Using alternating electric fields to treat cancer

By Lynne Eldridge, MD 

 Medically reviewed by Doru Paul, MD

Tumor treating fields (TTF) are a new type of cancer treatment. Unlike many therapies, however, this treatment is non-invasive and essentially side-effect free with the exception of mild skin irritation. The therapy uses low-intensity, intermediate frequency, alternating electric fields to disrupt cell division in cancer cells without affecting normal cells. Currently approved for glioblastoma multiforme (the most common and aggressive type of brain cancer) and inoperable pleural mesothelioma, tumor treating fields are also being studied in other cancers, such as non-small cell lung cancer, pancreatic cancer, and ovarian cancer.

We will look at the effectiveness of tumor treating fields, how they appear to work, how skin irritation is managed, and what you can expect when undergoing this treatment.

Importance and History

Tumor treating fields are sometimes referred to as the "fourth modality" of cancer treatment, joining surgery, radiation therapy, and systemic treatments (chemotherapy, targeted therapy, hormonal therapy, and immunotherapy). As both the incidence and survival rates from cancer increase, researchers have been taking particular interest in treatments that have less impact on the quality of life for people living with cancer.

Tumor treating fields were first studied in preclinical studies (lab and animal studies) in the early 2000s and were found to interfere with the division of cancer cells, as well as make the cancer cells more sensitive to chemotherapy. In addition to treating cancer locally, it's thought that tumor treating fields may affect cancer in other regions of the body by priming the immune system (the abscopal effect).

Tumor treating fields (Optune) were originally approved in 2011 for recurrent glioblastoma multiforme. At the time, the approval was based on similar survival rates relative to other treatments, but with fewer side effects. Subsequent studies, however, have found that tumor treating fields can improve both deterioration-free survival and overall survival for people with these brain tumors. Improved survival (more than double of that seen with previous therapies) led to the approval of tumor treating fields for people with newly diagnosed glioblastoma as well. TTFs are also approved for inoperable pleural mesothelioma.

Uses and Effectiveness

Tumor treating fields have been approved for both newly diagnosed (in combination with temozolomide) and recurrent glioblastoma as well as inoperable pleural mesothelioma, and are being studied in non-small cell lung cancer, pancreatic cancer, and for brain metastases due to lung cancer. The best electrical frequency, however, varies with the particular type of cancer.

Glioblastoma Multiforme

As noted, tumor treating fields were first approved for recurrent glioblastoma not based on greater effectiveness, but for similar effectiveness with fewer side effects. Subsequent studies, however, have found the treatment to be superior to previously available treatments and it is now offered for people who have newly diagnosed tumors. In those who are newly diagnosed, tumor treating fields are started after surgery and radiation and along with Temodar (temozolomide).

Effectiveness

With recurrent glioblastoma, research following the approval of tumor treating fields found that people who received the treatment had more than double the 1-year and 2-year survival rates of those not treated.¹

With newly diagnosed glioblastoma, a 2017 study published in JAMA compared the outcomes of people who received maintenance Temodar chemotherapy alone with that of people who receive the combination of Temodar and tumor treating fields. (The treatments were started after people had surgery to remove the tumor or a biopsy and had finished chemotherapy/radiation.) The combination of Temodar and tumor treating fields resulted in significantly improved overall survival as well as progression-free survival).²

Quality of Life

A follow-up study of newly diagnosed glioblastoma patients in 2018 found that even though the combination of Temodar and tumor treating fields (in contrast to Temodar alone) did not have any negative impact on quality of life. People who were treated with the combination actually had better physical functioning, emotional functioning, and suffered less pain.³

Brain Tumor Location

A common question people ask about tumor treating fields is whether the location of the tumor matters. With surgery and radiation therapy, the specific location of a brain tumor can have a significant impact on whether the treatment can be used or how effective it may be. Tumor treating fields do not attenuate (die out) with distance from the transponder, so they can be used even for tumors deep in the brain.⁴

Tumor treating fields are indicated for "supratentorial" tumors (tumors in the upper part of the brain or cerebrum), but not infratentorial tumors (tumors in the back of the brain such as the cerebellum).

