Systematic review of the registered clinical trials for oncological hyperthermia treatment

Abstract Background The use of heat to treat various diseases is called hyperthermia treatment (HT). Since the 1970s, the anti-cancer effects of HT have been investigated. Different HT techniques can be categorized as local, regional and whole-body hyperthermia treatment (WBHT). We aim to provide a summary of recent research done on HT to treat cancer. Methods In July 2020 ClinicalTrials.gov were systematically searched for all trials including hyperthermia and cancer registered between 2000 and 2020. Studies were excluded when they did not concern hyperthermal treatment, when they were not oncological studies, when they were observational or other non-interventional studies. Results Of 1654 identified trials, 235 were included. Of these 235 studies, 123 described the use of HIPEC (52.3%), 44 other types of regional HT (18.7%), 45 local HT (19.1%) and 15 WBHT (6.4%). A steady increase (720%) in research to hyperthermic intraperitoneal chemotherapy (HIPEC) can be observed in the last decade. Although HIPEC is the most researched HT modality, an evolution in other HT technologies could be observed during the past decade. Conclusions Research to HT to treat cancer has expanded fast. Some techniques, for example HIPEC start to be used outside of research context, but overall, more research is needed to establish a clear effect of these HT techniques.


Introduction
Heat has been used to treat tumors since ancient times. Even Hippocrates mentioned the use of heat to treat cancer [1]. The use of heat to treat malignancies is called hyperthermia treatment (HT). Since the 1970s, the biological effects of HT have been investigated. Various heating techniques have been introduced in the oncological field ever since. These techniques can be divided in two categories: ablation and HT. Ablation aims to destroy tumor cells directly by using temperatures above 50 C. HT aims to sensitize tumor cells to chemo-or radiotherapy by using temperatures below 45 C [2].
The destructive effect of HT can be partially explained by induction of direct apoptosis. The temperature and duration of HT necessary to induce apoptosis can be defined as the thermal effective dose (TED) [3]. The TED differs between cell type and the phase of the cell-cycle. The TED may be altered by induced thermotolerance as well [4]. In addition, HT increases the tumor blood flow, permeability, pO 2, pH and tumor nutritional status [5]. These alterations can have an additive effect when HT is compared with other anticancer therapies, since they seem to be complementary.
Many techniques have been developed to deliver heat to a tumor. In general, these can be divided in three main categories; local-, regional-and whole-body hyperthermia treatment (WBHT) [6]. Local HT aims to heat a small part of the body to destroy cancer cells and blood vessels. Examples of local HT include interstitial HT, where a needle is used to administer heat to the tissue [7]; high-intensity frequency ultrasounds (HIFU), which uses ultrasound to deliver the heat [8]; nanoparticle based magnetic HT [9][10][11] and electroporation [2]. Local HT has been used to treat tumors in different organs, such as head and neck [12], gynecological [13], breast [14,15], brain [16] and thyroid [17].
Regional HT aims to heat a body cavity. It is most often used in combination with radiotherapy or administered as heated chemotherapy [6]. The most frequently used technique, hyperthermic intraperitoneal chemotherapy (HIPEC), aims to create a flow of heated chemotherapy through the abdominal cavity. HIPEC is most often used to treat gastrointestinal [18] and gynecological tumors [19,20]. Other techniques to heat body cavities are being developed; these include hyperthermic intravesical chemotherapy (HIVEC) [21] and hyperthermic intrathoracic chemotherapy (HITOC) [22]. Last, isolated limb perfusion is a technique that temporarily replaces the blood in a limb with a heated chemotherapeutic agent. It is mainly used to treat soft tissues sarcomas [23] and melanomas [24].
WBHT aims to elevate the temperature of the entire body by heating directly the body or the blood. Temperature may be raised to a fever range (39-40 C) or to higher temperatures (41-43 C). WBHT is most often used in combination with chemo and/or radiotherapy [25] for advanced or metastasized cancers of the lung, ovarian, colon, pancreas or sarcomas.
ClinicalTrials.gov is a website established in 2000 and maintained by the National Library of Medicine and the National Institutes of Health [26]. Since 2008, investigators must upload the study protocol of their clinical trial before conducting any clinical trial. Study progress and results related to the trial can be uploaded as well; however, this is not mandatory. Due to the obligation of uploading the clinical trial study protocol, drafting databases from all listed studies on a specific topic is possible.
Cihoric et al. [27] published an initial article about the research of HT, using the ClinicalTrials.gov database [28]. He mainly concluded a growing interest in HT as a cancer treatment modality and the large amount of HIPEC studies within the HT research. Since the publication of this article, an extensive number of new research in HT has been conducted. This systematic review aims to update and summarizes the clinical studies available on clinicaltrials.gov carried out on HT for cancer treatment.

