Radiation therapy combined with hyperthermia versus cisplatin for locally advanced cervical cancer: Results of the randomized RADCHOC trial

doi:10.1016/j.radonc.2016.02.010

Radiotherapy and Oncology

Volume 120, Issue 3, September 2016, Pages 378-382

https://doi.org/10.1016/j.radonc.2016.02.010 Get rights and content

Abstract

Background

Chemoradiation (RT-CT) is standard treatment for locally advanced cervical cancer (LACC). This study tried to establish if radiotherapy combined with hyperthermia (RT-HT) should be preferred in bulky and/or FIGO-stage ⩾III.

Methods

In this open-label, multicenter randomized trial, patients with LACC were randomly assigned by a computer-generated, biased coin minimization technique to RT-CT or RT-HT. Central randomization was done with stratification by FIGO-stage, tumour diameter and nodal status. Primary endpoint was event free survival (EFS). Secondary endpoints were pelvic recurrence free survival (PRFS), overall survival (OS) and treatment related toxicity. Analysis was done by intention to treat.

Results

The trial was closed prematurely (87 of 376 planned patients enrolled: 43 RT-CT; 44 RT-HT). Median follow-up time was 7.1 years. The cumulative incidence of an event was 33% in the RT-CT group and 35% in the RT-HT group. The corresponding hazard rate (HR) for EFS was 1.15 (CI: 0.56–2.36, p = 0.7). Also the hazards for PRFS (0.94; CI 0.36–2.44) and OS (1.04; CI 0.48–2.23) at 5 years were comparable between both treatment arms as was grade ⩾3 radiation related late toxicity (6 RT-CT and 5 RT-HT patients).

Conclusion

After 25% of intended accrual, data suggest comparable outcome for RT-CT and RT-HT.

Section snippets

Eligibility

The study protocol and consent procedure were approved by the Medical Ethics Review Board of participating centres. Patients with a biopsy proven cervical carcinoma FIGO-stage IB–IIA (⩾4 cm) or IIB–IVA, negative para-aortic lymph nodes (CT-scan short axis diameter ⩽ 1 cm), suitable to undergo radical radiotherapy combined with chemotherapy and/or hyperthermia and able to undergo brachytherapy, were eligible.

Clinical staging included pelvic examination under anaesthesia; pelvic MR-scan; abdominal

Results

This trial was closed prematurely because of poor accrual after 87 patients being enrolled between 2003 and 2009 (23% of 376 patients planned). Three patients were excluded from analysis: two with PAO lymph node metastases and one with distant metastasis. Intention to treat analyses encompassed 84 patients: 42 patients in the RT-CT arm and 42 patients in the RT-HT arm (Fig. 1). Patient and tumour characteristics were comparable (Table 1).

Discussion

The present trial comparing RT-CT to RT-HT in LACC, is underpowered. In addition tumour characteristics observed were significantly different from those anticipated when designing this trial, i.e. the majority of patients had tumours ⩽6 cm diameter and/or FIGO stage ⩽IIB, precluding any conclusion regarding the hypothesis to be tested. Nevertheless, important observations were made. For the current patient population with LACC FIGO stage significantly correlated with EFS and OS, whereas clinical

Conflict of interest statement

No funding was obtained for the trial.

All authors declare that they have no financial or personal relationships with other people or organizations that could inappropriately influence (bias) their work.

References (16)

J. van der Zee et al.
Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicenter trial
Lancet
(2000)
A. Trotti et al.
Common toxicity criteria: version 2.0. an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy
Int J Radiat Oncol Biol Phys
(2000)
M. Franckena et al.
Long-term improvement in treatment outcome after radiotherapy and hyperthermia in locoregionally advanced cervix cancer: an update of the Dutch Deep Hyperthermia Trial
Int J Radiat Oncol Biol Phys
(2008)
R. Potter et al.
Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology
Radiother Oncol
(2006)
R. Potter et al.
Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer
Radiother Oncol
(2011)
M. Franckena et al.
Radiotherapy and hyperthermia for treatment of primary locally advanced cervix cancer: results in 378 patients
Int J Radiat Oncol Biol Phys
(2009)
M.P. Schmid et al.
Distant metastasis patients with cervical cancer after primary radiotherapy with or without chemo-therapy and image guided adaptive brachytherapy
Gynecol Oncol
(2014)
M. Morris et al.
Pelvic radiation with concurrent chemo-therapy compared with pelvic and para-aortic radiation for high-risk cervical cancer
N Engl J Med
(1999)

There are more references available in the full text version of this article.

