Locoregional Hyperthermia in Cancer Treatment: A Narrative Review with Updates and Perspectives

Simple Summary

The significance and utility of locoregional hyperthermia (RHT) in active oncological and palliative treatments has been debated for decades in medical literature. However, articles consistently report the efficacy and feasibility of hyperthermia (HT) in terms of cancer control and regression and longer survival. Despite these results, HT has never been considered truly useful by most radiation and medical oncologists. Due to this disinterest and unfamiliarity, it has not become a widespread therapy in institutions treating cancer.

Abstract

The applicability of RHT in the treatment and supportive care of tumors has been discussed for years in many publications. There are hundreds of articles that have reported on the good acceptance and feasibility of HT, as well as its value in terms of controlling malignant diseases, enhancing response and, in some randomized controlled trials (RCTs), clear improvements in OS. Despite this, HT has never fully been accepted as a standard treatment among radiation and medical oncologists. The increased activity that HT offers in the context of chemotherapy (CHT), radiotherapy (RT), chemoradiotherapy (CRT), and immunotherapy, thus facilitating programmed cell death (PCD), has been documented in many studies. This aspect has been demonstrated in many tumors, including soft tissue sarcoma, cancers of the cervix, esophagus, stomach, colon/rectum, pancreas, breast, head and neck, and prostate, and bone metastases. HT improves cancer cell death through many modalities, targeting both the tumor microenvironment (TME) and the cancer cells directly. Targeted HT increases the temperature of the primary tumor and surrounding tissues to 39–43 °C, causing the tumor cells to become more immune-responsive. HT can also activate the immune response of the TME through inducing heat shock proteins (HSPs), which also promote an immunological response and PCD. HT can oxygenate hypoxic tumors, facilitating RT-induced DNA damage in cancer cells. At present, it seems that the combination of HT and RT, CHT, and immunotherapy might lead to immune enhancement effects in the TME, making cancer cells more responsive to immunotherapies. This narrative review presents the novel aspects of HT reported in recent years.

1. Introduction

Hyperthermia (HT) is based on the administration of heat to selected organs or body sites, thus enhancing the therapeutic efficiency of cancer therapy. Many heating techniques exist, including infrared, ultrasound, nanoparticles, laser and radiofrequency ablation, whole-body hyperthermia, intracavitary (peritoneal, pleural, and urinary bladder cavities), limb perfusion, capacitive, and radiative hyperthermia [1]. Mild HT is defined as that using a temperature range of 39–43 °C [2,3,4]. RHT techniques adopt a radiative or capacitive method [2,3,4], in which applicators are positioned externally over a defined part of the body. Non-ionizing electromagnetic microwaves, adopting various types of radio-frequencies (RFs), are oriented with respect to the tumor area. In the site of interest, the energy is then released and transformed into heat. With the birth of oncological hyperthermia, the need to establish the temperature obtained in the tumor emerged. The first study on definition and monitoring of temperature was performed by Sapareto [5]. This author proposed a thermal iso-effective dose to convert one-time temperature combination to a standard level, an equivalent number of minutes at 43 °C (CEM43°C). A few years later, this formula was further modified by Dewey to CEM43°C T90 to define the cumulative number of equivalent minutes at 43 °C exceeded by 90% of the temperature points within the treated part of the body that is affected by a tumor [6,7,8].

The guideline of the European Society for Hyperthermic Oncology (ESHO) for the application of superficial HT, which is simpler to define with respect to deep HT, has therefore recommended that temperatures achieved in 10, 50, and 90% of measured temperature points should be reported as T10, T50, and T90 and the thermal dose as CEM43°C T10, CEM43°C T50, and CEM43°C T90, respectively [9,10,11,12,13]. In addition, the guideline suggests aiming for a T90 exceeding 40 °C and T50 more than 41 °C [9,10,11,12]. The application of this recommended thermal dose reporting can ensure the quality in the delivery and evaluation of HT treatment in all centers that practice regional HT, allowing scientifically and statistically better uniform results.

Adequate temperature monitoring during HT may significantly improve clinical outcomes, since the amount of thermal damage depends on the tissue temperature and the exposure time [11,12], and many authors have reported that consideration of a dose–effect relationship is necessary [13,14].

Thermometric techniques can be classified as either contact-based or contactless methods. Contact-based techniques involve the insertion of the sensing element within the treated tissue. This category includes thermocouples, thermistors, and fluoroptic sensors. Contactless techniques do not require direct contact with the measurement site. This category comprises diagnostic imaging techniques such as magnetic resonance imaging, computed tomography, and ultrasound thermometry.

From a practical point of view, physicians calculate heating diffusion and tumor temperatures, either directly using positioned thermo-probes or through calculation. Computers connected to hyperthermia machines utilize programs that calculate and convert the Kilojoules provided by the device into degrees centigrade of heat at the treatment target. This is visible on computer monitors and can be printed to be placed as a treatment file in a patient’s record. A real increase in temperature is necessary to obtain clinical results. Another type of HT, modulated electro-hyperthermia (mEHT), adopts uneven heating and presumably selectively affects cancer cells. This should lead to the destructuring of malignant cell membranes and is a method that has recently begun to spread [2]. In recent years, a better understanding of thermal physiology, new technological advances, and new clinical experiences and protocols have evidenced the utility of HT. Despite this evidence, hyperthermia remains poorly known and is not widespread among doctors who treat cancer. In this review, we report on the most significant clinical results (in our opinion) that have appeared in the recent literature, thus offering doctors who are not familiar with HT updated evidence regarding the applications of HT—either alone or in combination with chemotherapy and radiotherapy—as more active anticancer therapies.

2. Materials and Methods

A wide literature analysis was carried out using PubMed. The retrieved papers included those focused on regional hyperthermia, mild hyperthermia, adjunctive hyperthermia, and palliative hyperthermia. Only articles written in English referring to well-reported observational phase II and prospective III studies, systematic reviews, and meta-analyses were considered, which were published mainly between 2020 and 2025. We considered for inclusion all clinical studies that reported survival data, tumor response, or safety after the treatment of cancer with HTA from January 2020 to March 2025; survival was considered using survival rates, the number of deaths, or survival curves. The literature search, screening of studies eligibility, data extraction, and database completion were performed independently by two investigators (G.F and D.S), and any discrepancies were resolved by consensus and, if necessary, by the opinion of a third reviewer (A.M.). Data were represented in tables and a narrative synthesis was made in text. No automation tool was used during the literature search. All the selected studies were performed with devices for radiative hyperthermia, and the studies that used other devices were specified and reported the method as mEHT in cervical and pancreatic tumors and ultrasound hyperthermia in head and neck tumors. Studies on whole-body hyperthermia were also included, because even if whole body hyperthermia was not a method referable to regional hyperthermia, we wanted to include this information for further clarification and completeness. We did not include studies on HIPEC, because even if HIPEC used hyperthermia, it remained a method exclusively of the surgical branch.

