Alternating electric field therapy (AEFT) is a nonchemical solution designed to interrupt tumor growth and provide patients with new options in fighting cancer. AEFT utilizes low-intensity electric fields that push and pull on key structures inside tumor cells in different directions, making it harder for them to multiply and thus making treatment more likely successful.
TTFields are delivered through surface transducer arrays which adhere to a patient’s head for 18 hours per day, continuously emitting antimitotic alternating electric fields that interfere with mitosis and lead to metaphase arrest and cell death. Preclinical studies have confirmed this effect.
Low-intensity electric fields
Alternating electric fields (AEFs) have many applications in medical medicine. From cell division control and tumor growth inhibition to treating pain and reducing inflammation, ELF waves have many uses in health. Their creation can be accomplished using devices such as ultrasound machines or pulsed electromagnets; but ELF waves may also be naturally generated within our bodies – unlike radiofrequency (RF) and microwave radiation sources, which may damage DNA; ELF waves do not cause DNA damage and therefore are generally accepted by most health professionals as harmless.
Researches conducted experiments to demonstrate that low-intensity electric fields could inhibit cancer cell mitosis. Their findings were reported in Science Advances journal. Results revealed that electric fields at frequencies ranging from 100-300 kHz significantly reduced cancer cell viability in vitro. Cytotoxic effects were most pronounced between 150 and 200 kHz and increased with increasing intensity of field. These findings led to the creation of a device called tumor-treating fields (TTFields), which generates magnetic fields using liquid metal electrodes and delivers them via liquid metal channels. Results show that using this device is effective at slowing the development of various cancers in mice and may provide an effective means of increasing survival for people living with glioblastoma multiforme, the most prevalent primary brain tumor among adults.
Optune Gio, manufactured by Novocure, is currently the only device capable of creating low-intensity electric fields to treat glioblastoma. Worn on the head and consisting of 4 sets of electrodes connected to a battery pack, it produces tumor-treating fields which may specifically target cancerous cells in the brain more effectively than their healthy counterparts.
Though electric fields have long been associated with various effects on brain activity and function, their exact mechanisms remain elusive. Here we examined voltage-sensitive dye signals caused by low intensity alternating electric fields in rodent cortical slices – these signals exhibited two distinct components; passive ones corresponded directly to membrane potential changes caused by the field; active ones depended on excitatory synaptic transmission.
Tumor-treating fields
Tumor-treating fields (TTFields) is a noninvasive technology that employs electric fields to treat tumors noninvasively and nonsurgically. Electric fields are delivered using a portable device with multiple electrodes for placement on the skin, creating a sinusoidal electric field with variable frequency that disrupts cell processes and promotes cell death. TTFields has demonstrated promising clinical results in several cancer trials, and are being researched further for use against other forms of tumors.
TTFields may be combined with other standard-of-care treatments to enhance outcomes, increasing radiation therapy effectiveness or chemotherapy drug sensitivity to tumor cells, improving immunotherapies, increasing their penetration into cells and efficacy, disrupting mitosis, downregulating DNA damage response genes and interfering with cell migration/movement/migration processes, as well as interfering with movement/migration pathways in tumor cells. Studies have also demonstrated TTField’s effect on tumor cells by disrupting mitosis disruption and downregulating DNA damage response genes, interfering with cell movement/migration mechanisms and disrupting mitosis disruption for greater therapeutic effect; effects observed include disrupted mitosis disruption, downregulated DNA damage response genes as well as interfering with migration/ movement/migration patterns as well as interfering with movement/migration patterns resulting from their interference affecting cell movement/migration patterns.
Electric fields generated by a tumor-treating field therapy device are delivered directly to tumor cells, leading to rapid cell death and reduced formation of new blood vessels in tumors as well as inhibiting angiogenic factors that promote tumor progression. Furthermore, TTFields help stimulate immune responses that enhance chemotherapy sensitivity and radiosensitivity.
Clinical trial data has demonstrated the efficacy of TTFields therapy on improving survival rates of patients suffering from recurrent glioblastoma multiforme. Receivers who received combined radiation and chemotherapy had greatly increased overall survival while experiencing better quality-of-life and less hospitalizations as a result of using the device.