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Hyperthermia is a potent sensitizer of radiation therapy that improves both tumor control and survival in women with locally advanced cervical cancer (LACC). The optimal sequence and interval between hyperthermia and radiation therapy are still under debate.
We investigated the interval and sequence in vitro in cervical cancer cell lines, patient-derived organoids, and SiHa cervical cancer hind leg xenografts in athymic nude mice and compared the results with retrospective results from 58 women with LACC treated with thermoradiotherapy.
All 3 approaches confirmed that shortening the interval between hyperthermia and radiation therapy enhanced hyperthermic radiosensitization by 2 to 8 times more DNA double-strand breaks and apoptosis and 10 to 100 times lower cell survival, delayed tumor growth in mice, and increased the 5-year survival rate of women with LACC from 22% (interval ≥80 minutes) to 54% (interval <80 minutes). In vitro and in vivo results showed that the sequence of hyperthermia and radiation therapy did not affect the outcome.
Shortening the interval between hyperthermia and radiation therapy significantly improves treatment outcomes. The sequence of hyperthermia and radiation therapy (before or after) does not seem to matter.
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In this prospective phase II trial, patients with locally advanced rectal cancer were treated with 5-fluorouracil based preoperative radiochemotherapy with 50.4 Gy in 28 fractions. Deep regional hyperthermia was scheduled twice weekly. Pathological tumor regression was scored according to the Dworak regression system. The primary endpoint was pathological complete response (pCR). Further endpoints were local control (LC), distant control (DC), disease-free survival (DFS) and overall survival (OS). Hyperthermia was defined as feasible if 70% of patients received at least eight treatments. Quality of life was assessed at follow-up by the EORTC-QLQ-C30 and QLQ-CR29 questionnaires. Time to event data was analyzed according to Kaplan-Meier based on first-events. The study was registered on clinicaltrials.gov (NCT02353858).
From 2012 until 2017, 78 patients were recruited. Median follow-up was 54 months. Based on magnetic resonance imaging, the mesorectal fascia was involved or threatened in 60% of the patients. Compliance with radiotherapy was 99%, 91% received both cycles of chemotherapy and 77% had eight or more hyperthermia treatments. Median time from the end of radiotherapy to surgery was 6.7 weeks. A pathological complete response was reported in 14% of the patients, 50% had either Dworak 4 (complete regression) or Dworak 3 regression (scattered tumor cells only). Three year estimates for OS, DFS, LC and DC were 94%, 81%, 96% and 87%. Patients with higher hyperthermia related cumulative temperatures showed stronger tumor regression. Global health status based on EORTC-QLQ-C30 was comparable with data from the general population.
Deep regional hyperthermia was feasible, did not compromise standard treatments and resulted in promising long-term oncological outcomes and QoL.
Heat shock increases levels of reactive oxygen species, autophagy and apoptosis
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Citation Excerpt :
Temperatures in the range of 40 to 44 °C are applied to a localized area of the body that has been invaded by a tumor [2]. Hyperthermia sensitizes cells to radiation and anticancer drugs, thus increasing their therapeutic efficacies without enhancing normal tissue morbidities [1–7]. Heat can eliminate drug-resistant tumor cells and is by far, the best radiosensitizer known [2,8,9].
Hyperthermia is a promising anticancer treatment used in combination with radiotherapy and chemotherapy. Temperatures above 41.5 °C are cytotoxic and hyperthermia treatments can target a localized area of the body that has been invaded by a tumor. However, non-lethal temperatures (39–41 °C) can increase cellular defenses, such as heat shock proteins. This adaptive survival response, thermotolerance, can protect cells against subsequent cytotoxic stress such as anticancer treatments and heat shock (>41.5 °C). Autophagy is another survival process that is activated by stress. This study aims to determine whether autophagy can be activated by heat shock at 42 °C, and if this response is mediated by reactive oxygen species (ROS). Autophagy was increased during shorter heating times (<60 min) at 42 °C in cells. Levels of acidic vesicular organelles (AVO) and autophagy proteins Beclin-1, LC3-II/LC-3I, Atg7 and Atg12-Atg5 were increased. Heat shock at 42 °C increased levels of ROS. Increased levels of LC3 and AVOs at 42 °C were inhibited by antioxidants. Therefore, increased autophagy during heat shock at 42 °C (<60 min) was mediated by ROS. Conversely, heat shock at 42 °C for longer times (1−3 h) caused apoptosis and activation of caspases in the mitochondrial, death receptor and endoplasmic reticulum (ER) pathways. Thermotolerant cells, which were developed at 40 °C, were resistant to activation of apoptosis at 42 °C. Autophagy inhibitors 3-methyladenine and bafilomycin sensitized cells to activation of apoptosis by heat shock (42 °C). Improved understanding of autophagy in cellular responses to heat shock could be useful for optimizing the efficacy of hyperthermia in the clinic.