3. Results

3.1. Soft Tissue Sarcoma (STS)

Studies on STS are of value for the accuracy and clarity of results, and this has allowed the inclusion of HT in NCCN and ESMO guidelines for the treatment of STS as adjunctive treatment. STSs have several histopathological subtypes and leiomyosarcoma (LMS) is among the most represented (10–20%). Patients with LMS and high-risk characteristics (G2/G3; size ≥ 5 cm; infiltrating the fascia) have a poor prognosis. Patients with locally advanced high-grade LMS, including limited metastases, were treated with Doxorubicin plus Dacarbazine (AD) + RHT or Doxorubicin plus Ifosfamide (AI) + RT. They had a 2-year OS of 84.5% (95% CI: 77.2–92.3%) and 2-year PFS of 50.3% (95% CI: 41.0–61.7%). No difference was observed in the two groups concerning the 2-year OS (88.7% with 95% CI of 81.2–97.6% for AI versus 73.9% with 95% CI of 58.3–93.6% for AD; p = 0.21). A significantly improved PFS (HR: 0.32; 95% CI: 0.13–0.74; p = 0.0081) was observed after the treatment with AD + RHT [15] (

Table 1. Soft tissue sarcoma.

Author	Type of Study	Type of Tumor	N of Patients	Type of Treatment	Outcome	HT-Associated Adverse Events
Berclaz 2025 [15]	Retrospective observational cohort study	Locally advanced high-grade LMS, including limited metastases	105	CHT with Doxorubicin and Dacarbazine + HT Versus Doxorubicin and Ifosfamide + HT	Doxorubicin and Dacarbazine + HT had improved PFS (HR: 0.32; 95% CI: 0.13–0.74; p = 0.0081)	None
Potkrajcic 2025 [16]	Retrospective observational cohort study	Myxoid liposarcoma (MLPS)	7	Neoadjuvant RT + HT	85.7% of patients had significant tumor volume shrinkage (≥25%), no local recurrences, and no distant metastases during follow-up.	None
Willner 2023 [17]	Retrospective observational cohort study	Soft tissue sarcomas	101	Neoadjuvant CRT Versus CRT + HT	CRT + HT improved remission and regression (90% vs. 22%). At 6 years, local control and overall survival rates for CRT + HT vs. CRT were 85 vs. 78% (p = 0.938) and 79 vs. 71% (p = 0.215).	Major wound complications occurred in 15% (CRT) vs. 25% (CRT + HT) of cases (p = 0.19).
Willner 2021 [18]	Retrospective observational cohort study	Retroperitoneal sarcomas (RPSs)	27	Neoadjuvant CRT Versus CRT + HT	There was no difference in distant metastatic and abdominal PFS between patients with and without hyperthermia treatment.	None

RT = radiotherapy; HT = hyperthermia; PFS = progression-free survival; HR = hazard ratio; CHT = chemotherapy; CRT = chemoradiotherapy.

).

Liposarcomas are the second most common STS, representing 15–20% of all STSs. myxoid liposarcoma (MLPS) accounts for 30% of all the different types of liposarcoma. Neoadjuvant hyperthermia in addition to preoperative radiotherapy (n = 7) resulted in 85.7% of patients having a significant tumor volume shrinkage (≥25%), no local recurrences, and no distant metastases during follow-up [16]. Neoadjuvant hyperthermia + CRT improved the remission of patients with high- or intermediate-grade STS or isolated local recurrences of STS compared to those with CRT alone, concerning the following: regression (90% vs. 22%; p = 0.197), local control (85 vs. 78%; p = 0.938), OS rates (79 vs. 71%; p = 0.215), and major wound complications (25% vs. 15%; p = 0.19) [17].

Retroperitoneal sarcomas (RPSs) have poor local and abdominal tumor control. A study on 27 patients with RPS treated with CRT + HT vs. CRT showed that there was no difference in distant metastatic and abdominal PFS between patients with and without hyperthermia treatment [18].

To understand these interesting results, an immunological study was carried out on the TMEs present in the removed lesions. Immune cells in the tissue samples before and after up-front treatment were evaluated in 109 patients. The presence of a high number of lymphocytes infiltrating sarcomas was related to higher LPFS. Significant relationships between high CD8 or TIL T cell counts and tumor regression were observed for patients treated with HT (p = 0.02) but were not present in patients who had not received HT. It can be hypothesized that HT elicited a reaction in the TMEs, likely allowing for greater immune reactivity against aggressive high-risk sarcomas [19].

3.2. Cervical Cancer

Treatment options in locally advanced cervix cancer (LACC) have evolved around RT, CT, CRT, and HT. Several important scientific contributions have been published regarding the temperature and thermal dose, time interval between radiation and HT, and thermal dose as a predictor of local control [20,21,22,23,24,25]. Datta reported another review to highlight the efficacy and safety of HT in terms of LRC, OS, and grade ≥ 3 acute toxicity (AT) and a late toxicity (LT) of 30 (Table 2). A total of 59 randomized trials focused on untreated LACC were shortlisted. Of the 9894 patients evaluated, the total events reported for LRC, OS, AT, and LT were 5431 of 8197, 4482 of 7958, 1710 of 7183, and 441 of 6333, respectively. The three interventions with the highest values for all four endpoints were HT-RT, HT-CRT, and CRT (with cisplatin given every 3 weeks). The three more effective modalities of therapy for LRC after long follow-up were HT + RT, CRT + adjuvant chemotherapy, and HT + CRT. The best three types of therapy to improve overall survival were CRT (with cisplatin given every 3 weeks), HT + CRT, and CRT with other types of chemotherapy. The preferred combinations for all parameters (i.e., overall survival, LRC, AT, and LT grade ≥3 morbidity) were HT + RT, HT + CRT, and CRT (with cisplatin administered every 3 weeks) [23]. Yea recently carried out a systematic review and meta-analysis on 536 patients (CRT with HT group: 268; CRT group: 268). The CRT with HT group had significantly better five-year OS than the CRT group did (HR: 0.67; 95% confidence interval [CI]: 0.47–0.96; p = 0.03). The LRFS of patients was superior in the CRT with HT group compared to in the CRT group, but without significance (HR: 0.74; 95% CI: 0.49–1.12; p = 0.16) without increasing acute and chronic toxicity [24]. Wang reported on 373 patients by per-protocol (PP) analysis. The 5-year OS in the RCT plus HT group (81.9%) was better than that in the RCT group (72.3%), and the log-rank test showed a statistically significant difference between the two groups (p = 0.040). Univariate and multivariate Cox regression analysis for 5-year OS showed a statistically significant difference (p = 0.043 and p = 0.045, respectively). The 5-year local relapse-free survival with RCT plus HT (86.8%) was also better than that with RCT (82.7%), but the difference was not significant. Acute or late toxicity was not significantly different between the two groups [25].

