Thursday, December 17, 2015

Low intensity radiofrequency fields can block brain tumor progression

Joel's comments: The following study published today in the Journal of the American Medical Association reports on a randomized clinical trial for patients with brain cancer (i.e., glioblastoma).

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).
A paper recently published in Scientific Reports sheds light on the mechanism by which TTFields block tumor progression. The low intensity, radiofrequency fields interfere with cancer cell division (i.e., mitosis) resulting in cancer cell death. A control condition was employed in this study which used electrodes that generated heat comparable to what the TTFields produced; however, the manufacturer reports the device does not significantly heat tissue.
"In an electric field of alternating direction (ac field) all charges and polar molecules are subjected to forces of alternating direction so that ionic flows and dipole rotation oscillate (Fig. 1). In view of the relatively slow kinetics of the bioelectrical responses, as the ac fields' frequency is elevated, their biological effect (except for heating) is reduced such that, >10 kHz, it becomes negligible. Therefore, it is generally believed that ac fields of 100 kHz or above have no meaningful biological effects (5), although a number of nonsignificant effects have been described (6–8)."

According to an earlier report on TTFields, the best result is obtained at an intensity of 2.25 volts per centimeter and a frequency of 200 kHz.
It would be interesting to hear how scientists who deny that radiofrequency fields can have meaningful biological effects without heating tissue explain the results of these studies which are more than likely non-thermal effects.


