Standard cancer treatment consists of surgery, chemotherapy, and radiation therapy, either alone or in combination [1-3]. Of these, systemic chemotherapy and radiation therapy duration range from several weeks to several months, and takes at least several weeks to confirm the clinical outcomes. If the tumor size increases during follow-up after chemotherapy and/or radiation therapy, the prognosis is poor. Therefore, an effective combine therapy that enhances the efficacy of chemotherapy and radiation therapy can significantly improve clinical outcomes.

Recently, modulated electro-hyperthermia (mEHT), which can selectively maintain tumor cells at 42–43 °C using a high-frequency electromagnetic field (13.56 MHz) to the lesions, has been proposed as a promising combined modality therapy [4,5]. This technique operates based on a complex energy dose control paradigm rather than a straightforward temperature concept. The main targets of mEHT are the intercellular components and cell membranes of tumor tissues, and it acts selectively on malignant tumor cells with little damage to normal cells [4-6]. mEHT induces tumor cell death by increasing blood flow, suppressing hypoxia, and inhibiting DNA repair in tumors [7,8]. Additionally, when combined with systemic therapy, mEHT can enhance drug concentration within the lesion and increase the sensitivity of chemotherapy and radiation therapy [9,10]. Therefore, mEHT is a promising treatment that can be used in combination with systemic therapy and radiation therapy. This study reviews the clinical outcomes of mEHT in conjunction with chemotherapy and/or radiation therapy [11,12].

Conventional hyperthermia aims to directly kill cancer cells by using temperatures above 39 °C, but this approach has several drawbacks. First, the heterogeneous nature of tumors makes it challenging to deliver and maintain uniform thermal energy [13]. Second, thermal damage causes severe complications to the tumor-surrounding tissue. Third, as temperatures rise above 43 ℃, blood flow within the tumor decreases, potentially reducing the effectiveness of chemotherapy and/or radiation therapy [14]. Consequently, mEHT has emerged as an innovative method (Fig. 1). It selectively delivers thermal energy only to the tumor cell membrane and extracellular matrix, using temperatures below 43 °C, thereby minimizing the impact on surrounding tissues and addressing the limitations of traditional hyperthermia. mEHT selectivity for cancer cells was confirmed in vitro, and severe malignancy increases the degree of damage caused by mEHT [6]. Among the biological effects of mEHT, the most clinically useful are improving the perfusion and oxygenation conditions and interfering with the DNA repair mechanism of tumors [15-17]. Based on these characteristics, mEHT is being used as a combined therapy to enhance the effects of chemotherapy and radiation therapy.

Theoretically, mEHT is an excellent radiosensitizer. Conventional radiation therapy often causes hypoxic regions within tumors during treatment [18]. mEHT can not only increase tumor perfusion and oxygen supply, but also increase the tumor apoptotic effect of hyperthermic cells themselves on hypoxic cells, leading to improved efficacy of radiation therapy [19,20]. In addition, the local control rate could be improved by suppressing DNA repair in tumor cells by radiation therapy [20,21]. Since hyperthermia is highly effective on S phase cells, which are resistant to radiation therapy from a cell cycle perspective, concurrent therapy is more effective [22]. mEHT is a useful combined treatment to consider for cancer types that are highly resistant to radiation therapy. The prescribed dose is limited by the tolerance of the critical normal tissue surrounding the radiation treatment site, making hyperthermia highly necessary in cases of radiation retreatment. Since radiation continues to affect lesions even after treatment termination, mEHT could be highly effective in sequential treatments within several months post-radiation therapy. However, there is little information on this, and further study is needed.

mEHT increases blood flow and permeability, contributing to an environment that is conducive to drug delivery to tumors [7]. Owing to the effects of mEHT on tumor cells, including cell membrane damage and increased intratumoral stress, cancer cells compromised by this process may become even more susceptible to chemotherapy [23].

