [email protected]
ISSN 0265–6736 print/ISSN 1464–5157 online ß 2012 Informa UK Ltd.
DOI: 10.3109/02656736.2012.670835
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544
M. Franckena
Figure 1.
Figure 2.
Radiative hyperthermia system.
Capacitive hyperthermia system with external electrodes.
correlated with better tumour response [9]. Canters
et al. reveal the ins and outs of hyperthermia
treatment planning in clinical practice on pp. 570–
581 of this issue.
Second, the publication of quality assurance
guidelines for deep locoregional hyperthermia in
clinical studies should facilitate the participation in
international studies to newcomers in the field [10].
Third, real-time 3D thermometry using magnetic
resonance imaging (MRI), which is currently already
in clinical use in some hyperthermia institutes, can
help us reveal inadequacies in treatment delivery
during treatment so we can correct for them [11–12].
Biological effects of hyperthermia
One of the challenges of treating cervical cancer with
radiotherapy alone is that bulky tumours contain
many tumour cells that are in a hypoxic, nutrientdeprived and acidic microenvironment.
At tissue temperatures of 39 C and upward,
hyperthermia increases blood flow thereby decreasing hypoxia, nutrient deprivation and anaerobic
dissimilation in the tumour area. These effects
make tumour cells more sensitive to the cytotoxic
effects of radiotherapy and/or chemotherapy.
Increasing blood flow also allows for better delivery
of the chemotherapeutic agent to the target area.
In the same temperature range, hyperthermia also
inhibits DNA repair mechanisms also sensitising
tumour cells to the cytotoxic effects of radiotherapy.
Further, at temperatures of 42 C and upward
direct cytotoxicity due to heat occurs specifically
targeting those cells that are less sensitive to
the cytotoxic effects of radiotherapy and chemotherapy [13–15].
For years studies on the biological effects of
hyperthermia have focused on its direct cytotoxic
effect and on the chemo- and radiosensitising effect.
In recent years, it has become clear that hyperthermia
not only affects cells in the treated area, but systemic
effects may also play an important role [16–17]. This
subject is further elaborated on by Frey et al. in this
special issue on pp. 528–542.
The mechanism by which hyperthermia achieves
its main cytotoxic effect, and which of the mechanisms described above is the clinically prevalent one is
yet unknown. An important step towards unravelling
Radiotherapy and hyperthermia for cervical cancer
545
Table I. Studies comparing radiotherapy (RT) to radiotherapy þ hyperthermia (RTþHT).
CR
Datta
Sharma
Chen
Harima
Vasanthan
Van der Zee
PC
OS
FIGO
N
RT
RTþHT
RT
RTþHT
RT
RTþHT
Time
IIIb
II, III
IIb, IIIb
IIIb
IIb–IV
IIb–IV
64
50
120
40
110
114
58%
74%
46%
50%
67%
70%
73%
81%
2 years
1.5 years
48%
50%
72%
80%
57%
83%
49%
80%
37%
80%
70%
56%
48%
73%
20%
58%
73%
37%
3 years
3 years
12 years
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FIGO, International Federation of Gynecology and Obstetrics tumour stage; N, number of patients included in the study; CR, complete
response rate; PC, pelvic tumour control rate; OS, overall survival rate; Time, time of evaluation. All significant differences are in bold.
the efficacy of hyperthermia was recently made
by
Krawczyk
et
al.
They
found
that
hyperthermia inhibits an important repair mechanism for DNA double strand breaks, which is further
elaborated on by Eppink et al. in this special issue on
pp. 509–517 [18].
Current results in the primary treatment of cervical
cancer
To date, six randomised trials have been published
comparing radiotherapy to radiotherapy and
hyperthermia for primary cervical cancer (Table I)
[19–25]. The first report appeared in the Indian
Medical Gazette in 1987 [19]. Datta et al. treated 64
patients with primary cervical cancer FIGO
stage IIIb with either radiotherapy alone or
combined
with
hyperthermia.