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.
Glioblastoma is the most common malignant tumor of the central nervous system,1 and one of the most difficult cancers to treat. Standard therapy includes maximal surgical resection, high-dose external-beam radiation therapy, and regional or systemic chemotherapy. Still, 5-year survival rates are only 5%.1 Current therapies lack specificity, fail to address tumor heterogeneity, or are limited because of an inability to penetrate the blood-brain barrier. Because conventional strategies lack success, investigational approaches,26 with varying degrees of supportive evidence, are often used. Historically, advances in this field have been separated by decades of failure. Life expectancy for patients with glioblastoma has changed little during the past decade, and median survival remains at less than 15 months.7
In this issue of JAMA, Stupp and colleagues8 report their evaluation of a novel approach to the treatment of glioblastoma using transcutaneous delivery of low-intensity intermediate-frequency alternating electric fields (AEFs), also referred to as tumor-treating fields (TTFields). In this multisite randomized clinical trial, adult patients with supratentorial glioblastoma who had no evidence of tumor progression following the completion of standard chemoradiotherapy were randomized (2:1) to receive maintenance treatment with either TTFields and temozolomide (n = 466) or temozolomide alone (n = 229), with median time from diagnosis to randomization of 3.8 months in both groups. The study was not blinded because a sham treatment was considered inappropriate.
The trial was terminated as a result of a planned interim analysis demonstrating a benefit in progression-free survival (PFS) in the intent-to-treat population, which was the primary end point of the study. The interim analysis included 210 patients randomized to the TTFields and temozolomide group and 105 patients randomized to the temozolomide alone group. Median PFS in the intent-to-treat population was 7.1 months in the TTFields and temozolomide group vs 4.0 months in the temozolomide group (hazard ratio, 0.62 [98.7% CI, 0.43-0.89]; P  = .001). Overall survival, a powered secondary end point prespecified to be based on the per-protocol population, was also significantly enhanced when study accrual was halted. Median overall survival was 20.5 months in the TTFields and temozolomide group vs 15.6 months in the temozolomide alone group (hazard ratio, 0.64 [99.4% CI, 0.42-0.98]; P  = .004). The robustness of this interim analysis was supported by additional analyses on all 695 patients randomized in the study to date (with final analysis planned after follow-up data collection is completed in the entire study population). As expected from a locally delivered therapy, the delivery of AEFs was not associated with any significant increase in systemic toxic effects, though there was a higher incidence of scalp irritation, anxiety, confusion, insomnia, and headaches. The incidence of seizures was not increased.
It has been hypothesized that the polarity of AEFs at specific frequencies can disrupt spindle formation during cell division and lead to mitotic arrest. When AEFs are applied to human and rodent cancer cell lines in vitro using insulated wires fixed to the bottom of standard cell culture dishes, there was a significant inhibition of cellular proliferation across all cell lines tested.9 Microphotography showed examples of prolonged mitoses with nuclear rotation, proliferation arrest, and apoptotic cell death supporting the hypothesis. In mice, AEFs generated by intradermal insulated wires placed alongside subcutaneous tumors inhibited growth.9 Similarly, growth of orthotopic rat gliomas was inhibited using 3 electrodes positioned on the head that generated a calculated 1 to 2 V/cm at the tumor when accounting for the impedance of the electrode insulation and the rat head.10 Further studies, again by the same group,11 demonstrated an additive effect with some chemotherapies, although temozolomide, the specific chemotherapy used to treat patients in this study, was not tested. Overall, even though the ability of AEFs to inhibit cell growth is apparent in some situations and appears to be dependent on the frequency, intensity, and direction of the electrical field, the specificity of this effect for cancerous cells has not been established and the exact mechanism still remains unclear.
Early human studies supported by Novocure Ltd, the company marketing the TTFields device, were encouraging. In a single group pilot trial of 10 patients with recurrent glioblastoma, the scalps of patients were covered with insulated electrodes and 50 V was applied.10 This was designed to produce 1 to 2 V/cm deep within the brain based on 3-D phantom simulations that were apparently validated in 1 patient undergoing surgery for hydrocephalus. A frequency of 200 kHz was used because this was thought to be the optimal frequency in rat and human experimental glioma models. The field directions alternated in 2 perpendicular directions. The median PFS and overall survival for treated patients was encouraging at 26.1 weeks (range, 3-124 weeks) and 62.2 weeks (range, 20.3-124.0 weeks), respectively.
A subsequent phase 3 trial also in patients with recurrent glioblastoma was not as convincing. Patients were randomized to receive TTFields using the NovoTTF-100A device (20-24 h/d) or a physician’s choice of chemotherapy. The device produced no increase in overall survival in this study with a power of 80% to detect a hazard ratio for death of 0.63, although more partial or complete radiological responses were observed in the TTFields group. Some suggested, however, that these data supported equivalence of this new therapy to standard chemotherapy regimens that can have activity in this setting. Despite agreeing that TTFields did not demonstrate superiority and identifying several methodological flaws in study execution, the device was approved by the US Food and Drug Administration (FDA) for recurrent glioblastoma.12 Still, the Centers for Medicare & Medicaid Services (CMS) administrative contractors for Medicare subsequently issued a coverage determination that TTFields therapy was not medically necessary.13 When the final results of the study by Stupp et al are available, this coverage determination in patients with recurrent glioblastoma may be reconsidered, perhaps in the context of the recently updated CMS guidance document that outlines coverage with evidence development.14 This allows coverage for a device in the context of a clinical trial in which patient outcomes can be tracked to evaluate whether a benefit exists.
Data from the current study by Stupp et al8 appear to support the use of AEFs in combination with temozolomide for patients with glioblastoma prior to recurrence. Although the results presented by Stupp et al show less improvement in survival than in the pilot study,11 as can be expected in a randomized trial of any therapeutic intervention, this study represents the first in a decade to demonstrate an improvement in survival in this disease. As a result, the FDA recently approved this therapy in combination with temozolomide for patients with glioblastoma prior to recurrence as well. The current cost of the device is approximately $20 000 per month, partly because the electrodes are disposable and are replaced frequently.
Several aspects of this study deserve further consideration. The study was neither blinded nor placebo-controlled, so the potential power of a placebo effect cannot be assessed. Although the placebo effect has been described,15 and arguably misinterpreted for decades, most physicians would acknowledge its potential to influence symptomatic and even some physiological outcomes.1618 Understanding the effect of placebos on survival, however, is more complicated.
Placebos are rarely associated with tumor responses in well-designed randomized clinical trials.19 Still, patients who only take placebos reliably live longer than those who do not.20 So, rather than a true placebo effect, could the lack of a sham treatment in this study produce an effect similar to an adherence bias? Patients who adhere to prescribed therapies are also more likely to exhibit other healthy behaviors or beneficial interactions that can produce real and significant survival advantages. In some studies, adherence is one of the strongest independent variables associated with outcome.20 Similarly, in studies of this device, adherence is associated with better overall survival.21,22 A survival benefit might be associated with use of this device if either the device works or it produces a type of adherence bias. There is no way to tell from this study. Evidence of a consistent preferential benefit of the device in a subset of patients who did not differ in adherence might reduce these concerns.
There could also be another related confounding factor in this study. Patients in the temozolomide alone (control) group received less adjuvant chemotherapy than those in the treatment group. Patients in the control group received a median of only 4 cycles of temozolomide before tumor progression, whereas patients in the TTFields and temozolomide cohort received 6 cycles. Similar treatment disparities have raised concerns in other studies.23 In the pivotal study of sipuleucel-T immunotherapy for prostate cancer, a higher percentage of patients received docetaxel following study drug than received placebo, and these patients also received chemotherapy earlier. Although the FDA ultimately found no specific evidence that docetaxel treatment following randomization affected survival in the case of sipuleucel-T, these analyses were limited by patient numbers.
In the report by Stupp et al,8 the question arises as to why patients in the TTFields and temozolomide group received more temozolomide. Is it because they were benefitting from the device? If so, they would not have had signs of tumor progression, and temozolomide would have been continued. On the other hand, could patients and physicians have minimized symptoms or signs of a recurrent tumor in the group being treated with TTFields and temozolomide because of the assumption that the device would work? This would also have prolonged the use of temozolomide, an effective chemotherapy for glioblastoma, in these patients. Delays in central radiographic review could have further potentiated such a bias in this study, though the number of discrepancies between local and central radiographic interpretations was low. Against these additional doses of temozolomide having a significant effect are data from another study4 in a similar patient population wherein increased exposure to temozolomide produced no increase in median survival. Patients with glioblastoma and clinicians who treat them will eagerly await the final study report to see if the favorable PFS and overall survival results reported in this interim analysis are sustained, even though a significant crossover of patients may also cloud the interpretation of these final results.
Successful treatments for glioblastoma are few and far between. The TTFields device produces locally delivered AEFs that are purported to arrest mitosis in tumor cells deep inside the brain. The mechanisms whereby this novel approach can treat tumors and leverage chemotherapy, however, remain unclear. Given the survival benefit reported in this study, it should now be a priority to understand the scientific basis for the efficacy of TTFields; achieving this may require the development of robust and widely available large animal models for glioblastoma, which do not currently exist. Perhaps most concerning, because of the study design chosen, doubts may remain as to the true efficacy of this therapy. So, if TTFields therapy fails to be adopted, will this decision be attributed to professional parochialism or to data that are not trusted? The current study provides additional important data on a novel device for the treatment of glioblastoma, but it will not completely resolve that debate.
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.

JAMA. 2015;314(23):2535-2543. doi:10.1001/jama.2015.16669.

Importance  Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly.
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 Identifier: NCT00916409
Open source paper:
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.

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.

Joel M. Moskowitz, Ph.D., Director
Center for Family and Community Health
School of Public Health
University of California, Berkeley

Electromagnetic Radiation Safety

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