A randomized controlled trial that compared CRT plus mEHT vs. CRT for two hundred and ten women was published. At a follow-up of six months, the odds ratios (ORs) to reach LDC and LRFS were 0.39 (p = 0.006) and 0.36 (p = 0.002) and significant with an advantage for patients treated with mEHT + CTRT. Two- and three-year disease-free survival was increased when performing mEHT (HR of 0.67 with p = 0.017 and HR of 0.70 with p = 0.035, respectively). However, 3-year OS was not clearly increased (HR: 0.72; p = 0.74), except for those with stage III disease (HR: 0.62; p = 0.040) [26]. Note that 16.2% of patients who received mEHT reported acute toxicity (grade 1–2) and adverse events such as local pain, skin burns, and adipose and tissue reactions, from which they recovered after 12 weeks. There was no severe toxicity (grade ≥ 3) observed. Promptly, after six weeks, the mEHT subset presented improved QoL scores and reduced fatigue and pain levels. At two years, in the mEHT group, all the parameters of quality of life referring to the presence of pain and cognitive function were statistically improved. The economic analysis showed a benefit for patients who received mEHT + CRT. This combination is superior to CRT, reducing the cost of hospitalization and subsequent care required for recurrences or disease progression [27]. Noteworthy, in 108 women who received PET scans before and at 6 months after therapy, a complete response was observed in the initial PET positivity lymphatic nodes outside the area of treatment (24.1% vs. 5.6%; p = 0.013), assuming an improvement in the abscopal effect with mEHT [28]. Recently, Lee presented the clinical validation of mEHT in LACC other types of tumors [29].

Table 2. Cervical cancer.

Author	Type of Study	Type of Tumor	N of Patients	Type of Treatment	Outcome	HT-Associated Adverse Events
Wang 2020 [25]	Randomized clinical trial	Stage IB-IV FIGO cervical cancer	373	CRT vs. CRT + mEHT	Five-year OS was improved in the CRT + mEHT group (81.9%) compared to that in CRT group (72.3%; p = 0.04). This was confirmed by univariate and multivariate Cox regression analysis (p = 0.043 and p = 0.045, respectively). The 5-year local relapse-free survival was longer with CRT + mEHT (86.8%) than that with CRT (82.7%), but the difference was not significant.	Similar toxicity in the two groups
Minnaar 2022 [26]	Randomized clinical trial	Stages IIB to IIIB squamous cell carcinoma of the cervix; HIV-positive patients	210	CRT vs. CRT + mEHT	At a follow-up of six months, the odds ratios (ORs) to reach LDC and LRFS were 0.39 (p = 0.006) and 0.36 (p = 0.002) and significant with an advantage for patients treated with mEHT + CTRT. Two- and three-year disease-free survival was increased when performing mEHT (HR of 0.67 with p = 0.017 and HR of 0.70 with p = 0.035, respectively).	16.2% of adverse events (grade 1–2): local pain, skin burns, and adipose and tissue reactions
Servayge 2024 [30]	Retrospective observational cohort study	Locally advanced cervical cancer, stage IB2 and IIA2 to IVA	370	CRT vs. CRT + lymph node debulking CRT + lymph node debulking + HT	Five-year OS was comparable between the three treatment groups, with 53% (95% CI: 46–59%) in the CRT group, 45% (33–56%) in the CRT + lymph node debulking group, and 53% (40–64%) in the CRT + HT group (p = 0.472).	None
Gao 2022 [31]	Retrospective observational cohort study	Advanced cervical cancer	105	CRT + HT	Five-year overall survival was 58% (95% CI: 47.8–68.6) and eighty-six patients (82%) had a complete response after completing therapy.

HT = hyperthermia; HR = hazard ratio; OS = overall survival; CRT = chemoradiotherapy; mEHT = modulated electro-hyperthermia.

Table 2. Cervical cancer.

Author	Type of Study	Type of Tumor	N of Patients	Type of Treatment	Outcome	HT-Associated Adverse Events
Wang 2020 [25]	Randomized clinical trial	Stage IB-IV FIGO cervical cancer	373	CRT vs. CRT + mEHT	Five-year OS was improved in the CRT + mEHT group (81.9%) compared to that in CRT group (72.3%; p = 0.04). This was confirmed by univariate and multivariate Cox regression analysis (p = 0.043 and p = 0.045, respectively). The 5-year local relapse-free survival was longer with CRT + mEHT (86.8%) than that with CRT (82.7%), but the difference was not significant.	Similar toxicity in the two groups
Minnaar 2022 [26]	Randomized clinical trial	Stages IIB to IIIB squamous cell carcinoma of the cervix; HIV-positive patients	210	CRT vs. CRT + mEHT	At a follow-up of six months, the odds ratios (ORs) to reach LDC and LRFS were 0.39 (p = 0.006) and 0.36 (p = 0.002) and significant with an advantage for patients treated with mEHT + CTRT. Two- and three-year disease-free survival was increased when performing mEHT (HR of 0.67 with p = 0.017 and HR of 0.70 with p = 0.035, respectively).	16.2% of adverse events (grade 1–2): local pain, skin burns, and adipose and tissue reactions
Servayge 2024 [30]	Retrospective observational cohort study	Locally advanced cervical cancer, stage IB2 and IIA2 to IVA	370	CRT vs. CRT + lymph node debulking CRT + lymph node debulking + HT	Five-year OS was comparable between the three treatment groups, with 53% (95% CI: 46–59%) in the CRT group, 45% (33–56%) in the CRT + lymph node debulking group, and 53% (40–64%) in the CRT + HT group (p = 0.472).	None
Gao 2022 [31]	Retrospective observational cohort study	Advanced cervical cancer	105	CRT + HT	Five-year overall survival was 58% (95% CI: 47.8–68.6) and eighty-six patients (82%) had a complete response after completing therapy.