Radiotherapy
consisted of 5000–5500 cGy in 25–28 fractions
applied over 5–5.5 weeks using a 60Co machine,
with a 1000–1500 cGy boost in 5–8 fractions. For
hyperthermia treatment delivery, they used a 27-MHz
capacitive heating device with external electrodes
twice a week after radiotherapy and achieved intravaginal temperatures of 42.5 C for 15 to 20 min per
treatment. Response rate, pelvic control and overall
survival trended higher with the addition of hyperthermia to radiotherapy, although the differences did not
reach statistical significance.
Sharma et al. also used a capacitive heating device,
but with an intravaginal electrode. They applied
hyperthermia three times a week before radiotherapy
and achieved temperatures of 42–43 C at the tumour
surface for 30 min. The radiotherapy was delivered
using a 60Co machine to apply 45 Gy in 20 fractions
over 4 weeks. A boost was delivered using either
LDR brachytherapy or 20 Gy in 10 fractions of
external beam radiotherapy. Fifty cervical cancer
patients were randomised, and in this study pelvic
control was improved at 1.5 years follow-up [25].
The first to detect a significant improvement was
Chen et al. who randomised 120 patients with
cervical cancer FIGO stage IIb and IIIb to receive
either radiotherapy alone, radiotherapy combined
with chemotherapy, radiotherapy combined with
hyperthermia, or radiotherapy combined with both
chemotherapy and hyperthermia. As this publication
is in Chinese, most of the data is inaccessible, but
they found a significant improvement in complete
response rate (48% versus 72%) with the addition of
hyperthermia [20].
Next, Harima et al. irradiated the whole pelvis to
30.6 Gy in 1.8 Gy fractions and then went on to a
total dose of 52.2 Gy after placing a central shield.
A boost was delivered to the tumour area using
brachytherapy. For hyperthermia, they used an
8 MHz Thermotron capacitive heating device with
external electrodes, and randomised 40 patients with
cervical cancer FIGO stage IIIb in 2001. They
applied three hyperthermia treatments during the
period of external beam radiotherapy for 60 min after
radiotherapy and achieved intravaginal temperatures
of 40.6 C on average. They found a significant
improvement in both complete response rate and
pelvic control at 3 years follow-up [21].
In 2000 and 2008 reports were published on 114
patients with locally advanced cervical cancer (FIGO
IIb–IVa) treated in a multicentre randomised trial, at
3 and 12 years follow-up respectively [23–24].
Radiotherapy was delivered to a total dose of
46–50.4 Gy in 1.8–2.0 Gy fractions to the tumour
area and the pelvic lymph nodes. A brachytherapy
boost was applied with either LDR or HDR
according to the participating hospital’s protocols.
For hyperthermia, a radiative system was used once a
week for 5 times during the period of external beam
radiotherapy. The aim of treatment was to continue
for 60 min after the tumour had reached 42 C, to a
maximum of 90 min. Power levels were increased to
patient tolerance in this trial and an intravaginal
temperature of 40.1 C was reached. In these reports,
not only response and local control were clearly
improved, but also overall survival was significantly
better with the addition of hyperthermia.
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546
M. Franckena
Moreover, this improvement was obtained without
adding to long-term toxicity and the results proved to
be reproducible in a much larger, unselected group
of cervical cancer patients [9]. At 12 years follow-up,
an absolute gain in overall survival of 17% was found
without increased treatment-related toxicity. In this
trial, hyperthermia’s cost effectiveness was also
determined. Although hyperthermia requires the
purchase of a dedicated machine and training of
staff members, hyperthermia proved to be very cost
effective with the cost per life year gained estimated
at E3956.