Pornpak Khunatorn / Getty Images

Mesothelioma

In 2019, tumor treating fields were approved for first-line treatment in people with unresectable (inoperable) pleural mesothelioma, in combination with a platinum-based chemotherapy drug (such as cisplatin or carboplatin) and Alimta (pemetrexed). In an abstract presented in 2019, researchers found that people receiving the combination of tumor treating fields with the chemotherapy had a median overall survival of 18.2 months compared with only 12.1 months in those who received the chemotherapy drugs alone. The treatment was well tolerated, with the vast majority of symptoms related to chemotherapy.⁵

Other Cancers

Preclinical studies (lab and animal studies) using tumor treating fields are in progress with a number of different cancers including breast, cervical, colon, stomach, liver, kidney, bladder, lung, and melanoma. In some of these studies it's thought that tumor treating fields may work together with some treatments (chemotherapy, immunotherapy, and radiation therapy) to make them more effective (a synergistic effect).

Clinical trials with humans are already in progress for some other cancers. Examples include:

• Brain metastases from non-small cell lung cancer: After early research found TTF very safe in this setting, a phase III clinical trial is evaluating TTF after stereotactic body radiotherapy (SBRT or "cyberknife") in people who have 1-10 brain metastases after stereotactic body radiotherapy. The hope is that people can benefit from TTF without the cognitive dysfunction see with whole brain radiation.⁶

• Pancreatic cancer: TTF is being studied in combination with chemotherapy.

• Non-small cell lung cancer: TTF is being studied with both lung adenocarcinoma and squamous cell carcinoma of the lungs. In a small European trial, combining TTF with Alimta as a second-line therapy improved the effectiveness with no increase in side effects.⁷

Side Effects and Contraindications

As with any cancer treatment, tumor treating fields can have side effects as well as reasons why the therapy should not be used (contraindications).

Common Side Effects

Overall, tumor treating fields have very few side effects with the exception of scalp irritation which is very common and can include dryness, flaking, and itching. In some cases this can lead to secondary skin infections or open sores (ulcers), but most of these reactions can either be prevented or treated if they occur (see management below). In the 2017 JAMA study on people with newly diagnosed glioblastoma, slightly over half of the people experienced mild to moderate skin reactions, but severe reactions (grade 3) occurred in only 2% of people.³

Skin irritation is more likely to occur in people who have previously had radiation to the area or in some environments (such as hot or humid climates). Some medications may also increase the risk of skin irritation.

Since tumor treating fields are a local treatment, side effects common with treatments such as chemotherapy are absent. No increase in seizures has been noted.²

Cautions

Some personal care products (moisturizing creams, etc.) may need to be avoided while using tumor treating fields, as research has found that some could potentially increase electrical impedance resulting in increased temperature under the arrays.⁸

People who have allergies to adhesive tape or hydrogel may not be able to tolerate the treatment.

Contraindications

Contraindications may be either absolute (the treatment should not be used), or relative (the treatment may be used but caution should be observed).

At the current time, the manufacturer (Novocure) doesn't recommend using TTF for people with implanted medical devices. That said, a 2018 study evaluated TTF in 104 people who had either pacemakers, defibrillators, non-programmable implanted shunts, or programmable shunts and did not find any safety issues.⁹

Other contraindications include people who deep brain stimulators, and in people who have skull defects (due the risk of skin damage).

How it Works

In order for cancer cells to divide, special proteins in the cell orient to pull the dividing cell into two cells. Tumor treating fields take advantage of the fact that these molecules have very strong electrical polarity (as well as the fact that cancer cells usually divide much more rapidly than normal cells, especially in the brain).

When tumor treating cells are applied to a tumor, these large proteins are unable to line up properly to pull apart the genetic material allowing a cell to divide into two cells. Many cells end up being unable to divide completely, while those that do are frequently abnormal and usually self destruct (undergo apoptosis).

Mitosis is the process of cell division, and the term "antimitotic" is used to describe any treatment that inhibits cell division. While chemotherapy is antimitotic throughout the body, tumor treating fields are only antimitotic in the region where they are directed.

In addition to interfering with cell division, tumor treating fields are thought to reduce DNA repair in tumor cells, interfere with cancer cell migration and invasion, and stimulate an anti-tumor immune response.

Frequency

The frequency of TTF is between 100 kHz and 300 kHz, with some types of cancer responding better to difference frequencies within this range. This frequency range lies on the spectrum between radio waves and microwaves.

Undergoing TTF Treatment

If your healthcare provider believes you are a candidate for TTF, an MRI scan will be done to determine the best placement sites for the transducers and you will be instructed in the application and proper care of the device.

While many people have been able to apply the device themselves, having a family caregiver or friend assist you can be priceless.