HT = hyperthermia; HR = hazard ratio; OS = overall survival; CRT = chemoradiotherapy; mEHT = modulated electro-hyperthermia.

A retrospective study showed that 5-year OS was comparable between the three treatment groups (CRT alone or CRT with lymph node debulking or CRT with HT), with 53% (95% CI 46–59%) in the CRT group, 45% (33–56%) in the CRT + lymphnode debulking group, and 53% (40–64%) in the CRT + HT group (p = 0.472) [30].

A similar result was reported by Gao and colleagues, showing a 5-year overall survival of 58% and complete tumor response in 84% of LACC treated with CRT + HT [31].

3.3. Malignancies of the Head and Neck

Yang performed a phase II study reporting the outcomes of 35 patients with previously irradiated unresectable recurrent head and neck cancer. This study showed that hyperthermia addition to salvage CRT greatly enhanced the tumor response and survival rates of previously irradiated unresectable recurrent head and neck cancer, with manageable toxicities (

Table 3. Malignancies of the head and neck.

Author	Type of Study	Type of Tumor	N of Patients	Type of Treatment	Outcome	HT-Associated Adverse Events
Yang 2025 [32]	Single-arm phase II trial	Non-metastatic recurrent head and neck cancer	35	CRT + HT	ORR was 82.9%, OS was 32.8 months (95% CI, 16.7–48.9), and 2-year OS was 57.1% (95% CI, 40.6–73.6). Median PFS was 14.9 months (95% CI, 5.7–24.1), and 2-year PFS was 34.3% (95% CI, 18.6–50.0).	No definite burn injury occurred
Zheng 2021 [33]	Retrospective observational cohort study	Nasopharyngeal carcinoma (NPC)	239	CRT vs. CRT + WBH	5-year OS rates were 65.2% in the CRT group and 80.3% in the CRT + WBH group (p = 0.027). LRFS (74.7% vs. 87.6%; p = 0.152), DMFS (67.4% vs. 77.9%; p = 0.125) and PFS (53.1% vs. 69.2%; p = 0.115) were similar in the two groups.	None
Ren 2021 [34]	Phase II trial	Locally advanced resectable oral squamous cell carcinoma	120	CHT vs. CHT + HT	HT increased clinical response rate (65.45% vs. 40.0%; p = 0.0088) and DFS (p = 0.0335), but no changes in OS were reported.	Mild-grade side effects were observed in 3.33% of patients
Li 2021 [35]	Retrospective observational cohort study	Advanced oral squamous cell carcinoma	19	CRT + HT	ORR was 68.4%. The median follow-up time was 36 months (8–48 months), and the 2-year overall survival rates were 63.2%.	No serious adverse reactions were observed

HT = hyperthermia; PFS = progression-free survival; ORR = overall response rate; OS = overall survival; CHT = chemotherapy; CRT = chemoradiotherapy; LRFS = locoregional recurrence-free survival; DMFS = distant metastasis-free survival; WBH = whole-body hyperthermia.

). The ORR was 82.9% and the OS was 32.8 months (95% CI, 16.7–48.9) with a 2-year OS of 57.1% (95% CI, 40.6–73.6), whereas the median PFS was 14.9 months (95% CI, 5.7–24.1) with a 2-year PFS of 34.3% (95% CI, 18.6–50.0) [32].

Zheng reported that whole-body hyperthermia (WBH) added to CRT could improve OS of patients with advanced nasopharyngeal carcinoma; in particular, 5-year OS rates were 65.2% in the CRT group and 80.3% in the CRT + WBH group (p = 0.027). LRRFS (74.7% vs. 87.6%; p = 0.152), DMFS (67.4% vs. 77.9%; p = 0.125), and PFS (53.1% vs. 69.2%; p = 0.115) were similar in the two groups [33].

Ren compared the induction of NACT + HT versus NACT alone in 120 patients with advanced resectable oral squamous cell carcinoma (OSCC) [34]. Two cycles of NACT with TPF (docetaxel, cisplatin, and fluorouracil) and HT or two cycles of NACT alone were administered to the patients. The OSCC patients then received accurate resection and complementary radiotherapy. HT increased both complete and partial responses (65.45% vs. 40.0%; p = 0.0088) and increased DFS (p = 0.0335), but no changes in OS were reported. No acute toxicities or an increase in overall morbidity were reported. Mild side effects on the skin associated with HT were observed in 3.33% of patients.

Li showed that ultrasound hyperthermia in association with chemotherapy improved the tumor response and survival of elderly patients with advanced oral squamous cell carcinoma, reporting an ORR of 68.4% and 2-year OS of 63.2% [35].

3.4. Breast Cancer

Tello Valverde treated locoregional recurrent breast cancer with adjuvant RT + HT, showing that LRC increased according to an increase in thermal dose, with a maximum of 94% at 5 years, and the OR of recurrence decreased by 48% (95% CI: 18–84%) [36]. Similar observation was carried out by Bakker [20]. Another study on adjuvant RT + HT reported that this therapy significantly enhanced 5-year tumor control and DFS compared to RT alone in locally advanced breast cancer (

Table 4. Breast cancer.