In 2005 the first and only negative report appeared,
written by Vasanthan et al. They report on 110
patients staged FIGO IIb to IV treated with a variety
of radiation schedules according to the various local
treatment protocols using either a 60Co machine or a
6–10 MV linear accelerator. Hyperthermia was
applied using an 8 MHz capacitive system with
intravaginal electrodes in most patients. They found
no difference in local control or survival at 3 years
follow-up [22]. However, this study was criticised
internationally because of doubts about the adequacy
of treatment delivery [26–27]. Using intravaginal
electrodes for heating up the tumour volume, one
must keep in mind that very high temperatures can be
achieved at the tumour’s intravaginal surface, but
temperatures may steeply decline at the tumour’s
periphery. Moreover, we know capacitive heating
systems can be used to achieve substantial temperature increases in thin patients, i.e. patients with no
more than 2 cm of subcutaneous fat, when the skin is
precooled. In this trial, patients with a subcutaneous
fat thickness of 3 cm were allowed to participate and
precooling of the skin was available in only one of five
participating centres. Subcutaneous fat thickness may
have been a limiting factor in applying sufficient
power in this trial, as in another randomised trial more
than twice the power was needed and a beneficial
effect was found [21].
Recently, a Cochrane analysis confirmed improved
response rates, local control and survival with the
addition of hyperthermia to standard radiotherapy,
but reservations are made because of the limited
number of patients available for analysis, differences
in methodology and overrepresentation of patients
staged FIGO IIIb [28]. The authors stress that
hyperthermia has clear therapeutic benefit in terms of
a doubling of the local control rate, improved
survival, limited restrictions of its clinical application,
and low costs.
Discussion
In the last decade, combined radiotherapy and
chemotherapy has gained widespread acceptance in
the treatment of cervical cancer. Despite the undisputed benefit for lower stages of cervical cancer,
serious doubts can be raised whether this benefit also
extends to the more advanced stages of cervical
cancer. All reviews published in the last 10 years
conclude that the beneficial effect of chemoradiation
is clearly present for patients with FIGO stage I
and II malignancies, but a recent meta-analysis based
on individual data confirms earlier suspicions that
the gain in overall survival may only be 3% at 5 years
for patients with FIGO stage III–IVa cervical
cancer [4].
At the same time there is evidence to suggest that
the addition of chemotherapy increases the toxicity of
radiotherapy. Hyperthermia, however, equally
enhances treatment outcome, while generally no
additional radiation-induced toxicity is observed.
Hyperthermia-specific toxicity is usually mild and
does not cause delays or changes in treatment.
The value of hyperthermia when added to chemoradiation for cervical cancer remains unsure as
two international trials addressing this value recently
closed prematurely due to inadequate patient
accrual. However, a phase I/II trial showed that this
approach is feasible and showed promising results in
68 patients, predominantly FIGO IIb stage [29].
Image-guided radiotherapy is fast becoming the
new standard for both external beam radiotherapy
and brachytherapy, as the organs at risk can be
spared better without compromising the dose in the
target volume [30–31]. These changes in radiotherapy treatment delivery should not make a
difference to the beneficial effect of hyperthermia in
the subgroup of locally advanced cervical cancer
patients, as hyperthermia does not add to radiationinduced toxicity.
Conclusion
Hyperthermia is a potent enhancer of chemotherapy
and/or radiotherapy without adding to treatmentrelated toxicity. Its application knows few restrictions
and is inexpensive, but should be done in accordance
with current treatment quality guidelines to assure an
optimal result for the patient.
Combined radiotherapy and hyperthermia is a
valid option for the first line treatment of advancedstage cervical cancer as there is evidence that it is
equally effective for chemoradiation, if not more so
for patients with advanced-stage cervical cancer. And
it does not add to treatment-related toxicity.
For patients with lower-stage cervical cancer, it
could be a valuable alternative to chemoradiation for
patients in whom platin-based chemotherapy is
contraindicated.
Radiotherapy and hyperthermia for cervical cancer
Declaration of interest: The author reports no
conflicts of interest. The author alone is responsible
for the content and writing of the paper.
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