Tumor Treatment Fields in Oncology

Anatomy and Physiology

Physical Principles

The role of the macromolecules and organelles involved in the process of cell division is critically dependent on the polar nature of these molecules. Their appropriate location in the cell and movement in a definite pattern according to the cell cycle stage is important for cell division to happen. Application of external alternating electrical fields interferes with this coordinated natural movement of these electrically sensitive polar macromolecules disrupting mitosis. The following two effects of electric fields on these macromolecules are responsible for the negative impact on cell division:

1. Effect on Alignment: Any molecule with spatial separation of the positive and negative charges is called a dipole and is sensitive to experiencing differential forces in the presence of an external electric field. Such molecules are forced to align along the direction of the local electric field, which prevents them from attaining the appropriate alignment required for mitosis to progress. This dipole alignment effect is predominant on the random movement of tubulin protein and prevents its polymerization by inhibiting the formation of the mitotic spindle. This effect results in metaphase arrest.[4]

2. Effect on Location: These polar macromolecules also tend to concentrate in regions of high electric field density in the presence of non-uniform electric fields. The various factors that result in a non-uniform distribution of electrical fields are the geometry and the differential electrical property of the tissue. This displaces them from the specific spatial location in the cell they are supposed to be in the particular stage of the cell cycle.[5] 

This process, called dielectrophoresis, primarily affects the spatial location of the septin protein complex, which migrates to the constricted center of the dividing cell during the telophase due to high electric fields in that region due to the hourglass shape of the dividing cell. These electric fields exert minimal effects on normal tissue with a lower proliferative rate. Skin tissue surrounding the region may experience side effects because of a relatively higher turnover rate. There is some evidence that TTF may also cause alteration to oncogenes like p53.[6] The use of nanoparticles along with TTF has also been shown to have synergistic anti-neoplastic action.[7]

Indications

TTF has been studied for several solid organ malignancies and has received approval for use in primary and recurrent glioblastoma alone and in combination with other adjuvant therapies. The indications for the use of TTF and the current evidence are summarized below.

Glioblastoma

Glioblastoma is the most dangerous primary malignant brain tumor and has the worst prognosis. It is also the most common primary brain malignancy with an incidence rate of 3.2 to 4.5 per 100,000 individuals.[8] Despite significant advances in its treatment options, it still has a grim survival rate. Regardless of the treatment, recurrence in glioblastoma remains a major problem. Moreover, an effective treatment strategy for recurrent glioblastoma has not been found yet.[9]

TTF has emerged as a potential treatment option in glioblastoma due to its locally invasive nature and decreased propensity to metastasize to distant organs facilitating maximum coverage of the tumor-containing region. TTF was approved by the FDA for use in recurrent glioblastoma in 2011, followed by newly diagnosed glioblastoma in 2015. The median progression-free survival increased from 4 months to 7.1 months, while the median overall survival increased from 16 months to 20.9 months with the addition of TTF to maintenance temozolomide in a randomized clinical trial by Stupp et al. in 2017.[10] Additionally, it is safer to use TTF in glioblastoma as the brain does not contain non-cancerous dividing cells, unlike other organs.[3][11]

Pancreatic Cancer 

The utility of TTF is also being studied in pancreatic cancer, particularly advanced-stage carcinomas, due to its antiproliferative effects in preclinical trials. The replicability of these effects is being studied in an ongoing clinical trial, PANOVA, in which patients with pancreatic adenocarcinoma received either TTF along with gemcitabine or gemcitabine and nab-paclitaxel.

Ovarian Cancer 

TTF has also gained popularity in the treatment of recurrent ovarian cancer, and one such trial, INNOVATE, focuses on the safety and feasibility of TTF in combination with paclitaxel.

Non-small Cell Lung Carcinoma

The efficacy of TTF has been shown in animal models of advanced non-small cell lung carcinoma. Human studies have demonstrated the safety of the treatment, but its efficacy is still under evaluation. Ongoing LUNAR phase III trial aims to evaluate the efficacy of TTF with docetaxel in non-small cell lung carcinoma.

