Commentary on "Systematic review about complementary medical hyperthermia in oncology" by Liebl et al.

We read the recent article by Liebl et al. [1]. Unfortunately, several important critical points should be brought to the readers' attention. A variety of hyperthermia methods exist and each has fundamental differences in actions and effects. The authors discuss "complementary hyperthermia" and discriminately include only electrohyperthermia and whole-body hyperthermia (WBH) in this category. This is despite the appropriate definitions for methods of heating used in the field of oncologic hyperthermia having been described [2]. The selection of articles is not inclusive leading to a biased interpretation of the results. There are several positive phase III trials for capacitive hyperthermia (see Table 1), underscoring the authors' incorrect assessment of hyperthermia techniques. Our major points are:


The article only evaluates WBH and capacitive
coupled hyperthermia, and this selection does not meet the criteria for a "systematic review." Many applications (such as phased-array, RF radiative heating, nano-heating, and Japanese capacitive hyperthermia) are also techniques employed in the field of complimentary hyperthermia but have been systematically neglected. 2. Contrary to the title of the text of the article; a. The selection method described in the text is misleading for the readers: "… we have included in this review only hyperthermia methods that do not belong to conventional medicine and titled these alternative methods." Hyperthermia methods are mostly applied when other treatments alone do not provide satisfactory results. Hyperthermia is a complementary treatment, employed to compliment or enhance the efficacy of conventional therapies. Hyperthermia is not an alternative treatment 1 3 b. The referred methods have medically accepted and significant Phase III trial results, yet the authors claim that these "do not belong to conventional medicine." What is the definition of conventional medicine, according to the authors, and on what basis can they make such a claim when these results have been accepted in peerreviewed journals? a. "…125 studies did not use alternative hyperthermia". But all selected hyperthermia applications in the article are complementary to "conventional" (chemotherapy/radiotherapy) medicine and are not an alternative to "conventional" medicine. b. "…43 studies, multiple interventions were administered simultaneously." But almost all hyperthermia techniques, including those in the article, are applied complementary to other treatments and are therefore applied simultaneously with other therapies (mostly with chemotherapy). c. "…assessment of hyperthermia was not possible." Authors do not define how they measured the criteria of "assessment" in the selection.
5. The tables in the article combine the WBH and the local EH results. However, these techniques are fundamentally different, in their methods, indications, safety limits, and physiological actions, and can therefore not be compared directly or be discussed using the same criteria for evaluation. 6. Some statements lack the full information from the article that is referenced and this provides a negative or biased view. For example, when referring to the study on brain tumors by Fiorentini et al., the following statement is made: "Adverse events caused by EH in the RCT by Fiorentini et al.

{56} included headache, scalp burn and seizures. More than an hour after treatment, seizures occurred in 4 additional patients."
The authors fail to mention that the study is on brain tumors, and that indeed tumors themselves cause seizures and headaches and that it is not possible to confirm that the adverse events are from the hyperthermia treatments and not from the advanced stage of disease or the concurrent treatments. 7. The authors claim that only the adverse effects of the studies with multiple interventions are reported due to the difficulty in confirming the benefit of the hyperthermia when multiple interventions are administered. The same should therefore be true of the adverse events and toxicity. This is selective reporting of the negative effects of 43 trials without considering the benefits. 8 a. What is the difference between the "single-arm" and the "cohort study"? The single-arm study must also use a cohort; otherwise, it is only a case series. b. Authors should provide a better explanation for the difference between the "multiple intervention" category (Table 7) and the other categories (for example, the radio-chemo-thermo categories), in previous tables. c. The scoring system in Table 3  When considering the criticisms of individual studies, it is clear that the authors have either not understood the methodology of the studies. Unfortunately, this comes across as an attempt to discredit some studies by using only selective information. The interpretation and discussion should be reviewed and reassessed in order to prevent what could be perceived to be a biased interpretation of the results. For example, regarding the phase 3 clinical studies by Minnaar et al., the following statements are made, and when reviewing the articles, the answers to all of these questions can be found: 1. "No data on the target temperature in the tumor field are reported." The reason for the lack of temperature measurement and the dosing methods is discussed in detail {52}. 2. "In these studies, many calculations are performed.
However, in the exact comparison of the intervention and control group regarding the therapy, these data are missing. Therefore, it is not possible to accurately compare the treatments between the two arms with and without hyperthermia." There are numerous exact comparisons between the active (hyperthermia) and control arms. In fact, the objective of all three papers is to compare the hyperthermia arm to the non-hyperthermia arm, and therefore, all of the calculations are direct comparisons, including frequency tables with chi-squared and Fischer exact tests, multivariate regression analyses, and paired and unpaired t-tests evaluating local disease control, disease-free survival, toxicity, and quality of life between the two groups. All calculations are described in the methodology, reported in results and discussed in the discussion. 3. "In addition, information about prior treatments is not specified and a description of possible additional co-interventions is missing." Prior treatment to cervical cancer is an exclusion, and the investigation is into the primary management of locally advanced cervical cancer, there are therefore no related prior treatments to specify. Additionally, there are no co-interventions, and the prescribed treatments are described in detail and include only radiotherapy, brachytherapy and cisplatin -the standard of care recognized internationally. There are no other standard/accepted interventions for locally advanced cervical cancer. This statement is therefore redundant. The systemic review and the conclusions derived by the authors are flawed due to (a) methodological errors in selection and interpretation of papers (b) incorrect interpretation of the technology for hyperthermia delivery and (c) excluding key articles from their systematic review as detailed above. These could result in the erroneous view of hyperthermia to the readers, thereby depriving patients of a multifaceted therapeutic modality that has been shown to be effective when used with radiotherapy and/or chemotherapy for a wide range of malignancies.
Acknowledgments Critical reading and remarks of our consultation partners, Prof. Stephan Bodis (Department Radiation Oncology, University Hospital Zurich, Medical Faculty University Zurich; ITIS Foundation Board Member, Switzerland) and Prof. Niloy Datta (Department of Radiotherapy, Mahatma Gandhi Institute of Medical Sciences, Sevagram, India), are highly appreciated. These researchers have recognition awards from the European Society of Hyperthermic Oncology. Their broad expertise in hyperthermia substantially helped our work.

Authors contribution
The consensus of the authors followed intensive discussions and all authors participated equally in the formulation and drafting of this letter. The authors are renowned experts in hyperthermia research (The sequence of their names is in alphabetic order): Prof. E.A is a Radiation oncologist; awarded internationally for her acknowledgments in radiation oncology; Hyperthermia Professor at University San Antonio of Murcia in Spain; responsible of hyperthermia's department of University Hospital Marqués de Valdecilla in Spain. Dr. G.F is an expert in locoregional treatments such as intra-arterial chemotherapy and clinical hyperthermia; Active clinical research on hyperthermia for more than 25 years. Prof. P.G is a Radiation oncologist, head of Charité hyperthermia center, clinical scientist. Dr. C.M is an expert in the use of modulated electro-hyperthermia, principle investigator of a phase III randomized controlled trial on mEHT, with international recognition and awards. Dr. A.M.S is a Head of science at cancer center of Semmelweis University, translational and clinical scientist with an expertise in modulated electro-hyperthermic treatments and responsible for the ongoing randomized, prospective, open-label clinical trial in breast cancer. Author of 120 + publications including deep analyses of efficiency of medical approaches utilized in a concomitant manner. Prof. A.S is a developer of modulated electrohyperthermia, scientific director of Oncotherm Kft/GmbH, Hungary/Germany.
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