Electromagnetic hyperthermia remains experimental treatment after 40 years of research and application in view of its “temperature concept” based on the belief that temperature is the only parameter of the efficacy. Initial “extreme hyperthermia” concept was based on the wrong premise of much higher thermal susceptibility of malignant cells and broad therapeutic range of hyperthermia, allowing to kill tumor cells by above-threshold (>43°C) temperature without damaging healthy tissues. Indeed, this therapeutic gap is minor or absent which makes the extreme hyperthermia impossible. The next concept of “thermal dose” was based on the ungrounded extrapolation of the biochemical Arrhenius relationship onto the living matter and formed the basis of “moderate hyperthermia” concept, believing that it could enhance tumor oxygenation and radio- and chemosensitivity, ignoring the special features of tumor blood flow. Both concepts have not been confirmed; “thermal dose” is currently proven to be not connected with any clinical outcome. Analysis of randomized trials with respect to biases has not confirmed hyperthermia efficacy. The growing evidence of athermal effects and their broad application has caused development of some athermal cancer treatments. Hyperthermia concept should be cardinally reevaluated now with respect to obvious bankruptcy of the temperature concept and development of the athermal concept.

ObjectiveTo assess the efficacy and cost-effectiveness of modulated electrohyperthermia (mEHT) concurrent to dose-dense temozolomide (ddTMZ) 21/28 days regimen versus ddTMZ 21/28 days alone in patients with recurrent glioblastoma (GBM).DesignA cohort of 54 patients with recurrent GBM treated with ddTMZ+mEHT in 2000–2005 was systematically retrospectively compared with five pooled ddTMZ 21/28 days cohorts (114 patients) enrolled in 2008–2013.ResultsThe ddTMZ+mEHT cohort had a not significantly improved mean survival time (mST) versus the comparator (p=0.531) after a significantly less mean number of cycles (1.56 vs 3.98, p<0.001). Effect-to-treatment analysis (ETA) suggests that mEHT significantly enhances the efficacy of the ddTMZ 21/28 days regimen (p=0.011), with significantly less toxicity (no grade III–IV toxicity vs 45%–92%, p<0.0001). An estimated maximal attainable median survival time is 10.10 months (9.10–11.10). Cost-effectiveness analysis suggests that, unlike ddTMZ 21/28 days alone, ddTMZ+mEHT is cost-effective versus the applicable cost-effectiveness thresholds €US$25 000–50 000/quality-adjusted life year (QALY). Budget impact analysis suggests a significant saving of €8 577 947/$11 201 761 with 29.1–38.5 QALY gained per 1000 patients per year. Cost-benefit analysis suggests that mEHT is profitable and will generate revenues between €3 124 574 and $6 458 400, with a total economic effect (saving+revenues) of €5 700 034 to $8 237 432 per mEHT device over an 8-year period.ConclusionsOur ETA suggests that mEHT significantly improves survival of patients receiving the ddTMZ 21/28 days regimen. Economic evaluation suggests that ddTMZ+mEHT is cost-effective, budget-saving and profitable. After confirmation of the results, mEHT could be recommended for the treatment of recurrent GBM as a cost-effective enhancer of ddTMZ regimens, and, probably, of the regular 5/28 days regimen. mEHT is applicable also as a single treatment if chemotherapy is impossible, and as a salvage treatment after the failure of chemotherapy.

Hyperthermia in oncology still remains an experimental treatment with no realistic future in clinical cancer therapy, though declaration of the undisputed efficacy of hyperthermia is a common place in every hyperthermia paper. We have studied the available randomized trials on hyperthermia from the position of "null hypothesis" to confirm or refuse the efficacy and safety of clinical hyperthermia, taking into account also the possible biases. Unfortunately, careful analysis of 14 randomized clinical trials has not confirmed a clinical benefit of hyperthermia independently of its type: superficial, deep or whole-body. We have not found any positive trial not affected with biases. With correction to the distortions, there is no trial with obvious long-term positive effect of hyperthermia. Effect of hyperthermia could be shown in experimentally designed clinical trial or versus inadequate comparator. In clinical setting and provided that study design is correct, hyperthermia is not effective at all or not effective enough to justify its obvious disadvantages: toxicity and labor intensity. Thermal concept of hyperthermia seems to be irrelevant. Nevertheless, multiple publications of positive trials, reviews, and meta-analyses create an impression of hyperthermia renaissance.

Abstract. The purpose of this study was to develop a safe and non-toxic alternative to the conventional conservative treatment of peritoneal carcinomatosis with malignant ascites (PCMA) by investigating the efficacy and safety of local modulated electro-hyperthermia (mEHT) combined with the traditional Chinese medicine (TCM) 'Shi Pi' herbal decoction, compared with standard intraperitoneal chemoinfusion (IPCI). A randomized, controlled, single-center, open-label clinical trial (phase II) with two parallel groups (allocation ratio, 1:1) was conducted to investigate the efficacy and safety of mEHT+TCM (study group, SG) vs. standard IPCI (control group, CG) in patients with PCMA by intention-to-treat analysis. A total of 260 patients with PCMA were randomly allocated into the two groups (130/130); mEHT was applied for 60 min per session every second day for 4 weeks, for a total of 14 sessions. The TCM decoction was administered orally, at 400 ml daily. In CG, occlusive IPCI with cisplatin (30-60 mg) and fluorouracil (500-600 mg/m 2 ) was applied twice, biweekly. The objective response rate (ORR), quality of life (QoL) and adverse event rate (AER) in the two groups were evaluated 1 month after treatment, analyzed and compared. The present study is registered on ClinicalTrials.gov (NCT02638051). No case was lost or excluded (0/260). The ORR in SG was 77.69% (101/130) vs. 63.85% (73/130) in CG (P<0.05). The QoL in SG was 49.23% vs. 32.3% in CG (P<0.05). The AER in SG was 2.3% (3/130) vs. 12.3% (16/130) in CG (P<0.05). All the adverse events were grade I. In conclusion, the combination of mEHT with TCM achieves better control of PCMA compared with standard IPCI, with less toxicity. Both components of the combination are non-toxic treatments easily tolerated by patients. Thus, this combined treatment may be preferred due to the better benefit-harm balance.

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