Tumor Treating Fields; Its Use in Glioblastoma Multiforme

1. Tumor Treating Fields
Its Use in Brain Tumors
Ade Wijaya MD – July 2019

2. Low intensity electric fields alternating at an intermediate frequency (200 KHz)
Block cell division
Interfere with organelle assembly
Hottinger AF, Pacheco P, Stupp R. Tumor treating fields: a novel treatment modality and its use in brain tumors. Neuro-oncology. 2016 Sep 23;18(10):1338-49.

3. Mechanism of Action
• Living cells consist of charged or polar molecules and ions and thus are
responsive to electrical fields and currents
• Cellular processes can be influenced by electric fields
• The overall effect will depend upon the magnitude of the potential difference
between the 2 electrodes (field intensity) and the frequency
Hottinger AF, Pacheco P, Stupp R. Tumor treating fields: a novel treatment modality and its use in brain tumors. Neuro-oncology. 2016 Sep 23;18(10):1338-49.

4. Mechanism of Action
Low Frequency ( < 1 KHz ) 
depolarize cells (neurons & myocytes)
• Cardiac pacemakers
• Deep brain stimulators
Very High Frequency ( > MHz )  heat
• Radiofrequency ablation
• Diathermy
INTERMEDIATE FREQUENCY (10-300 Khz)  Inhibit cell division
Palti Y. Stimulation of internal organs by means of externally applied electrodes. J Appl Physiol. 1966;21(5):1619–1623.
Storm FK, Morton DL, Kaiser LR et al. Clinical radiofrequency hyperthermia: a review. Natl Cancer Inst Monogr. 1982;61:343–350.
Kirson ED, Gurvich Z, Schneiderman R et al. Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004;64(9):3288–3295.

5. Mechanism of Action
• TTFields will block the mitotic cell cycle, in particular during metaphase,
anaphase, and telophase
• Cells will die in apoptosis
• The field intensity and frequency needs to be adapted to the tumor type and
cell properties (eg, cell size)
• As the cell division may occur at any time, prolonged exposure to the
electrical fields is required for maximal effect
Kirson ED, Gurvich Z, Schneiderman R et al. Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004;64(9):3288–3295.

6. Mechanism of Action
Giladi M, Schneiderman RS, Porat Y et al. Mitotic disruption and reduced clonogenicity of pancreatic cancer cells in vitro and in vivo by tumor treating fields. Pancreatology. 2014;14(1):54–63.
Kirson ED, Dbaly V, Tovarys F et al. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A. 2007;104(24):10152–10157.

7. Hottinger AF, Pacheco P, Stupp R. Tumor treating fields: a novel treatment modality and its use in brain tumors. Neuro-oncology. 2016 Sep 23;18(10):1338-49.

8. Tumor Treating Fields in
Glioblastoma
Multiforme
Stupp R, Wong ET, Kanner AA et al. NovoTTF-100A versus
physician’s choice chemotherapy in recurrent glioblastoma: a
randomised phase III trial of a novel treatment modality. Eur J
Cancer. 2012;48(14):2192–2202.
Stupp R, Taillibert S, Kanner AA et al. Maintenance Therapy
With Tumor-Treating Fields Plus Temozolomide vs
Temozolomide Alone for Glioblastoma: A Randomized
Clinical Trial. JAMA. 2015;314(23):2535–2543

9. Tumor Treating Fields in Glioblastoma
Multiforme
• In October 2015, the FDA approved TTFields for use in newly diagnosed
GBM patients
• Toxicity: local skin irritation which is usually mild, self-limiting, easily
manageable with local application of steroid-containing ointments, and may
require an occasional treatment break for a few days
• Some nonspecific adverse effects including nervous system disorders such as
grade 1–2 headache (21% in the experimental group vs 14% in patients with
TMZ alone), mild anxiety, confusion, insomnia, and headaches
Stupp R, Wong ET, Kanner AA et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012;48(14):2192–2202.
Stupp R, Taillibert S, Kanner AA et al. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015;314(23):2535–2543

10. Summary
• Tumor Treating Fields are able to positively impact tumor growth and
significantly extend survival in GBM
• TTFields is a locoregional treatment, and extending its use to other tumor
types and metastatic disease is most promising in clinical situations where
locoregional disease control is key for quality of life
• In October 2015, the FDA approved TTFields for use in newly diagnosed
GBM patients