Editorial

Cervical cancer is one of the most common cancers in women worldwide, and one of the tumour entities for which hyperthermia has been proven to be effective. During the last few decades, prevention, screening and treatment of cervical carcinoma have changed considerably.

The contributions in this special issue on cervical cancer present several of these changes and their background, and some exciting new developments in the field of hyperthermia which will have an impact on future applications.

Crosbie and Kitchener [1] report how the human papilloma virus (HPV) was discovered to be the carcinogenic factor in cervical cancer. This finding has led to the development of vaccines which are now used all over the world for vaccination of young women. First results show that vaccination is very effective in preventing cervical cancer precursor lesions; as a result the number of women with cervical cancer is expected to decrease. Screening based on detection of HPV in cervical smears is more sensitive than cytology in the detection of (pre)malignant lesions and will replace cytology in the near future. Whether a therapeutic vaccine can be effective in the eradication of premalignant lesions is under investigation. When a woman is HPV negative after the removal of a premalignant lesion, the risk of residual disease and developing a new cervical lesion is not increased compared to that in the normal population, so that she can be followed according to the routine screening programme instead of annual screening.

When cervical cancer is diagnosed in an early stage, surgery can now be less extensive than radical hysterectomy, which is important for both quality of life and for retaining reproductive function [2]. Laparoscopy and robotic surgery have contributed to the development of optimal surgical management. The key issue is how to select patients; parameters such as tumour size, stromal invasion, (lympho)vascular invasion, perineural involvement and histopathological type are of importance. In properly selected patients, limited surgery has been shown to be safe.

Once a more advanced stage of cervical cancer has developed, brachytherapy, in addition to external beam irradiation, is essential for the achievement of local control. Conibear et al. [3] describe how the application of brachytherapy has changed. With the advancement of diagnostic tools (MRI, PET-CT), the tumour extension now can be visualised more exactly and the treatment plan can be adjusted accordingly. After the placement of the brachytherapy applicators, the tumour volume is delineated on the planning scan and the appropriate radiation delivery strategy determined, with the aim to adequately cover the whole volume at risk whilst taking the organs at risk into account. The implementation of MRI guided brachytherapy is arguably the most important new development in radiotherapy techniques for cervix cancer patients over the last decade as it improves local control rates without adding to toxicity.

It had been shown before that hyperthermia impairs the repair of radiation-induced DNA damage. More recently it was found that hyperthermia inhibits homologous recombination of DNA double-strand breaks by degradation of the BRCA2 protein [4]. This not only helps to explain why hyperthermia sensitises cells to radiation and chemotherapy, but opens a large new window of opportunity for new combination therapies.

Vaupel and Kelleher [5] have reviewed the pathophysiology and energetic status of cervical cancer for us. Untreated tumours are mostly hypoxic, acidic, exhibit substrate and energy deprivations and show lactate accumulation. All these characteristics are spatially and temporally heterogeneous. Additionally a relatively homogeneous interstitial hypertension is observed. There is a lack of data concerning changes occurring in patients during and after hyperthermia treatments, and the authors stress that clinical studies are urgently needed.

Frey et al. [6] present an overview of modulations of the immune system induced by hyperthermia. Most of the studies show that the effect of hyperthermia combined with other therapies contribute to immune activation against the tumour. In the future, a personalised cancer treatment approach will be feasible by combining hyperthermia with other therapies.

Hyperthermia has been shown to be effective in cervical cancer [7]. The addition of hyperthermia to radiotherapy for locally advanced cervix cancer improves both local control rates without adding to toxicity, as summarised by Franckena [8]. We find it amazing that now a systematic overview of chemotherapy addition to radiotherapy has shown that the absolute gain in 5 years overall survival in stages III-IV cervical cancer is only 3% [9] whilst toxicity is increased with this combination, there is no discussion on whether this combined treatment should continue to be the standard. The hyperthermia results have convinced the FDA to release a humanitarian device exemption marketing approval for the BSD-2000 hyperthermia system, for use in conjunction with radiotherapy for cervical cancer patients who are ineligible for chemotherapy due to patient related factors.

The findings of improvement of radiotherapy results by both cisplatin and hyperthermia has led not only to the question of whether one of these two additional modalities might be more effective in the different stages of cervical cancer, but also to the question of whether combining all three modalities would improve results further. Three separate phase I–II studies were started and the results evaluated together. Westermann et al. [10] report that the three-modality treatment indeed can be given safely, with toxicity similar to that reported from chemoradiation without hyperthermia. Pelvic tumour control and overall survival seem promising, but a randomised trial to compare this three-modality regime to the current standard of chemoradiotherapy unfortunately had to be closed prematurely, due to insufficient patient accrual.

Patients with large primary tumour and/or voluminous lymph node metastasis or para-aortic positive nodes have a bad prognosis when treated with radiotherapy or chemoradiation. Heijkoop et al. [11] treated such patients with neo-adjuvant chemotherapy followed by radiation combined with hyperthermia. This combined treatment resulted in 55% 5 years overall survival, which is higher than reported from chemoradiation in patients with para-aortic positive nodes.

When hyperthermia is going to be used on a larger scale, and also when hyperthermia is further tested in multi-institutional trials, it is very important to establish quality management, including audits. Bruggmoser [12] describes some of the needs for quality management in deep regional hyperthermia. Part of good quality hyperthermia treatment has been described in guidelines, but a large part still has to be done.

The possibility to prescribe hyperthermia treatment and to apply it in a reproduceable way is very important for the general acceptance of hyperthermia. Both would become easier when SAR distribution could be used as a dose descriptor. Canters et al. [13] describe how the energy distribution can be optimised during treatment, using hyperthermia treatment planning and applying constraints to hot spot locations which limit the energy input. If such treatment planning can be combined with three-dimensional temperature control, computer-controlled hyperthermia treatment comes within reach.

The papers in this issue represent some of the most important new insights in the diagnosis and treatment of cervix cancer over the last decades, with special attention to the role of hyperthermia and how that role can be consolidated and elaborated.

The articles in this special issue can be seen as stepping stones for this consolidation and elaboration in the future.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.