Author	Type of Study	Type of Tumor	N of Patients	Type of Treatment	Outcome	HT-Associated Adverse Events
Tello Valverde 2025 [36]	Retrospective observational cohort study	Locoregional recurrent breast cancer	112	RT + HT	LRC increased according to the increase in thermal dose, with a maximum of 94% at 5 years, and the OR of recurrence decreased by 48% (95% CI, 18–84%)
Overgaard 2024 [37]	Multicenter randomized trial	Locally advanced breast carcinoma	151	Adjuvant RT vs. RT + HT	The 5-year LRFS was 57%. Univariate analysis showed a significant influence of hyperthermia on LRRFS (RT (68%) versus RT + HT (50%); p = 0.04) and DFS (36% vs. 19%; p = 0.021).	Moderate to severe pain and discomfort in 15% of the treatments
Schouten 2022 [38]	Multicenter randomized phase II trial	Locoregional recurrent breast cancer	49	Adjuvant RT + HT vs. CRT + HT	LRC (91.3% vs. 94.4; p = 0.87), 1-year OS (63.4% vs. 57.4%; p = 0.79) and LRRFS (81.5% vs. 88.1%; p = 0.95) were similar in the two groups.	G3–4 adverse events were similar in the two groups (25% vs. 29%, p = 0.79)
De Colle 2022 [39]	Retrospective observational cohort study	Recurrent, newly diagnosed non-resectable or high risk resected breast cancer	196	RT + HT	LRC at 2, 5, and 10 years was 76.4, 72.8, and 69.5%, respectively. OS at 2, 5, and 10 years was 73.5, 52.3, and 35.5%, respectively. PFS at 2, 5, and 10 years was 55.6, 41, and 33.6%, respectively.	No acute or late toxicities higher than grade 3 were observed
Stoetzer 2021 [40]	Retrospective observational cohort study	Triple-negative primary breast cancer with residual invasive carcinoma after neoadjuvant chemotherapy	53	Adjuvant CHT + HT	DFS at 3 years was 57.5%. In patients with no lymph node involvement at baseline (cN0), DFS (80 vs. 31%; p = 0.001) and OS (93 vs. 70.4%; p = 0.02) were higher than those in initially node-positive (cN+) patients at 3 years.
Nagata 2021 [41]	Retrospective observational cohort study	Locally advanced and/or recurrent breast cancer	10	Adjuvant CH/CRT/OT + HT	Partial response was achieved in 3 patients (30%), disease stability in 3 (30%), and progressive disease in 4 (40%).	None
Loboda 2020 [42]	Retrospective observational cohort study	Locally advanced breast cancer	200	Neoadjuvant CHT vs. CHT + HT	The reduction in the size of the primary tumor (31.24 ± 3.85% vs. 22.95 ± 3.61%; p = 0.034) and 10-year OS (log-rank: p = 0.009) were higher in patients receiving CHT + HT than those in the CHT group.

RT = radiotherapy; HT = hyperthermia; PFS = progression-free survival; OS = overall survival; CHT = chemotherapy; CRT = chemoradiotherapy; LRFS = locoregional recurrence-free survival; OT = hormonal therapy.

). The 5-year LRRFS was 57%. Univariate analysis showed a significant influence of hyperthermia on LRRFS (RT (68%) versus RT + HT (50%); p = 0.04) and DFS (36% vs. 19%; p = 0.021). Concerning safety, there were moderate to severe pain and discomfort in 15% of the treatments. The results substantiate the potential clinical benefit of hyperthermic oncology [37]. The addition of chemotherapy to RT + HT did not improve LRRFS, OS, and LRC in locally advanced breast cancer. LRC (91.3% vs. 94.4%; p = 0.87), 1-year OS (63.4% vs. 57.4%; p = 0.79), and LRRFS (81.5% vs. 88.1%; p = 0.95) were similar in the CRT + HT and RT + HT groups [38].

De Colle reported long-term high local control rates with acceptable safety for patients with recurrent, newly diagnosed non-resectable or resectable breast cancer at high risk of relapse that were treated with RT + HT. LRC was 76.4, 72.8, and 69.5%, OS was 73.5, 52.3, and 35.5%, and PFS was 55.6, 41, and 33.6% at 2, 5, and 10 years, respectively [39].

Adjuvant CHT + HT improved DFS in triple-negative breast cancer patients; in particular, DFS at 3 years was 57.5%. In patients with no lymph node involvement at baseline (cN0), DFS (80 vs. 31%; p = 0.001) and OS (93 vs. 70.4%; p = 0.02) were higher than those in initially node-positive (cN+) patients at 3 years [40]. Nagata and colleagues added mEHT to adjuvant CHT, CRT, or hormonal therapy in locally advanced and/or recurrent breast cancer, showing partial response in three patients (30%), disease stability in 3 (30%), and progressive disease in 4 (40%) [41].

The association of HT + CHT in a neoadjuvant setting increased the reduction in the size of the primary tumor (31.24 ± 3.85% vs. 22.95 ± 3.61%; p = 0.034) and 10-year OS (log-rank: p = 0.009) compared to that in the CHT group in patients with locally advanced breast cancer [42].

3.5. Pancreatic Cancer

Hoheneck showed that palliative CHT vs. CHT + HT resulted in a significant difference in survival curves for hyperthermia therapy (p = 0.003). Median OS for patients receiving CHT (n = 25) was 8.6 months (95% CI, 4.7–15.4), whereas the median OS for early HT (n = 18) was 16.0 months (95% CI, 5.4–22.6) and 23.5 months (95% CI, 15.8–26.4) for late HT (n = 33) [43].

A polycentric retrospective study in patients with stage III and IV pancreatic cancer was recently published, in which 217 patients were included. Of these, 89 patients were treated with mEHT (alone or in combination with CHT), while 128 (59%) received second- or third-line CHT (no-mEHT). The mEHT treatment was applied at a power that was gradually increased from 60 to 150 Watts for a median cure time of 60 min, with antennas located on the upper abdomen. CHT was infused concurrently or within 72 h of mEHT administration (

Table 5. Pancreatic cancer.

