Tumor-Treating Field Therapy Looks Beyond Brain Cancer

Roger Stupp, MD

The National Comprehensive Cancer Network (NCCN) made history when it updated its glioblastoma treatment guidelines in March. The group became the first learned body to endorse the routine frontline use of an entirely new treatment modality known as tumor-treating fields (TTFs).

The Optune system, a wearable device that the FDA initially approved in 2011 for glioblastoma following tumor recurrence, now carries an NCCN category 1 recommendation in combination with radiotherapy and temozolomide for patients who have undergone surgery.¹

The technology uses low-intensity electrical fields to disrupt tumor cell division, and it represents the biggest step forward against glioblastoma in more than a decade. A phase III trial published last December in the Journal of the American Medical Association (JAMA) found that using TTFs in addition to temozolomide extended median progression-free survival (PFS) by 2.7 months and median overall survival (OS) by 4.9 months over temozolomide alone.²

Investigators are currently exploring TTF—and at least 2 related technologies—against a wide variety of additional tumor types in hopes that this new modality may prove as broadly effective as immunotherapy, or even chemotherapy.

Novocure, the company that developed Optune, is testing the technology in approximately 30 ongoing studies, including pivotal phase III trials in patients with pancreatic cancer (PANOVA-3; NCT03377491), non-small cell lung cancer (NSCLC) with up to 10 brain metastases following radiosurgery (METIS; NCT02831959), and stage IV NSCLC (LUNAR; NCT02973789).

More than 20 cancer centers throughout the world are studying Novocure’s TTF therapy, according to the company. The technology uses electrical fields that alternate 100,000 to 300,000 times per second; electromagnetic frequencies targeted to specific tumor types are 150 kHz for pancreatic cancer and NSCLC to 200 kHz for glioblastoma and ovarian cancers.³ Those frequencies are below those used in x-rays and slightly above those in ultrasound (Figure).

If effective, TTF therapy would likely complement other treatment types rather than replace them. Trials to date suggest that it would be safe to use with other modalities because its adverse events (AEs) do not mimic those of other therapies. Indeed, trials to date have found limited AEs associated with TTFs. The most prevalent AE associated with TTF in the glioblastoma trial was mild-to-moderate skin irritation from the transducer arrays that attach to the patient’s head.

Nevertheless, the use of electromagnetic currents as anticancer therapy is far from widespread adoption. Its success requires not only demonstrable efficacy against many tumor types but also eventual acceptance by skeptical oncologists.

“Chemical and electrical processes are both important to the body’s operation, but medicine has always focused so much on the chemical side that the idea of treating disease with electricity still seems vaguely crazy to most people, including a lot of doctors,” said Warsito P. Taruno, PhD, who developed an electrical field system after his sister developed breast cancer.

Taruno’s sister has survived until now, so he continued developing the technology at CTECH Laboratories, a company based in Jakarta, Indonesia, that he runs. CTECH lags market-leader Optune, but Taruno believes that the modality will be a large enough industry to support many companies.

Figure. Tumor-Treating Fields in the Radiofrequency Spectrum

A Growing Body of Research

“It actually makes more sense to treat cancer from an electrical perspective rather than a chemical perspective because cancer tends to be chemically stable and electrically instable,” Taruno said. “In theory, it should be possible to disrupt the electrical activity in many cancers and force tumors to commit suicide.”The idea of using electromagnetic fields to treat cancer dates back at least as far as the 1920s, when investigators demonstrated that ultrashort wavelengths initially spurred rapid growth and then tumor destruction in plants.⁴ It wasn’t until the 1990s, however, that investigators found a practical use for electromagnetic fields in cancer treatment: radiofrequency ablations for hepatic cancers.⁵ In the study, a needle electrode was advanced into the tumor for the delivery of a high-frequency alternating current. Although surgical resection was still favored, the results showed radiofrequency ablation of unresectable tumors provided local disease control.

Novocure has been testing the idea of using much gentler electrical fields for more than 15 years now. The company began its life in the basement of Yoram Palti, MD, PhD, a physiologist at the Technion-Israel Institute of Technology who thought that the effects of electromagnetic fields on cell division might make them a potent cancer treatment. A steady stream of positive trial results led the FDA to approve the company’s first device for the treatment of some patients with recurrent glioblastoma in 2011.

