Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors

doi:10.1073/pnas.0702916104

Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors

*NovoCure Limited, Matam Advanced Technology Centre, Haifa 31905, Israel;
^†Na Homolce Hospital, Roentgenova 2, 150 30 Prague 5, Czech Republic;
^‡Rambam Medical Center, PO Box 9602, Haifa 31096, Israel;
^§Basel University Hospitals, Hebelstrasse 32, 4031 Basel, Switzerland;
^¶Centre National de la Recherche Scientifique, Laboratoire d'immunologie et Embryologie Moléculaire, Rue de la Ferollerie, 45071 Orleans, France;
^‖Weizmann Institute of Science, PO Box 26, Rehovot 76100, Israel; and
**B. Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Technion City, Haifa 32000, Israel

Communicated by Joseph Schlessinger, Yale University School of Medicine, New Haven, CT, April 5, 2007 (received for review January 15, 2007)

Abstract

We have recently shown that low intensity, intermediate frequency, electric fields inhibit by an anti-microtubule mechanism of action, cancerous cell growth in vitro. Using implanted electrodes, these fields were also shown to inhibit the growth of dermal tumors in mice. The present study extends these findings to additional cell lines [human breast carcinoma; MDA-MB-231, and human non-small-cell lung carcinoma (H1299)] and to animal tumor models (intradermal B16F1 melanoma and intracranial F-98 glioma) using external insulated electrodes. These findings led to the initiation of a pilot clinical trial of the effects of TTFields in 10 patients with recurrent glioblastoma (GBM). Median time to disease progression in these patients was 26.1 weeks and median overall survival was 62.2 weeks. These time to disease progression and OS values are more than double the reported medians of historical control patients. No device-related serious adverse events were seen after >70 months of cumulative treatment in all of the patients. The only device-related side effect seen was a mild to moderate contact dermatitis beneath the field delivering electrodes. We conclude that TTFields are a safe and effective new treatment modality which effectively slows down tumor growth in vitro, in vivo and, as demonstrated here, in human cancer patients.

Footnotes

^††To whom correspondence should be addressed. E-mail: yoram{at}novo-cure.com
Author contributions: E.D.K., D.M., R.S., Y.W., E.D., and Y.P. designed research; E.D.K., V.D., F.T., J.V., J.F.S., A.I., D.M., S.S.-S., Z.G., R.S., M.S., B.R., D.G., E.D., and Y.P. performed research; E.D. contributed new reagents/analytic tools; E.D.K., V.D., F.T., J.V., D.M., S.S.-S., Z.G., R.S., Y.W., E.D., and Y.P. analyzed data; and E.D.K., R.S., and Y.P. wrote the paper.
Conflict of interest statement: Y.P. has a minority holding in NovoCure Ltd. and is a member of the company board of directors; E.D.K., A.I., D.M., S.S.-S., Z.G., R.S., and Y.W. are employed in full or part by NovoCure Ltd.; and M.S. is a clinical trial consultant to NovoCure Ltd.
This article contains supporting information online at www.pnas.org/cgi/content/full/0702916104/DC1.
↵ ‡‡ Kirson, E. D., Dbalý, V., Rochlitz, C., Tovaryš, F., Salzberg, M., Palti, Y., AACR Meeting Abstracts, April 5, 2006, Washington, DC, Abstract 5259.
↵ §§ Dbalý, V., Kirson, E. D., Palti, Y., Gutin, P.H., Congress of Neurological Surgeons, October 13, 2005, Boston, MA (abstr.).
↵ ¶¶ Gutin, P., Kirson, E., Palti, Y., Dbalý, V., International Brain Tumor Research and Therapy Meeting, April 26, 2006, Napa Valley, CA (abstr.).
Abbreviations:

FEM,

finite element mesh;

GBM,

glioblastoma;

OS,

overall survival;

PFS6,

progression-free survival at 6 months;

TTFields,

tumor treating fields;

TTP,

time to disease progression.
Freely available online through the PNAS open access option.