In Regard to Datta et al.
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Datta et al. demonstrated in a systematic review with conventional and network meta-analysis that in locally advanced cervical cancer thermoradiotherapy, thermochemoradiotherapy, and chemoradiation (3-weekly cisplatin) are the strategies achieving best clinical results for long-term locoregional tumour control, overall survival as well as acceptable side effects [68]. Lutgens et al. found similar effectiveness of thermoradiotherapy compared to the standard chemoradiation treatment of locally advanced cervical cancer in a prematurely closed randomized trial [81]. All mechanisms discussed in 2.1 and 2.2 are shown in Fig. 2.
Mild hyperthermia, local heating of the tumour up to temperatures <43 °C, has been clinically applied for almost four decades and has been proven to substantially enhance the effectiveness of both radiotherapy and chemotherapy in treatment of primary and recurrent tumours. Clinical results and mechanisms of action are discussed in this review, including the molecular and biological rationale of hyperthermia as radio- and chemosensitizer as established in in vitro and in vivo experiments. Proven mechanisms include inhibition of different DNA repair processes, (in)direct reduction of the hypoxic tumour cell fraction, enhanced drug uptake, increased perfusion and oxygen levels. All mechanisms show different dose effect relationships and different optimal scheduling with radiotherapy and chemotherapy. Therefore, obtaining the ideal multi-modality treatment still requires elucidation of more detailed data on dose, sequence, duration, and possible synergisms between modalities. A multidisciplinary approach with different modalities including hyperthermia might further increase anti-tumour effects and diminish normal tissue damage.
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Radiosensitizing effects are maximum when radiation and HT are delivered simultaneously or within several minutes of one another.123 Clinical efficacy and safety of locoregional HT adjuvant to EBRT has been shown in large prospective randomized trials, notably in patients with pelvic malignancies.124,125 Few studies have been performed examining clinical applications of BT with concurrent HT.
Fundamentals in radiobiology commonly known as the ‘4R's’ concept (ie, reoxygenation, repair, redistribution, and repopulation) have mostly been investigated for external beam radiotherapy. However, these fundamentals can be applied to brachytherapy (BT) by accounting for differences in dose rate, fractionation, and response to immunologic agents for this treatment modality. Many improvements have been achieved in the era of dosimetric optimization but still limited data are available regarding radiobiological opportunities for BT. As BT is characterized by a large degree of dose heterogeneity, a wide range of dose rates and fractionations exist within the implanted volume. Calculations based on the linear quadratic model can be used to estimate the dose-response equivalence between various BT modalities. Such models are helpful in daily practice and open possibilities in terms of radiobiological optimization. However, some limitations should be highlighted in terms of the applicability of the linear quadratic model. Furthermore, in vitro models do not account for the complex interplay between the tumor and its microenvironment, including vascularization and/or immune response. Recently, an improved understanding of the tumor's microenvironment has led to investigations of immunomodulatory agents in combination with radiotherapy. BT is a promising candidate to enhance the immunogenic response with concomitant immunotherapy. This review summarizes some of the main mechanisms involved in tissue response to BT. Preclinical data, clinical evidence, as well as novel approaches to radiobiology are highlighted.

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Phase III randomised trialRadiation therapy combined with hyperthermia versus cisplatin for locally advanced cervical cancer: Results of the randomized RADCHOC trial

Abstract

Background

Methods

Results

Conclusion

Section snippets

Eligibility

Results

Discussion

Conflict of interest statement

Lancet

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Pelvic radiation with concurrent chemo-therapy compared with pelvic and para-aortic radiation for high-risk cervical cancer

N Engl J Med

Phase III randomised trial
Radiation therapy combined with hyperthermia versus cisplatin for locally advanced cervical cancer: Results of the randomized RADCHOC trial