Author	Type of Study	Type of Tumor	N of Patients	Type of Treatment	Outcome	HT-Associated Adverse Events
Hohneck 2023 [43]	Retrospective observational cohort study	Advanced pancreatic cancer	142	Palliative CHT vs. CHT + HT	A significant difference in survival curves was found for hyperthermia therapy (p = 0.003); median survival for patients receiving chemotherapy alone (n = 25) was 8.6 months (95% CI, 4.7–15.4) and median survival for early hyperthermia (n = 18) was 16.0 months (95% CI, 5.4–22.6), while late hyperthermia (n = 33) resulted in 23.5 months (95% CI, 15.8–26.4).
Fiorentini 2023 [44]	Retrospective observational cohort study	Locally advanced or metastatic pancreatic cancer (stage III and IV)	217	CHT vs. CHT + mEHT	CHT + mEHT group had a median OS greater than that of the CHT group (20 mo with range of 1.6–24 vs. 9 mo with range of 0.4–56.25; p < 0.001). CHT + had a higher number of partial responses (45% vs. 24%; p = 0.0018) and a lower number of progressions (4% vs. 31%; p < 0.001) than the CHT group did. At a 3-month follow-up,	Mild skin burns in 2.6% of mEHT sessions
Issels 2023 [45]	Multicenter randomized trial	Advanced pancreatic ductal adenocarcinoma	117	CHT vs. CHT + HT	DFS (12.7 vs. 11.2 months; p = 0.394) and OS (33.2 versus 25.2 months; p = 0.099; 5-year survival rates of 28.4% versus 18.7%) were similar in the CHT + HT and CHT groups. Median PFS was significantly longer in the CHT + HT group (15.3 vs. 9.8 months; p = 0.031). Median OS reached 33.2 versus 25.2 months (p = 0.099) with 5-year survival rates of 28.4% versus 18.7%.
Petenyi 2021 [46]	Retrospective observational case–control study	Stage III/IV pancreatic ductal adenocarcinoma	78	CHT vs. CHT + mEHT	mEHT improved OS (one-year OS: 66.7% vs. 41.0%; p= 0.0240) and PFS (1-year PFS: 38.5% vs. 17.9%; p = 0.0455) compared to CHT alone.
Shimomura 2021 [47]	Retrospective observational cohort study	Unresectable locally advanced pancreatic ductal adenocarcinoma	21	CRT + HT	Median overall survival (OS) was 23.6 months. Conversion surgery was performed in 5 patients (23.8%)	Mild skin redness or minor skin complications
Rogers 2021 [48]	Phase II trial	Locally advanced pancreatic cancer	9	CRT + HT	The median OS was 24 months and 1-year overall survival was 100%, while conversion to surgery was 22.2%.	None

HT = hyperthermia; PFS = progression-free survival; OS = overall survival; CHT = chemotherapy; CRT = chemoradiotherapy.

). The subset that received mEHT had a higher median OS than the non-heated subset of patients—with 20 months (range, 1.6–24) vs. 9 months (range, 0.4–56.25)—with significance (p < 0.001). After a three-month clinical control, the mEHT cases showed a better number of PRs (45% vs. 24%; p = 0.0018) and less PD (exactly 4% vs. 31%; p < 0.001) than the no-mEHT cases. Mild local skin pain and G2 blisters in 2.6% of heating sessions were reported [44].

A randomized trial with 117 patients with advanced pancreatic ductal adenocarcinoma showed that DFS (12.7 vs. 11.2 months; p = 0.394) and OS (33.2 versus 25.2 months; p = 0.099; 5-year survival rates of 28.4% versus 18.7%) were similar in the CHT + HT and CHT groups. Median PFS was significantly longer in the CHT + HT group (15.3 vs. 9.8 months; p = 0.031). Median OS reached 33.2 versus 25.2 months (p = 0.099) with 5-year survival rates of 28.4% versus 18.7% [45].

A single center case–control study reported that mEHT improved OS (one-year OS 66.7% vs. 41.0%; p = 0.0240) and PFS (one-year PFS 38.5% vs. 17.9%; p = 0.0455) compared to CHT alone in patients affect by stage III/IV pancreatic ductal adenocarcinoma [46].

HT was used in association with CHT and RT with interesting results in terms of median OS (23.6 months) and conversion surgery (23.8%) for unresectable locally advanced pancreatic ductal adenocarcinoma [47]. Similar results were reported by Rogers, with a median OS of 24 months, 1-year overall survival of 100%, and conversion to surgery of 22.2% in nine patients with locally advanced pancreatic ductal adenocarcinoma [48].

3.6. Recto-Anal Cancer

Several papers reported the efficacy of CRT + HT in neoadjuvant therapy of locally advanced or recurrent rectal cancer [49,50,51,52,53,54,55]. Phase II trials showed that CRT + HT resulted in CR of 14–29.8%, 5-year PFS of 54.8%, DFS of 94.0%, and OS of 71.1–73.5%; 3-year estimates for OS, DFS, LC, and DC were 94%, 81%, 96%, and 87%, respectively (

Table 6. Rectal cancer.

Author	Type of Study	Type of Tumor	N of Patients	Type of Treatment	Outcome	HT-Associated Adverse Events
Schem 2022 [49]	Phase II	locally advanced rectal cancer or local recurrences	49	Neoadiuvant CRT + HT	CR was reported in 29.8% of the patients; 5-year PFS was 54.8% and OS was 73.5%.	none
Wang 2022 [50]	Retrospective observational case–control study	locally advanced rectal cancer	152	Neoadiuvant CRT vs. CRT + HT	CRT + HT had a significantly higher T-downstaging rate than CRT group (82.0 vs. 62.7%; p = 0.016). OR  for HT as predictor of T-downstaging was 2.473; (95% confidence interval [CI], 1.050–5.826; p = 0.038). The 5-year rates of LRRFS (96.8 vs. 94.7%; p = 0.959), DFS (61.4 vs. 79.3%; p = 0.242), and OS (92.7 vs. 89.8%; p = 0.831) were not statistically different in the two groups.	none
Lee 2022 [51]	Phase II	locally advanced rectal cancer	60	Neoadiuvant RT + mEHT	Total or near-total tumor regression was reported in 20 (33.3%) patients, including 9 (15%) in the CR group. T- and N-downstaging was observed in 40 (66.6%) and 53 (88.3%) patients, respectively. The 5-year OS and DFS were 94.0% and 77.1%, respectively.
Kim 2021 [52]	Retrospective observational case–control study	locally advanced rectal cancer	160	Neoadiuvant CRT vs. CRT + mEHT	Dowstaging was 80.7% in the CRT + mEHT group and 67.2% in the CRT group. The 2-year OS was 100% in the CRT + mEHT group and 96% in CRT group. The 2-year DFS was statistically greater in the CRT + mEHT group (96% vs. 76%; p = 0.054). The 2-year LRRFS was 98% and 94% and the 2-year DMFS was 94% and 79% in the CRT + mEHT and CRT groups, respectively.	3% of patients had grade 3 mEHT-related toxicity, one with hotspots and the other with suspected fat necrosis.
Gani 2021 [53]	Phase II	locally advanced rectal cancer	78	Neoadiuvant CRT + HT	CR was reported in 14% of patients, and 50% had complete regression or scattered tumor cells only. Three-year estimates for OS, DFS, LC, and DC were 94%, 81%, 96%, and 87%, respectively.	none
Ott 2021 [54]	Phase II	locally advanced rectal cancer or local recurrences	111	Neoadiuvant CRT + HT	CR was observed in 28% and 38% and complete resection rates (R0) in 99% and 67% of patients with locally advanced and locally recurrent rectal cancer, respectively.
You 2020 [55]	Phase II	locally advanced rectal cancer	76	Neoadiuvant CRT + HT	T- and N-downstaging was observed in 40 (66.7%) and 53 (88.3%) patients, respectively. CR was reported in 15% and 76.7% of T- and N-stage cases, respectively. Total or near-total tumor regression was noted in 20 (33.3%) patients	sixteen patients (26.7%) had thermal-related toxicity, which was mostly grade 1 (93.8%)

RT = radiotherapy; HT = hyperthermia; PFS = progression-free survival; OS = overall survival; CRT = chemoradiotherapy; LRRFS = locoregional recurrence-free survival; DMFS = distant metastasis-free survival; LC = local control; DC = distant control; CR = complete response.