Its inclusion in the NCCN guidelines for the treatment of newly diagnosed glioblastoma stems from the results of a randomized trial in 695 patients. Doctors first treated those patients with standard chemoradiation and then randomized them between the previous standard of care—temozolomide monotherapy—and temozolomide plus TTF therapy. The 466 patients receiving TTF therapy wore 4 transducer arrays on their shaved heads continuously. Cords running from the arrays connected to a portable generator that patients could carry around like a Walkman.

Median PFS from randomization was 6.7 months in the trial group and 4.0 months in the control group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median OS was 20.9 months in the trial group versus 16.0 months in the control group (HR, 0.63; 95% CI, 0.53-0.76; P <.001).²

The study authors noted that such numbers posed a striking contrast to those from 23 other glioblastoma trials conducted over the past decade, all of which tested novel agents or dosing regimens without producing significant benefits. TTF therapy is therefore the biggest breakthrough in glioblastoma treatment in at least a decade, and the final numbers from the trial represent the technology’s potential benefit.

An interim analysis in 2015 showed improvement in both PFS and OS, and the independent data safety and monitoring committee recommended the trial be terminated early, thereby allowing 26 control group patients (11%) to move into the experimental arm.⁶ Although these patients enjoyed the benefits of TTF, investigators still counted them as control group patients because they began with more favorable baseline characteristics than other patients, and study leaders did not want to bias results toward TTF by counting them with the TTF group or excluding them altogether.

Of course, glioblastoma is a rare cancer. The National Cancer Institute predicts that it will account for just 14,000 of roughly 1.74 million cancers diagnosed in the United States this year.^7,8 TTF therapy must prove itself effective against more common tumor types if it is to become an important new weapon in the war against cancer. The early signs are positive. Phase II trials of Novocure’s TTF technology have found that it improves outcomes for patients with brain metastasis (100,000 diagnoses per year⁹), NSCLC (224,390 diagnoses per year¹⁰), pancreatic cancer (55,400 diagnoses per year¹¹), and ovarian cancer (22,240 diagnoses per year¹¹).

Notably, a phase II trial of TTF therapy plus nab-paclitaxel (Abraxane) and gemcitabine in patients with advanced pancreatic cancer reported a median PFS of 12.7 months compared with 5.5 months in patients in historical controls taking nab-paclitaxel plus gemcitabine.¹² In ovarian cancer, the use of TTF therapy in combination with paclitaxel in the phase II INNOVATE trial demonstrated a median PFS of 8.9 months (95% CI, 4.7-not reached) and the median OS was not reached.³ This compared favorably with historical results of a 3.9-month median PFS with weekly paclitaxel and a 13.2-month median OS.³

That said, the sample sizes have been relatively small. For example, just 20 patients made up the cohort in the pancreatic cancer trial and 30 participated in the ovarian cancer study. The ongoing phase III trials are seeking to test the therapy in far larger cohorts: 270 patients in METIS, 534 in LUNAR, and 556 in PANOVA-3.

“We obviously won’t know what tumors do and don’t respond to TTF until pivotal trials report data. Our best guess, at this point, is that this type of TTF could work on a wide range of locally expanding tumors but that it won’t do much for widely disseminated cancers. The rule of thumb may well turn out to be that if surgery and/ or radiation have a role in treating a particular tumor, then TTF is likely to have a role as well,” said Roger Stupp, MD, the chief of neuro-oncology at Northwestern Medicine and associate director of its cancer center in Chicago, Illinois. He is the lead investigator of the TTF glioblastoma trials.

TTF appears to work by changing the alignment of polarized cells and distorting normal electromagnetic activity inside affected parts of the body—both of which hinder normal cell division. It doesn’t seem to have much impact on healthy cells, which never divide in the brain and rarely divide in many other parts of the body. It is much more destructive to tumors, however, because they divide much more rapidly. Results from lab studies show that it sometimes force tumors to kill themselves via faulty cell production.

New System in Development

“Wearing a device nearly 24-7 still strikes many people as a weird way to treat cancer, but then chemotherapy also seemed like a crazy idea at first. The skeptics said that no sane doctor would administer systemic poison and no sane patient would take it. Then all the trials showed significant benefit, and chemotherapy became the most common cancer treatment,” Stupp said. “If TTF can demonstrate therapeutic benefits, it will be adopted by everyone, including doctors and patients who cannot currently imagine treating cancer with a battery pack, some wires, and a few sticky transducer arrays.”A second electrical field system in development works differently from Novocure’s device. Rather than sending an electrical current from a set of arrays affixed to the afflicted body part, through the tumor, and back into opposing arrays, the TheraBionic system delivers a radiofrequency electromagnetic field (RF EMF) through the entire body via a spoon-shaped device that patients suck on for 3 daily sessions.

