All patients were treated with chemoradiation. Then two-thirds of the patients received low-intensity, intermediate frequency alternating electric fields in addition to oral chemotherapy. The remaining patients received only chemotherapy. The 200 kilohertz radiofrequency fields were delivered continuously (more than 18 hours per day) via four electronic devices placed on the shaved scalp and connected to a portable medical device. The chemotherapy (temozolomide) was given for 5 days of each 28-day cycle for 6-12 cycles.
Patients who received the electric fields (i.e., Tumor Treating Fields or TTFields) in addition to chemotherapy displayed a gain of 3 months in both median progression-free survival (from 4.0 months to 7.2 months) and median overall survival (from 16.6 months to 19.6 months).
Electric Fields for the Treatment of Glioblastoma
John H. Sampson. Alternating Electric Fields for the Treatment of Glioblastoma, JAMA. 2015;314(23):2511-2513. doi:10.1001/jama.2015.16701.
Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial
Roger Stupp et al. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.
Objective To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma.
Design, Setting, and Participants After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis.
Interventions Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle.
Main Outcomes and Measures The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up.
Results The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004).
Conclusions and Relevance In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival.
Trial Registration clinicaltrials.gov Identifier: NCT00916409
Open source paper: http://bit.ly/jamattfields
Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells
Moshe Giladi et al. Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells. Scientific Reports. 5. 2015. http://www.nature.com/
Tumor Treating Fields (TTFields) are low intensity, intermediate frequency, alternating electric fields. TTFields are a unique anti-mitotic treatment modality delivered in a continuous, noninvasive manner to the region of a tumor. It was previously postulated that by exerting directional forces on highly polar intracellular elements during mitosis, TTFields could disrupt the normal assembly of spindle microtubules. However there is limited evidence directly linking TTFields to an effect on microtubules. Here we report that TTFields decrease the ratio between polymerized and total tubulin, and prevent proper mitotic spindle assembly. The aberrant mitotic events induced by TTFields lead to abnormal chromosome segregation, cellular multinucleation, and caspase dependent apoptosis of daughter cells. The effect of TTFields on cell viability and clonogenic survival substantially depends upon the cell division rate. We show that by extending the duration of exposure to TTFields, slowly dividing cells can be affected to a similar extent as rapidly dividing cells
Electric fields of intermediate frequency (10 kHz to 1 MHz) were long considered to have no significant influence on biological processes as their alternation is too rapid to cause nerve-muscle stimulation and at low intensities cause minimal heating 5. It is only in recent years that the biological effects of intermediate frequency fields have been described. Electric fields in the frequency range of 100–500 kHz were found to have a profound inhibitory effect on the growth rate of a variety of cancer cell lines both in vitro and in vivo 6,7,8. This has subsequently led to the development of Tumor Treating Fields (TTFields) therapy. TTFields are low-intensity (1–3 V/cm) intermediate-frequency (100–300 kHz), alternating electric fields. Clinical trials have demonstrated the effectiveness and safety of continuous TTFields treatment in patients with glioblastoma and in patients with non-small cell lung cancer 9,10,11.
Control rats were treated by means of sham electrodes which were geometrically matched to the TTFields group. The Sham heat electrodes produced equal temperature changes to those produced by the field electrodes by means of a heating resistor incorporated within them.
Our results provide the first evidence supporting the direct effect of TTFields on microtubules, and specific effects on spindle assembly in replicating cells. We show for the first time, to our knowledge, that TTFields destabilize microtubules.
TTFields frequencies utilized in this series of investigation are the specific frequencies that have led to the highest reduction in cell counts, most likely by virtue of their effect on the mitotic spindle.
Center for Family and Community Health
School of Public Health
University of California, Berkeley
Electromagnetic Radiation Safety
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