Literature review: potential non-thermal molecular effects of external radiofrequency electromagnetic fields on cancer.

Hyperthermia therapy, the heating of tumors to temperatures of 39-44°C using radiofrequency electromagnetic fields (RF-EMF), has been proposed as an adjunct cancer treatment to established therapies such as radiation and chemotherapy. However, there are technical limitations in achieving the required temperatures deep within the body. In particular, patient thermoregulation, the heat transfer from target areas due to blood flow, presents a significant limitation for effective hyperthermia. The cancer-inhibiting effects of RF-EMF, which sensitize tumors to chemotherapy and radiotherapy, have so far been attributed to the induced temperature increases at the tumor site and the resulting effects.

A growing body of evidence suggests that RF-EMF may also have tumor-damaging effects beyond local temperature increases. Numerous clinical data suggest that the method of Tumor Treating Fields (TTF) (Novocure, Switzerland), which uses low-intensity, intermediate frequency RF-EMF at temperatures below 38°C, results in significant cancer cell death. The same is true for RF-EMF in the GHz spectrum at intensities that cause only negligible temperature increases (+1.58°C).

While the exact mechanisms through which non-thermal RF-EMF might exert anti-cancer effects remain largely unclear, there is a scientific consensus that certain features occur exclusively in tumor cells and not in healthy tissue cells. In addition to the altered expression of oncogenes, tumor promoters, and suppressor genes that are ubiquitous in cancer cells, these specific characteristics of cancer cells are thought to lie in their pronounced bioelectric properties, such as the expression of aberrant ion channels and membrane potentials, and in their specific mechanical properties, such as altered cell membrane elasticity and cytoskeletal organization.

This raises the question of whether these characteristics make cancer cells particularly susceptible to the effects of RF-EMF radiation. The exact nature of the molecular mechanisms activated during RF-EMF exposure remains to be investigated and identified.

The authors conducted a review according to PRISMA guidelines. All studies reporting effects induced by frequencies outside the RF spectrum were excluded. Studies without temperature control or those using RF-EMF that caused significant temperature increases within cells (> 40.5°C) were also excluded, as the aim was to only investigate the non-temperature-induced effects of RF-EMF.

A literature search was conducted in several databases, particularly PubMed (MEDLINE) and Scopus (Elsevier). Additional literature was identified by reviewing the sources of previously collected and selected papers. A risk of bias assessment was not performed as it was considered unsuitable for a preclinical investigation.

This review included 32 preclinical studies reporting a variety of EMF-induced molecular effects in cancer cells. The studies were divided into three EMF exposure groups:

Group 1 (20 studies): The "TTF" category, in which an alternating electric field is generated and applied to the patient's body via a pair of insulated wires. TTF is characterized by intermediate frequency and low intensity, and includes studies with a frequency range of 100-300 kHz. The field strength varied from 0.5 to 3 V/cm.

Group 2 (4 studies): "Therabionics/AutEMDev" approaches fall into the high frequency, low-intensity category. The included studies used frequencies between 27.12 MHz and 147 MHz, with SAR values ranging from 0.01 to 0.4 W/kg. This group is mainly characterized by uniform amplitude modulation with a particularly high modulation index of 80-85%.

Group 3 (6 studies): Millimeter waves (MMW) and microwave (MW) RF fall into the category of extremely high frequencies with low intensity. The frequencies range from 900 MHz to 105 GHz, the incident power densities range from 0.001 to 0.2 mW/m² (0.01 to 2 W/m²), and the SAR values are low (0.0038 to 1 W/kg).

Of the 32 preclinical studies analyzed, 26 directly reported reduced cancer cell proliferation, viability, or migration in vitro and in vivo in animal tumors after RF-EMF treatment. Several studies in this review reported significantly reduced cell proliferation after RF-EMF treatment, particularly in the intermediate RF-EMF spectrum between 100-300 kHz, applied via TTF or TTF-like devices.

Continuous TTF exposure at 1.5 V/cm for 24 hours significantly inhibited the proliferation rate of breast cancer cells, resulting in a marked decrease in cell number (p < 0.0001). Jimenez et al. (2019) observed significant proliferation inhibition after a 27.12 MHz amplitude-modulated EMF treatment with Therabionics. Beneduci et al. (2005) also reported growth inhibitory effects after RF-EMF application in the microwave spectrum at 53-78 GHz in human breast cancer cells (MCF-7), with a 60% reduction in cell growth.

The literature analysis provides a first overview of the diverse non-temperature-related molecular effects that can be observed in cancer cells under RF-EMF exposure, suggesting that RF-EMF treatment specifically targets ion channels and cell mechanics. None of the reviewed studies observed stimulation of cancer cell proliferation or migration by RF-EMF treatment. This is noteworthy because the observed RF-EMF effects on cancer cells appear to contrast with the positive stimulatory effects of EMF on healthy tissue cells (potentially increasing cancer risk).

Careful dosimetry is essential for safe and effective RF therapy. Many studies have reported the importance of optimal frequency selection for TTF application in different cancer cell lines. They indicate that each cancer cell line has a specific frequency optimum at which the anti-cancer effect is maximal. Frequencies outside of this optimum result in either a reduced or no significant anti-cancer effect.

The existing literature suggests an untapped therapeutic potential of RF-EMF treatment when appropriate and careful dosimetry is applied. Further research is essential to determine optimal cancer-specific RF-EMF frequencies, field intensities, and exposure intervals. (AT)

"The results suggest that RF-EMF treatment can disrupt different cellular structures."