Many people wonder how quickly they will see results. It's important to note that studies looking at people with recurrent glioblastoma who ultimately had a durable response (long term control of their cancer with many people alive seven years after the treatment was started), roughly 15% had an initial worsening of their cancer (tumor growth) before the tumor began to shrink.¹⁰

Shaving Your Head

In order for the device to work effectively, your head must be cleanly shaved. This should be done prior to applying the device, and then every three to four days depending on how rapidly your hair grows.

Wearing the Device

The small transducers are attached to your head with adhesive bandages and will appear somewhat like a swimmer's cap when in place. It's important to make certain the transducers are applied properly and are comfortable, as the device is worn continuously (but may be removed for short periods of time to shower, etc.).

The transducers, in turn, are attached to wires that plug into the battery. The battery pack, which is roughly the size of a paperback book, can then be carried in whatever way is most comfortable for you. Some people prefer using a backpack, while others prefer a pack across the body or over the shoulder. You will need to carry the pack with you wherever you go, so you may wish to experiment to find the most comfortable method for you personally. The device may also be plugged directly into an AC plug.

The original device weighed around 5 pounds, but the device now used weighs only 2.7 pounds.

Unplugging

You may unplug the device for short periods of time to bathe and shower, but it's important to plug the device back in promptly so you don't forget. Unlike some medical treatments, tumor treating fields only work when they are applied.

Removing and Reapplying the Device

The site of the transducer arrays will need to be changed every three to four days on average. This is done to lower the chance of skin irritation, but the arrays do not need to be moved far (usually slightly less than an inch, but your healthcare provider will let you know). If you live in a hot or humid climate, or if you are very active and become sweaty this may need to be done more often.

Removing the Arrays

Prior to changing the site of the transducers, it's important to wash your hands well. This is especially important if you are also receiving chemotherapy, and is one of the most important steps you can take to stay out of the hospital.

The transducer arrays should then be removed by pulling back on the edges very slowly. To describe how slowly, it's been recommended that people spend roughly one minute removing each array. If the transducers aren't coming off easily, applying mineral oil to the edges may help with removal.

Inspecting the Scalp or Other Region

Before reapplying the arrays, it's important to carefully inspect the area where the transducers were placed looking for any redness, irritation, or signs of skin breakdown (discussed below). This is a step in which it's very helpful to have a caregiver present who can assist with the device. If you note any areas of concern, it's important to let your healthcare provider know. If you're uncertain whether any findings are of concern, you, a friend, or a family member might consider taking a photo of the area and send it to your practitioner to avoid an unnecessary trip to the clinic. Talk to your healthcare provider when you are fitted with your device to see if this is an option at your clinic.

Reapplying

The arrays should then be placed in their new position, roughly 3/4 of an inch from their previous location (or what your healthcare provider recommends). There will small areas of indentation where the arrays were previously placed which can be helpful as you make sure to reapply them in a new position.

When placing the arrays, try to avoid:

• Any areas that are red or irritated

• Surgical scars

• Bony prominences

Batteries

Several batteries as well as a charging station are included with the device package, and the device will alert you when it's time to change or charge the batteries.

Tolerability

Since the device must worn continuously, some people wonder how well the treatment is tolerated. In one study, it was found that 75% of people were able to stick with the treatment at least 75% of the time (were able to use the device 18 or more hours each day).¹⁰

Dealing with Skin Irritation

Skin irritation is very common during TTF treatment, but careful preventive care and promptly managing problems when they arise can lower the chance that your treatment will be interrupted for any period of time.

The average time from beginning tumor treating fields to the onset of adverse skin reactions ranges from two to six weeks.⁴

Prevention

Careful care of the area where the arrays are applied is very helpful, and may include changing the sites more frequently if needed. Some healthcare providers have recommended applying a topical aluminum chloride chloride to the scalp for those who sweat a lot, but this should be discussed with your healthcare provider first.

Treatment

Even with meticulous scalp care, irritation may still occur. That said, symptoms are usually managed without needing to temporarily discontinue the device.

Skin Irritation (Dryness/Flaking)

Mild irritation is usually managed with topical preparations. It's important to talk to your healthcare provider about what creams may or may not be used. You can also ask her for recommendations about shampoo. When irritation is substantial, prescription topical corticosteroid creams are often recommended (high potency creams such as Temovate (clobetasol) are used most often).¹¹

Skin Breakdown/Open Sores

If there are any regions of skin breakdown or open sores, a topical antibiotic is often recommended. For relatively mild breakdown, topical antibiotics such as Bactroban (muciprocin) are usually sufficient, with oral antibiotics needed for moderate or severe irritation.

