The schemes, mechanisms and molecular pathway changes of Tumor Treating Fields (TTFields) alone or in combination with radiotherapy and chemotherapy

Our plain-English summary of The schemes, mechanisms and molecular pathway changes of Tumor Treating Fields (TTFields) alone or in combination with radiotherapy and chemotherapy, by G. Tanzhu, L. Chen, G. Xiao, et al (Cell Death Discovery, 2022).

The study

• Authors: G. Tanzhu, L. Chen, G. Xiao, W. Shi, H. Peng, D. Chen, R. Zhou
• Journal: Cell Death Discovery
• Published: 2022;8(1):416
• Type of article: Review
• Cited by: 51 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Tumor Treating Fields (TTFields) is a physical therapy that uses moderate frequency (100-300 kHz) and low-intensity (1-3 V/cm) alternating electric fields to inhibit tumors. Currently, the Food and Drug Administration approves TTFields for treating recurrent or newly diagnosed glioblastoma (GBM) and malignant pleural mesothelioma (MPM). The classical mechanism of TTFields is mitotic inhibition by hindering the formation of tubulin and spindle. In addition, TTFields inhibits cell proliferation, invasion, migration and induces cell death, such as apoptosis, autophagy, pyroptosis, and cell cycle arrest. Meanwhile, it regulates immune function and changes the permeability of the nuclear membrane, cell membrane, and blood-brain barrier. Based on the current researches on TTFields in various tumors, this review comprehensively summarizes the in-vitro effects, changes in pathways and molecules corresponding to relevant parameters of TTFields (frequency, intensity, and duration). In addition, radiotherapy and chemotherapy are common tumor treatments. Thus, we also pay attention to the sequence and dose when TTFields combined with radiotherapy or chemotherapy. TTFields has inhibitory effects in a variety of tumors. The study of TTFields mechanism is conducive to subsequent research. How to combine common tumor therapy such as radiotherapy and chemotherapy to obtain the maximum benefit is also a problem that's worthy of our attention.

© 2022. The Author(s).

In plain English

This article was a review, not a new study. The authors summarized published research on Tumor Treating Fields (TTFields), a treatment that applies alternating electric fields (100 to 300 kHz, 1 to 3 V/cm) to tumors, either alone or combined with radiotherapy or chemotherapy. The review focused on laboratory (in-vitro) studies of tumor cell lines, mostly glioma and glioblastoma. It stated that the Food and Drug Administration approves TTFields for glioblastoma and malignant pleural mesothelioma. In the studies reviewed, malignant pleural mesothelioma cells were mostly inhibited at 150 or 200 kHz, and the most common intensity was 1.75 V/cm. Several forms of cell death were reported. Most radiotherapy studies showed a combined effect. In mesothelioma cells, pemetrexed with TTFields was reported as additive, and cisplatin with TTFields as synergistic. Not every combination helped: in lung cancer cells, TTFields restrained cell death caused by the drug osimertinib. The side effects cited from clinical studies were mostly mild skin reactions. The authors concluded that the best combination could not yet be made clear because adequate research is lacking.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published research (mainly in-vitro laboratory studies)
• Who was studied: Published studies of TTFields, mainly in tumor cell lines (largely glioma and glioblastoma), with a few studies of primary cells, animal cell lines, animal models and clinical trials
• Exposure: Tumor Treating Fields: medium-frequency (100 to 300 kHz), low-intensity (1 to 3 V/cm) alternating electric fields, alone or combined with radiotherapy or chemotherapy drugs. Asbestos is not an exposure in this article.
• Main results:
  • The review states that the Food and Drug Administration approves TTFields for recurrent or newly diagnosed glioblastoma and for malignant pleural mesothelioma.
  • In the studies reviewed, malignant pleural mesothelioma cells were mostly inhibited at 150 or 200 kHz.
  • Across the laboratory studies reviewed, the commonly applied intensity was 1 to 2 V/cm, most often 1.75 V/cm.
  • The studies reviewed reported several modes of cell death with TTFields, including apoptosis, autophagy, immunogenic cell death and pyroptosis.
  • Whichever was applied first, ionizing radiation or TTFields, most studies of the combination showed a combined effect.
  • In malignant pleural mesothelioma cell lines (MSTO-211H, NCI-H2052), pemetrexed plus TTFields was reported as additive, and cisplatin plus TTFields as synergistic.
  • Not every combination was beneficial: in lung adenocarcinoma cells, TTFields restrained apoptosis induced by osimertinib and reduced that drug's efficacy.
  • The clinical studies cited reported mostly grade 1 to 2 skin reactions, such as mild to moderate rash under the electrodes.
  • The authors stated that TTFields has inhibitory effects in a variety of tumors.
• The authors' conclusion: The authors concluded that TTFields alone or combined with radiotherapy and chemotherapy has shown effects in various tumors, but that the best combination scheme is difficult to make clear because adequate research is lacking.
• Limitations the authors state:
  • The authors state that TTFields studies are relatively limited.
  • The authors state that few studies have examined drug-resistant cell lines.
  • The authors state that few studies have examined the mechanism by which TTFields increases permeability.

Topics

Medical terms in this study, explained in our Lexicon: Tumor Treating Fields (TTFields), Chemotherapy, Pleural Mesothelioma, Apoptosis.

Related studies

• Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models — H. Mumblat, A. Martinez-Conde, et al. (2021)
• The safety profile of Tumor Treating Fields (TTFields) therapy in glioblastoma patients with ventriculoperitoneal shunts — N.A. Oberheim-Bush, W. Shi, et al. (2022)
• Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Acting Dynamics — T. Voloshin, R.S. Schneiderman, et al. (2020)
• A review of tumor treating fields (TTFields): advancements in clinical applications and mechanistic insights — X. Li, K. Liu, et al. (2023)
• Expert guidance on prophylaxis and treatment of dermatologic adverse events with Tumor Treating Fields (TTFields) therapy in the thoracic region — M.J. Anadkat, M. Lacouture, et al. (2022)
• Treatment with tumor-treating fields (TTFields) suppresses intercellular tunneling nanotube formation in vitro and upregulates immuno-oncologic biomarkers in vivo in malignant mesothelioma — A. Sarkari, S. Korenfeld, et al. (2023)

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