TheraBionic was developed by Alexandre Barbault and Boris Pasche, MD, PhD, at nearly the exact same time that Palti was tinkering in his basement with what eventually became the Optune system.

Pasche, who is now the director of Wake Forest Baptist Health’s Comprehensive Cancer Center, was treating patients with cancer in France and Switzerland in 2001. He and his fellow investigators recruited 163 of those patients to try the experimental device by using the argument that it exposed them to less RF EMF currents than a cellphone and that those who benefited might be included in a longer study.

They exposed different patients to different frequencies and eventually found that specific frequencies consistently produced physiological effects in patients with particular tumor types but no effects in healthy patients or in patients with other tumor types. Grade 1 fatigue was observed in 3 patients; there were no grade 2, 3, or 4 toxicities. Pasche and his colleagues kept providing treatment to 28 patients to assess the effect on cancer progression, and 6 of those patients had complete response (n = 1), partial response (n = 1) or sustained stable disease (n = 4).¹³

The technology was next tested in a single-arm, single-facility trial on 41 patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh A or B disease. Patients self-administered 3 treatments daily at 60 minutes each with the frequency that had been found to affect HCC until patients experienced disease progression or death. Investigators reported that 4 patients had objective responses (including 2 that lasted nearly 5 years) and 14 patients had stable disease for more than 6 months. Median PFS was 4.4 months (95% CI, 2.1-5.3 months) and median OS was 6.7 months (95% CI, 3.0-10.2 months).¹⁴

Those trials, along with an in vitro study that further demonstrated that frequencies found to disrupt particular cancers would consistently disrupt their intended targets, but not other cancers, generated significant media coverage.¹⁵

Since then, however, North Carolina-based TheraBionic LLC has gone silent—its website hasn’t been updated since 2012—but Pasche says the look of inactivity is deceiving. TheraBionic GmbH has been operating in Germany since 2013 and is seeking permission to sell its device for the treatment of advanced liver cancers in those who have failed on all other treatments.

“The device that generates the RF electromagnetic field is about the size of a portable CD player, and it’s connected to the mouthpiece by a long wire, so patients can sit on a chair with the box beside them and watch TV or read a book while they undergo treatment every day,” said Pasche, who became interested in cancer treatment after his brother died of leukemia while he was attending medical school.

Differences in Technologies

“I did a research fellowship at Memorial Sloan Kettering after medical school, and when I saw how much pain and disability patients suffered from existing treatments, I dreamed of finding a gentle treatment that was still genuinely effective. Chemotherapy in particular seemed slightly barbaric to me and—odd as this probably sounds coming from the director of a cancer center— it still does.”Although the hypotheses underlying the use of electrical fields are similar to those of TTF therapy, CTECH’s system has a different mechanism: It directs a low-intensity, intermediate-frequency electrostatic wave from 1 capacitive electrode, through a tumor, and into another electrode. The use of capacitive electrodes to distribute the electrical field eliminates the current’s going into the body and, thus, the requirement of direct contact of the electrodes with the skin. The device can be used over clothes or air layers. CTECH has named the system Electro-Capacitive Cancer Therapy.The company has not yet conducted trials in humans, but it has published preclinical study results demonstrating that its system can fight tumors.

Results from an in vitro study of MCF-7 breast cancer cell lines revealed that cells exposed to electrostatic waves decreased in number and proliferated less rapidly than nonexposed cells. Also, the external electrostatic treatment caused 28% to 39% growth inhibition efficacy of MCF-7 cells. The first group of results, which were published in the same paper, found that 2 weeks of exposure produced no physical changes in placebo mice, but tumors in 9 mice that had been injected with breast cancer shrank by an average of 67%.¹⁶

Results from a second study, presented at the Biennial Congress of European Association for Cancer Research in July, detailed outcomes for 27 rats (2 groups of 9 rats with mammary tumors plus 9 healthy rats in a placebo group). After 3 weeks of receiving treatment for 10 hours a day, the mammary-tumor rats had significantly lower tumor growth rates than the mammary-tumor rats that received no treatment (0.01 cm²/day versus 0.121 cm²/day).¹⁷

“Because of differences in the underlying technology, we believe that our system will work on different types of cancer than the Novocure system. Parts of the body with higher conductivity—like muscles or the brain—are not ideal. Our system should work better in lower-conductivity areas such as the breasts and lungs,” said Taruno. “But we’ll know more shortly. Phase I/II trials should be getting underway shortly.”