This treatment works by disturbing the polarity of centrosomes within a tumor. This prevents centromeres from forming properly and impairs their ability to divide chromosomes into two identical copies, inhibiting mitosis. Chp23, an effector cellular factor involved with mitosis regulation, plays a key role; most notable in metaphase when centrosomes are closer together. Furthermore, TTFields interfere with spindle assembly by disrupting tubulin subunit alignment during metaphase and telophase.
Tumor-targeting fields
Tissue-targeting fields provide a noninvasive form of cancer therapy. Consisting of low-intensity, intermediate frequency alternating electric fields with the goal of disrupting mitosis and inhibiting tumor growth, these can be delivered using electrodes around a tumor site. Their frequency, duration and intensity depend on each patient’s medical history and tumor type – thus making this technology adaptable enough to use alongside traditional therapies like surgery, chemotherapy or radiation for improved results; additionally it has shown promise against glioblastoma mesothelioma lung cancer patients; additionally this therapy reduces intratumoral immune privilege by significantly decreasing immune privilege within these three forms of therapy.
TTFields have yet to be fully explained, but their mechanisms of operation seem to work by interfering with subcellular structures that regulate cell growth and proliferation. For instance, 200kHz TTFields appear to affect mitosis cells’ proliferative behavior by interfering with microtubule formation while exerting directional forces on charges and dipoles within cells undergoing mitosis resulting in their destabilization and disintegration; this effect likely due to interference with microtubule formation as well as exerted by charges and dipoles within them by these fields on charges and dipoles within cells.
These effects may also cause the cell to release pro-apoptotic proteins that activate an intrinsic apoptosis pathway and destroy it, or disrupt DNA repair machinery and cause cell integrity issues, prompting mitochondria to produce apoptotic proteins which result in cell death. Another theory suggests TTFields interfere with DNA repair machinery and cause loss of integrity for mitochondria which in turn release pro-apoptotic proteins leading to cell death.
Studies of TTFields have demonstrated their increasing cytotoxic effects as their frequency and field intensity increase; for instance, fields applied at 200kHz tend to kill more cells than lower frequencies; further experiments suggest changing direction every two seconds increases effectiveness by killing 20% more cells than constant-direction fields.
TTFields may interact with tumor endothelium cells that supply oxygen and nutrients into tumors. A recent study demonstrated how low-intensity ETTFs could curb tumor growth by altering endothelial cell density; they also decreased CD34-positive cell counts necessary for supporting the tumor microenvironment, potentially having implications for future therapies that target this region of tumor microenvironment to stimulate antitumor immunity.
Safety
Glioblastoma (GBM) is the most prevalent and lethal primary CNS malignancy, yet current therapies only provide marginally improved survival with significant side effects. New strategies must therefore be devised to improve outcomes of this disease; AEFs have proven successful at reducing GBM recurrence rates as well as having potential application against other cancers; however, dose distribution remains uncertain and needs further study.
Researchers participating in the PriCoTTF phase I clinical trial studied the effect of AEFs on radio-chemotherapy treatment plans by employing computational modelling and human body impedance measurements, as well as different array configurations for TTFields therapy. Their researchers discovered that first principal component variations varied per patient and covered an oblique plane; second principal component variations stayed within CTV (clinical target volume) limits and were relatively consistent over time.
TTFields are locoregionally applied, low intensity intermediate frequency alternating electric fields delivered using portable medical devices. When combined with temozolomide and radiation therapy, their use has significantly improved overall survival in recurrent glioblastoma patients. Preclinical studies of AEFs have demonstrated enhanced antimitotic activity of TMZ as well as improved radiosensitivity through modulating DNA damage repair pathways; they may even interfere with artificial intelligence-based devices operating under electromagnetic spectrum such as pacemakers; however these interactions may be reduced by adjusting settings of AEF device settings or wearing head coverings that cover electrodes from visible electrodes on devices or by wearing head coverings which obscure electrodes hidden under clothing that obscure electrodes hidden beneath head coverings which camouflage them from view.