). T- and N-downstaging was observed in 40 (66.7%) and 53 (88.3%) patients, respectively. CR was reported in 15% and 76.7% for T- and N-stages, respectively [49,51,53,54,55].

Two retrospective observational case–control studies compared neoadjuvant CRT vs. CRT + HT and observed that CRT + HT had a significantly higher T-downstaging rate than the CRT group (80–82% vs. 62.7–67.2%; p < 0.05). OR for HT as predictor of T-downstaging was 2.473 (95% confidence interval [CI], 1.050–5.826; p = 0.038). The 5-year rates of LRRFS (96.8 vs. 94.7%; p = 0.959), DFS (61.4 vs. 79.3%; p = 0.242), and OS (92.7 vs. 89.8%; p = 0.831) were not statistically different in the two groups. The 2-year OS was 100% in the CRT + mEHT group and 96% in CRT group. The 2-year DFS was statistically greater in the CRT + mEHT group (96% vs. 76%; p = 0.054). The 2-year LRRFS was 98% and 94% and the 2-year DMFS was 94% and 79% in CRT + mEHT and CRT groups, respectively [50,52].

Concerning adverse events related to HT, three studies reported no adverse events, one observed 3% of patients with grade 3 mEHT-related toxicity, one with hotspots and the other with suspected fat necrosis, and one reported 26.7% thermal-related toxicity, which was mostly grade 1 (93.8%) [49,50,52,53,55].

3.7. Glioma

Mahadavi treated 38 patients with malignant glioma in a prospective study, who received either CRT or CRT + HT [56]. A capacitive device (Celsius 42+) was used to deliver HT. MRI controls (pre- and post-treatment) were compared, and improvements in tumor shrinkage in favor of HT were documented. The 15-month overall survival and change in performance score were statistically similar between patients treated with or without HT. No evidence of toxicity was reported, and HT was well accepted in all patients treated with it [56].

3.8. Melanoma and Skin Cancer

A retrospective observational cohort study on 110 cases of stage IV metastatic melanoma showed that RT + HT was an effective treatment; in particular, the 1- and 2-year LC rates were 93.5% (95% confidence interval (CI): 88.1–99.3%) and 88.3% (95% CI: 79.9–97.6%), respectively, and the mean reduction in tumor size was 72%. The 1- and 2-year OS rates were 100% and 95% (95% CI: 90.4–99.9%), respectively [57].

3.9. Prostate Cancer

The elevation of temperature beyond the physiological range has been shown to both increase tumor oxygenation and reduce DNA repair capabilities in prostatic cancer cells. Thus, HT combined with RT represents a very interesting treatment modality to improve the therapeutic ratio in prostate cancer patients [58]. HT and RT have been tested mainly in patients with locally advanced tumors at a high risk of local relapse (LR), specifically patients with PSA > 20 ng/mL, T3–T4 tumors, or with an LR either after definitive RT or after radical prostatectomy [59].

A retrospective observational cohort study on high-risk localized prostate carcinoma showed that the 5-year DFS rates for patients with and without hyperthermia in association with RT were similar at 89.8% and 82.9%, respectively (p = 0.2170). The 5-year clinical RFS rate was higher for patients treated with RT + HT than those treated with RT alone (98.0% vs. 88.6%; p = 0.0229). Skin burn was seen in two (2.9%) patients [60].

An observational phase II study (HTProstate-NCT04159051) evaluating the increase in dosage in SRT (70 Gy/35 f.) and regional HT sessions (7–10) was carried out by Beck [61]. The endpoints of the research were acute genitourinary (GU) and gastrointestinal (GI) AEs, other side effects due to HT, and how many completed HT and SRT sessions patients tolerated. The two-step program of the study provided a first evaluation for acute GU and GI AEs and skin toxicity, in order to determine a modality with better patient acceptability and safety. After three years, 52 patients were enrolled into the study, of which 50 patients were treated, and scheduled observations were performed with at the 12-week follow-up: 10% of patients presented with immediate grade 2 GU and 4% GI toxicities, while HT skin side effects of grades 2 and 3 were observed in 4% and 2% of cases, respectively. Due to the scarcely significant toxicities observed, the safety of patients was considered achieved. In addition, hyperthermia was administered up to 7, demonstrating that the combination of HT + SRT is safe and administrable. No changes in QoL assessment were observed after three months of follow-up. Considering the mild toxicity observed in the GU and GI levels, the moderate and manageable symptoms specific to HT, and the good feasibility, it appears that the HT + SRT combination is an interesting therapeutic combination to adopt for biochemical recurrence after partial response in these patients.

3.10. Palliation of Bone Metastases

Painful bone metastases have a significant impact on patients’ quality of life (QoL). Standard pain treatments for patients with bone metastases include morphine-equivalent medication (MeM) and RT; however, these therapies are not always successful. HT and mEHT have been recently applied in addition to RT and MeM, showing promising synergistic results [62].

A marked decrease (≥2 points) in the brief inventory pain questionnaire (BPI) score (CR + PR) and improvement in QoL was observed in 95%, 90%, and 100% of patients with bone metastases treated with RT alone, mEHT alone, and RT + mEHT, respectively. A comparison of spinal and pelvic bone metastases showed similar results in both pain control and QoL (

Table 7. Bone metastases.

Author	Type of Study	Type of Tumor	N of Patients	Type of Treatment	Outcome	HT-Associated Adverse Events
Kim 2024 [62]	Retrospective observational cohort study	Pelvic and spinal bone metastases	61	RT vs. mEHT vs. RT + mEHT	A marked decrease (≥2 points) in the brief inventory pain questionnaire (BPI) score (CR + PR) and improvement in QoL was observed in 95%, 90%, and 100% of patients with bene metasteses treated with RT alone, mEHT alone, and RT + mEHT, respectively.
Moghaddam 2024 [63]	Randomized phase III trial	Prostate and breast cancer metastases	61	RT vs. RT + WBH	The CR rate was higher in the RT + WBH group than in RT-alone group (47.4% versus 5.3%; p < 0.05) within 2 months post-treatment. The time of complete pain relief was 10 days with RT + WBH and 4 weeks in the RT-alone arm.