References

1. NCCN clinical practice guidelines in oncology: central nervous system cancers version 1.2018. NCCN website. nccn.org/professionals/physician_gls/pdf/cns.pdf. Updated March 20, 2018. Accessed July 23, 2018.
2. Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318(23):2306—2316. doi:10.1001/jama.2017.18718.
3. Novocure (NVCR) overview. Novocure website. http://3sj0u94bgxp33grbz1fkt62h-wpengine.netdna-ssl.com/wp-content/uploads/2018/05/NVCR_201805_Corporate_Presentation_vFF.pdf. Updated May 2018. Accessed July 23, 2018.
4. Gosset A, Gutmann A, Lakhovsky G, Magrou I. Essai de therapeutique du cancer experimental des plantes. C R Seances Soc Biol Fil. 1924;91:626-628.
5. Curley SA. Radiofrequency ablation of malignant liver tumors. Oncologist. 2001;6(1):14-23. doi: 10.1634/theoncologist.6-1-14.
6. 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. doi: 10.1001/jama.2015.16669.
7. NCI Staff. Glioblastoma—Unraveling the threads: a Q&A with Drs. Mark Gilbert and Terri Armstrong of the NIH Neuro-Oncology Branch. National Cancer Institute website. https://www.cancer.gov/news-events/cancer-currents-blog/2017/glioblastoma-research-making-progress. Published August 3, 2017. Accessed July 17, 2018.
8. Cancer Statistics. National Cancer Institute website. https://www.cancer.gov/about-cancer/understanding/statistics. Updated April 27, 2018. Accessed July 17, 2018.
9. Metastatic brain tumors and secondary brain cancer. Memorial Sloan Kettering Cancer Center website. https://www.mskcc.org/cancer-care/types/brain-tumors-metastatic. Accessed July 17, 2018.
10. Benjamin M, Brahmer JR, Forde PM, Kernstine KH, Grannis FW. Non-small-cell lung cancer. Cancer Network website. cancernetwork.com/cancer-management/non-small-cell-lung-cancer. Published June 1, 2016. Accessed July 17, 2018.
11. Cancer Facts and Figures 2018. The American Cancer Society website. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed July 25, 2018.
12. Benavides M, Guillen C, Rivera F, Gallego J, Lopez-Martin J, King M. PANOVA: A phase II study of TTFields (150kHz) concomitant with standard chemotherapy for front line therapy of advanced pancreatic adenocarcinoma. Abstract presented at: AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT130. abstractsonline.com/pp8/#!/4292/presentation/12447.
13. Barbault A, Costa PF, Bottger B et al. Amplitude-modulated electromagnetic fields for the treatment of cancer: discovery of tumor-specific frequencies and assessment of a novel therapeutic approach. J Exp Clin Cancer Res. 2009;28:51. doi: 10.1186/1756-9966-28-51.
14. Costa FP, de Oliveira AC, Meirelles R, et al. Treatment of advanced hepatocellular carcinoma with very low levels of amplitude-modulated electromagnetic fields. Br J Cancer. 2011;105(5):640—648. doi: 10.1038/bjc.2011.292.
15. Zimmerman JW, Pennison MJ, Brezovich I, et al. Cancer cell proliferation is inhibited by specific modulation frequencies. Br J Cancer. 2012;106(2):307—313. doi: 10.1038/bjc.2011.523.
16. Alamsyah F, Ajrina IN, Dewi FNA, Iskandriati D, Prabandari SA, Taruno WP. Antiproliferative effect of electric fields on breast tumor cells in vitro and in vivo. IJCC. 2015;6(3):71-77. doi: 10.14499/indonesianjcanchemoprev6iss3pp71-77.
17. Alamsyah F, Fadhlurrahman, Pello JI, et al. Non-contact electric fields inhibit the growth of breast cancer cells in animal models and induce local immune reaction. Poster presented at: 25th Biennial Congress of the European Association for Cancer Research (EACR); June 30-July 3, 2018; Amsterdam, The Netherlands. ESMO Open. 2018;3(suppl 2):A269. Poster PO-111. doi: 10.1136/esmoopen-2018-EACR25.636