Malignant Mesothelioma 

The use of TTF in combination with pemetrexed and cisplatin or carboplatin in unresectable or metastatic mesothelioma has been FDA approved as the first-line treatment. A chest applicator has been developed to deliver TTF to the thoracic cavity. The side effects include mild to moderate dermatitis in about half of the patients.

Future Role of TTF

It is being evaluated in preclinical studies in several other malignancies, including breast carcinoma, urogenital malignancies, renal carcinoma, colorectal carcinoma, and hepatocellular carcinoma. Another avenue of further development is dose and delivery optimization which may further increase the list of indications. Long-term adverse effects and the impact of alternating electric fields on healthy tissue are also a matter of further research.

Contraindications

There are no absolute contraindications to the use of TTF. Though the manufacturer doesn’t recommend the use of TTF among patients with implanted medical devices like pacemakers, deep brain stimulation electrodes, etc., a study found no adverse effect of TTF in such patients. A pre-existing skin disorder may be considered a relative contraindication as TTF itself may cause allergic or contact dermatitis, resulting in its exacerbation.

Equipment

The TTF device consists of an electric field generator to generate electric fields and transducer arrays to deliver a particular electric field configuration to the patient. The electric field generator sits in a backpack that the patient can carry while going on with the daily activities. The lithium-ion battery in the device should be charged overnight, and the transducer coils are supposed to be changed every 3 or 4 days. For patients with glioblastoma, the scalp hair needs to be removed for proper contact between the transducer arrays and the scalp.

Technique or Treatment

The TTF delivery is tailored to the tumor's size, shape, and location.[12] The configuration in which the arrays are to be applied externally is individualized using proprietary software to achieve maximum field at the tumor target. The factors used for this calculation include morphometry and the specific location of the tumor.[13] Additionally, the intensity and direction of the electric field at all points can also be simulated. Such simulations can further help tailor the array configuration used for a particular patient.

Complications

The adverse effects of TTF are limited to mild to moderate dermatological complications like dermatitis in the region of the application of transducer arrays. The longest follow-up data is available for patients with glioblastoma treated with TTF, and the rate of dermatitis ranges from 16 to 43%. This complication has been seen around 2 to 6 weeks after the initiation of treatment in patients with glioblastoma. Dermatitis is usually easily controlled with topical steroids and antibiotics, oral antibiotics, and local skin protection.[14]

However, compliance with the therapy is generally found to be high. It attests to the safety of this treatment modality, at least for the limited duration of follow-up available. The long-term effects and complications of TTF will be known as more literature is available in the future.

Clinical Significance

The long-term outcomes of TTF are still not available, but the initial results have shown promise. TTF has been FDA approved for use in recurrent glioblastoma, and ongoing trials may establish its role in not only primary glioblastoma but other malignancies like pancreatic cancer, ovarian cancer, non-small cell lung carcinoma, and mesothelioma. It may also play a role in modulating the effect of currently accepted treatment modalities like chemotherapy, radiotherapy, and immunotherapy. The fine-tuning of physical parameters involved in TTF with further research on TTF dosimetry is likely to enhance the impact of this novel modality in cancer therapeutics.

Enhancing Healthcare Team Outcomes

TTF is a new treatment modality for neoplastic diseases that utilizes low intensity, intermediate-frequency alternating electric fields to produce anti-mitotic activity. It has been approved for the treatment of recurrent glioblastoma alone and in combination with chemotherapy and radiotherapy, in which it may have a synergistic action. Its role in several other malignancies is the subject of many ongoing clinical trials. It is a relatively safe treatment with minimal side effects limited to locoregional skin tissue in the form of dermatitis. 

Management of patients with malignancy requires the involvement of professionals from multiple disciplines like the specific surgical specialty, surgical oncology, radiation oncology, medical oncology, palliative care, and nursing staff.