RT = radiotherapy; WBH = whole-body hyperthermia; CR = complete response.

).

A randomized phase III trial on bone metastases from prostate and breast cancer showed that WBH + RT had a significant increase in pain relief and shorter response time than RT-alone. The CR rate was higher in the RT + WBH group than in the RT-alone group (47.4% versus 5.3%; p < 0.05) within 2 months post-treatment. The time of complete pain relief was 10 days with RT + WBH and 4 weeks in the RT-alone arm [63].

3.11. Hyperthermia Safety

Overall adverse event (AE) rates did not increase when adding HT in many studies [26,30,32,33,41,48,49,50]. Skin burns were reported in some studies; however, they were of mild intensity (G1–2) and resolved within a few days [34,35,41,42,49,52,55]. Hyperthermia did not increase hematological, hepatic, pulmonary, and metabolic toxicity due to concurrent CHT. No increased blood pressure or any other cardiac changes were observed for mEHT sessions in 19 pancreatic cancer patients who received adequate cardiological monitoring, including clinical examination, electrocardiograms, and echocardiograms [44].

4. Discussion

The available studies on HT included both retrospective data collection and experimental phase II or III prospective studies in different types of tumors, resulting in confirmation of the efficacy and safety of the HT association with CHT and/or RT [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]. In many studies, it was observed that the use of HT resulted in an improvement in OS. The use of HT in neoadjuvant settings showed that it improved tumor shrinkage and regression in association to CRT or RT alone, in patients with inoperable soft tissue sarcoma [16,17].

HT and, in particular, mEHT increased OS and prolonged LRFS in patients with locally advanced cervical cancer when associated with CRT compared to CRT alone, with a 5-year OS of 53–81.9% and LRFS of 74.7% [26,27,30,31,32]. Concerning malignancies of the head and neck, HT in association with CRT showed an ORR of 68.4–82.9% and PFS of 34.3–53.1% [32,33,34,35]. HT resulted in an LRC of 91.3–94% when associated with RT or CRT in the adjuvant setting for therapy for locally advanced or recurrent breast cancer [36,37,38,39,40,41]. Two studies on CHT + HT and two with CHT + mEHT reported a significantly improved OS of 16–20 months compared to that with CHT alone (8.6–9 months; p < 0.05) in patients affected by pancreatic cancer [43,44,45,46]. Good results in OS were shown also when HT was combined with RT for the treatment of pancreatic cancer, with an OS of 23.6–24 months [47,48].

HT and mEHT were used as neoadjuvant therapy in association with CRT in several studies regarding rectal cancer, resulting in significantly greater downstaging than CRT alone (80.7–82% vs. 62.7–67.2%; p < 0.05) [49,50,51,52,53,54,55]. Other beneficial effects of HT were observed in glioma, melanoma, and prostate cancer treatments [56,57,60]. HT, moreover, reduced the pain intensity of bone metastases [62,63].

Considering these valuable results, HT has been included in the NCCN and ESMO guidelines. A careful analysis reported a significant improvement in OS (by 5 years) when considering another severe clinical condition (LACC) in women undergoing radical HT-CTRT. Other published studies have also indicated the emerging significance of adopting HT as an immune modulator of the TME and as a possible agent to prolong responses and treatment holidays between chemo- or radiotherapy treatments. Of note is the possibility of dose treatment reduction, permitting chemotherapy even if leukopenia is present and in already-irradiated patients. Some of the reported clinical studies covered past decades and considered different types of studies, including observational case series, phase II, and RCT studies. These aspects could lead to a heterogeneity of patient subsets and hyperthermia methodologies, which may not clearly demonstrate the true therapeutic value of HT and the real applicability and validity of the obtained results.

However, in other words, as the same results have been found in different periods and with different schedules and devices, it seems that HT—called “the fourth pillar of cancer treatment” in the 1990s—is an effective treatment against cancer. Even though the methodologies for data collection and statistical calculations in the studies reported in this review may not be considered adequate when compared with current quality criteria and the results have not been fully accepted by all critics, we must recognize that the biological, immunological, and therapeutic aspects associated with HT are of great interest and the need to develop new studies remains imperative. A growing body of reports regarding the use of hyperthermia have been put forward, with many of these having been published within the past few years. The goal of our review is to identify and offer correct information, thus providing specialists with an adequate overview of HT as adjunctive cancer therapy. At present, the efficacy of adjunctive HT in new cancer treatments appears to be evident.

Although the scientific evidence is still debated, in the opinion of most critics, there are multiple clinical trials showing that HT is beneficial for some types and stages of cancer; as such, more RCTs focused on greater standardization of the used therapeutic modalities and HT administration are needed. Medical experts who use HT daily believe that the reasons for the low acceptance of HT do not include the poor efficacy of the method but the limited diffusion of qualified hyperthermia centers and the lack of guidelines for temperature monitoring and quality treatment schedules. In addition, the various existing centers have adopted heterogeneous practices and there is a lack of government funding, not to mention the disinterest of the pharmaceutical industry. Many centers have outdated technologies that can lead to poor patient tolerance for the technique and, finally, a lack of honest information serves to limit access to HT for patients. In the studies reported here, a general trend of improvement in clinical outcomes with HT can be noted, as has been observed in similar previous studies and reviews [64,65]. Future research should focus on detecting parameters such as patients’ acceptability and increases in quality of life, tumor response, local control rates, time to progression, and overall survival when HT is used as an adjunct to classical therapies.

5. Conclusions

Several studies reported worthy efficacy, feasibility, and safety of HT and mEHT concerning tumor response, survival, and relapse-free improvements in several tumor types, such as sarcoma, head–neck, breast, cervical, and gastrointestinal cancers, and other malignancies. HT and mEHT improve the benefits of CHT, RT, and CRT for the treatment of recurrent disease, resulting in better outcomes and low-grade toxicity. In order to make regional HT credible and disseminate it worldwide, it is essential that the thermal dose and its monitoring are recognized and well defined in every new study. Quality assurance in the delivery and evaluation of HT treatment will allow for better defined and repeatable clinical trials.