Study protocol
In this study, we try to provide an overview of all clinical trials that have been conducted on HT in cancer patients posted to ClinicalTrials.gov.

Search strategy and eligibility criteria (inclusion/exclusion)
For this systematic review, we conducted a search on the ClinicalTrials.gov website. Using 'Cancer' and 'Hyperthermia' as Medical Subject Headings (MeSH) terms. For this systematic review, we searched for studies focusing on the efficacy of any form of HT in humans with all types of cancer. Studies were excluded when they did not concern HT, when they were not oncological studies, when they were observational or other non-interventional studies.

Results
The great diversity among the methodology studies and insufficient information was an impeditive for achieving profound statistical analysis; therefore, a narrative report of the included studies was performed.

Data extraction
On 22 July 2020, records of 346,462 registered studies were retrieved from ClinicalTrials.gov. Studies were refined using the MeSH terms for database search. Cancer as MeSH term provided 75,772 hits, hyperthermia as MeSH term gave 6438 hits. The combination of these two provided 1654 hits. Hereafter, non-interventional studies, studies which did not concern HT nor cancer treatment were excluded manually. Eventually, 235 studies were included, which were classified into five types based on the HT used: HIPEC (n ¼ 123), Regional HT (n ¼ 44), Local HT (n ¼ 45), WBHT (n ¼ 15) and unknown (n ¼ 8). The search strategy and exclusion of trials are summarized in Figure 1. Later, included trials were characterized by location, enrollment, type of hyperthermic intervention (e.g., local, regional or WBHT), temperature, duration and frequency of the HT administered.

General characteristics of the clinical trials
After initial evaluation, we included 235 studies on HT. Of these 235 studies, 123 described the use of HIPEC (52.3%), 44 other types of regional HT (18.7%), 45

Evolution of hyperthermia studies
As illustrated in Figure 2, a large increase of HIPEC studies can be observed since 2010. Prior to 2010, 15 studies were found. After 2010, 108 new studies were published on HIPEC, an increase of 720%. Since 2014, a smaller increase in local and regional HT studies can be seen. WBHT is the least researched type of HT. Up until now, only 15 studies could be identified on ClinicalTrials.gov.

Use of hyperthermia treatment in different types of cancer
HIPEC is the most frequently analyzed type of HT for gastrointestinal tumors (n ¼ 68), especially gastric and colorectal tumors ( Figure 3). In addition, HIPEC is also the most used technique for gynecological cancers especially ovarian and fallopian tube malignancies. Local and regional HT (n ¼ 12, n ¼ 10, respectively) are used for other types of gastro-intestinal cancer like pancreatic and liver tumors. Tumors in the urological and respiratory tracts are most often treated with regional hyperthermic techniques. For malignancies in these locations, special techniques have been developed (e.g., HITOC-technique) for the respiratory tract and the intravesical hyperthermic chemotherapy for bladder cancer. Local HT techniques can be administered almost anywhere in the body. New types of local HT have been described in a wide arrange of organ systems. WBHT is used for advanced malignancies. Although it is used to treat a variety of tumor types, gynecological, respiratory and pancreatic malignancies have been investigated the most profoundly.

Location of hyperthermia treatment studies
Trials investigating HT-related cancer treatment are predominantly performed in the US, China and Europe (Table 2A). In Europe, most studies are done in western Europe, especially Belgium, the Netherlands, France, Italy and Germany (Table 2B).