Based on these theoretical foundations, studies on clinical outcomes where hyperthermia was combined with systemic chemotherapy for various cancer types have demonstrated improved clinical results [24-26]. In clinical practice, we often encounter cases where reduced doses of chemotherapy are necessary for patients with poor performance status due to advanced age or concomitant diseases, or for patients who experience severe side effects from chemotherapeutic agents. We believe that mEHT is an effective combination treatment option that can compensate for reduced doses of chemotherapy.

mEHT uses a heating temperature of approximately 42 °C, which is lower than that used in conventional hyperthermia treatments, and side effects from heat exposure are relatively few and minor [27]. A common complication from heat exposure is mild erythema in the skin adjacent treated area [5]. Although it is rare, skin burns can occur if the heat power is intense or not properly monitored. In addition to the potential for thermal damage to the surrounding normal tissue at the treatment site, there is an occasional risk of fat necrosis due to minor damage to subcutaneous adipose tissue [28]. Some patients experience mild discomfort, pain, or a burning sensation during or after treatment due to local heating, but most recover without any intervention. Currently, serious side effects from mEHT alone are very rare, although minor side effects may occur. Since these side effects can be managed and minimized through careful supervision by the treating physician, the authors recommend treatment in an outpatient clinic at least once a week. Regarding systemic symptoms, hyperthermia can cause fatigue and tiredness, particularly when used in conjunction with chemotherapy or radiation therapy. Overall, most side effects associated with hyperthermia are manageable in clinical practice or are minor enough for patients to tolerate. Hyperthermia therapy has an antitumor effect on its own, but it is primarily used as a cancer treatment with the expectation of a synergistic effect when combined with chemotherapy and radiation therapy. Therefore, whether the incidence of serious side effects changes when hyperthermia is administered in combination with chemotherapy and radiation therapy is a crucial factor in determining clinical treatment strategies. Several studies have reported that mEHT has a low correlation with toxicity and demonstrates good safety [29-32]. A case report has claimed that hyperthermia helps maintain patient performance status and reduces chemotherapy toxicity [33]. However, several studies have reported an increased incidence of hematologic toxicity in patients who received hyperthermia, suggesting that hyperthermia may enhance the side effects of chemotherapy [34,35]. Although the safety of mEHT is higher than that of conventional hyperthermia [27], further evidence regarding toxicity associated with the treatment should be revealed through multiple well-designed randomized clinical trials.

A small number of randomized clinical trial and systematic review have been conducted using hyperthermia in patients with solid tumors, and the characteristics and oncological outcomes of these studies are summarized in Tables 1 and 2 [16,29,36-55]. Hyperthermia is regarded as an effective palliative treatment for cancer patients and can be utilized either as a monotherapy or in combination with other treatments. A randomized phase III trial by Chi et al. [55] demonstrated that combining hyperthermia with radiotherapy in patients receiving palliative treatment for painful bone metastases extended the duration of pain relief and enhanced the overall pain control rate. Some studies have shown that hyperthermia enhances the therapeutic effect when combined with both chemotherapy and radiation therapy. The results of the EORTC 32961-ESHO 95 trial [47] suggest that for patients with localized high-risk soft tissue sarcoma, the combination of preoperative chemotherapy and hyperthermia is an effective treatment option. De Haas-Kock et al. [46] compared the efficacy of concurrent hyperthermia and radiation therapy with radiation therapy alone in the treatment of locally advanced rectal cancer. The results demonstrated that hyperthermia improved overall survival (hazard ratio, 2.06; 95% confidence interval [CI], 1.33–3.17; p=0.001), and increased complete tumor response rates (relative risk, 2.81; 95% CI, 1.22–6.45; p=0.01).

Hyperthermia may have an energy dose-dependent response, but little information is available on the appropriate dose or treatment schedule (twice a week vs. three times a week) that shows efficacy. It may vary depending on each cancer type, but also the combined treatment method. For example, in radiation therapy, conventional radiation regimens and stereotactic body radiation therapy show significant differences due to their unique treatment mechanisms; therefore, the optimal dose of mEHT to be combined should be explored. Since mEHT is a localized treatment, as with radiation therapy, the treatment dose may differ depending on the treatment site and limitations of treatment dose due to surrounding normal tissue; so well-designed studies must be carried out by dividing the tumor into each location.

Theoretically and experimentally, mEHT can play an important role in treating tumors, either alone or in combination with chemotherapy and radiation therapy. Although several studies have reported the clinical use of mEHT, particularly in improving oncological outcomes, further research is still required on the optimized treatment dose or schedule. In some patients, the effect of hyperthermia is minimal, so it cannot improve the disease state and may only increase the social and economic burden. Therefore, hyperthermia should be applied with appropriate monitoring in selected patients. Since various treatment methods and regimens are used in the treatment of tumors, we believe that multidisciplinary medical consultations are also useful in determining the treatment plan.