In addition to treating irritation and open sores, it's important to prevent further damage that could result from allowing the discs or adhesive tape to contact the site.

A few suggestions have been made for managing these areas when they are near the new placement sites of the discs. One option is to cut a hole in the tape around the area that is irritated (this will also make it much easier to apply a topical antibiotic cream), as long as it is not underneath the disc. Another option is to cover the affected area with nonstick gauze before applying the adhesive tape.¹¹

Infections

Infections may arise in the areas where the arrays were applied, but folliculits related to shaving may also occur. Symptoms such as significant redness, drainage (pus), or crusting may signify an infection is present and requires a visit with your healthcare provider. Before treatment, a culture is usually done. Either topical or oral antibiotics may be needed depending on the severity of the infection.

Severe Skin Irritation

If skin breakdown or an infection is severe, the device may need to be stopped for a period of time. Your healthcare provider may also recommend seeing a dermatologist.

11 Sources

Burri SH, Gondi V, Brown PD, Mehta PM. The Evolving Role of Tumor Treating Fields in Managing Glioblastoma: Guide for Oncologists. American Journal of Clinical Oncology. 2018. 41(2): 191–196. doi:10.1097/COC.0000000000000395

Stupp R, Talilibert 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

Taphoorn MJB, Dirven L, Kanner AA, et al. Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncology. 2018. 4(4):495-504. doi:10.1001/jamaoncol.2017.5082

Mun EJ, Babiker HM, Weinberg U, Kirson ED, Von Hoff, DD. Tumor-Treating Fields: A Fourth Modality in Cancer Treatment. Clinical Cancer Reearch. 2018. doi:10.1158/1078-0432.CCR-17-1117

Ceresoli GL, Aerts J, Madrzak J, et al. STELLAR: Final results of a phase 2 trial of tumor-treating fields with chemotherapy for first-line treatment of malignant pleural mesothelioma. Multidisciplinary Thoracic Cancers Symposium. Abstract 4. Presented March 14, 2019.

Mehta MP, Gondi V, Brown PD. METIS: A phase 3 study of radiosurgery with TTFields for 1-10 brain metastases from NSCLC. Journal of Clinical Oncology. 2017. 35(15_suppl). doi:10.1200/JCO.2017.35.15_suppl.TPS9106

Pless M, Droege C, von Moos R, Salzberg M, Betticher D. A phase I/II trial of Tumor Treating Fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer. Lung Cancer. 2013. 81(3):445-450. doi:10.1016/j.lungcan.2013.06.025

Lacouture M, Hershkovich HS, Blat R, et al. QLIF-20. SKIN CARE PRODUCTS COMPATIBLE WITH TUMOR TREATING FIELDS. Neuro-Oncology. 2017. 19(suppl_6):205. doi:10.1093/neuronc/nox168.830

Kew Y, Oberheim NA. Safety Profile of Tumor Treating Fields in Adult Glioblastoma Patients with Implanted Non-Programmable Shunts, Programmable Shunts, and Pacemakers/Defibrillators: 6-Year Updated Retrospective Analysis. Radiation Oncology Biology Physics. 2018. 102(3):e269-e270. doi:10.1016/j.ijrobp.2018.07.873

Vymazal J, Wong ET. Response patterns of recurrent glioblastomas treated with tumor-treating fields. Seminars in Oncology. 2014. 41(Suppl 6):S14-24. doi:10.1053/j.seminoncol.2014.09.009

Anthony P, McArdle S, McHugh M. Tumor Treating Fields: Adjuvant Treatment for High-grade Gliomas. Seminars in Oncology Nursing. 2018. 34(5):454-464. doi:10.1016/j.soncn.2018.10.007

Additional Reading

Stupp R, Tailibert 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):2535-43. doi: 10.1001/jama.2015.16669

Wang Y, Pandey M, Ballo MT. Integration of Tumor-Treating Fields into the Multidisciplinary Management of Patients with Solid Malignancies. Oncologist. 2019. doi:10.1634/theoncologist.2017-0603

By Lynne Eldridge, MD
 Lynne Eldrige, MD, is a lung cancer physician, patient advocate, and award-winning author of "Avoiding Cancer One Day at a Time."