Efficacy in hyperthermia treatment studies
Results from twelve phase III studies included in our analysis were identified. Six from the local-regional HT category and six including HIPEC. Five out of six local-regional HT studies showed increased overall survival (OS) and/or complete response for adding HT to standard chemo-and/or  radiotherapy (Table 3A). In the HIPEC category four out of six showed increased OS for the addition of HIPEC to standard of care treatment (Table 3B).

Discussion
Within this review, we aimed to provide an update for clinical research on the anticancer effect of HT. By analyzing 235 trials on ClinicalTrials.gov, we constructed a database to extrapolate trends that could explain the evolution of the HT research field. Our main findings include: 1) there are an expanding number of clinical trials on oncological HT and 2) HIPEC is by far the most researched and developed technique within the HT field. It is remarkable that more than half of studies included were focused on HIPEC. Although this technique was already discovered in the 80 s, a steady increase in research to HIPEC can be observed in the last decade. HIPEC is currently already being used in the clinical setting. For instance, HIPEC can be considered a standardized treatment option after neoadjuvant chemotherapy and interval CRS for Stage 3 primary epithelial ovarian cancer, Fallopian tube cancer or primary peritoneal carcinoma. In other oncological patients, there is insufficient evidence to consider HIPEC as a treatment modality, however in case of primary malignant mesothelioma or disseminated mucinous neoplasms, patients should be assessed by a HIPEC specialty center to determine whether they can receive HIPEC in a clinical trial setting [40]. The additive effect of HIPEC compared to normothermic intraperitoneal chemotherapy is still unclear and is currently being investigated in the HyNOVA trial [41].
For other oncological patients, there is insufficient or even negative evidence for HIPEC as a treatment. Qu enet et al. [36] demonstrated there was no additive effect of HIPEC for the treatment of peritoneal metastasis in patients with colon cancer. HIPEC research is more advanced compared to other HT modalities, with more Phase 3 trials than other modalities. Most of these advanced HIPEC research is performed in China, due to a high prevalence of gastric cancer there probably due to the consumption of very hot tea [42,43]. In recent years, an increase interest to local and regional hyperthermia it has also been observed. Both account for approximately 20% of HT research. Regional HT is most often used for bladder and lung cancer due to development of the HIVEC [44] and HITOC techniques. HIVEC trials have proven that the technique is safe and indicate an improved outcome, but more research is needed [45] in order to establish clear outcomes and indications. HITOC can be used in specific oncological settings. In Germany, recommendations for this technique have been described [46]. Indications for HITOC include malignant pleural mesothelioma, pleural dissemination of thymic tumors and specific cases of pleural carcinosis. The first clinical trials show promising results. For these two techniques, more research is being conducted in order to establish clear evidence of their efficacy.
Only a few studies on WBHT (n ¼ 15) could be identified. Novel WBHT techniques for cancer treatment have been explored in recent years. More elaborate trials are needed to be conducted to be able to conclude the effectiveness and safety of WBHT for cancer treatment.
Nearly all HT research has been done in North America, Europe, and China. China primarily focuses on HIPEC for its appliance in GI malignancies. Most of clinical research in WBHT has been conducted in North America and Europe. Both regions have also focused more on development of novel technologies European research is for a large part driven by certain institutions like UNICANCER [47] in France and the University of Erlangen-N€ urnberg in Germany [48]. Because of these specific institutions or research groups a lot of European research is concentrated in certain countries like France, Italy, Belgium, The Netherlands and Germany.
The research on HT is different in comparison to classical drug research. Research to medical devices requires a smaller enrollment. Furthermore, this research does not follow the phases of classical drug discovery methods. Therefore, research to HT which relies most often on medical devices, could experience a rapid growth in a few years.

Conclusion
HT covers a lot of techniques and technologies. Recently, the research to HT in the oncological setting has increased exponentially. The grade of research done to these techniques differs considerably with HIPEC as the most researched technique. In general, although many studies show an increased therapeutic effect of HT and in some cases these techniques already can be used in the clinical setting, more advanced research needs to be done in this field. Especially more novel technologies, like for example HIVEC, HITOC and WBHT, need to be investigated more in order to establish the therapeutic effect of these techniques.

Disclosure statement
At the time of writing, all the authors were associated with the company ElmediX, which is actively developing a whole-body hyperthermia device.

Funding
The author(s) reported there is no funding associated with the work featured in this article.