Wearable Therapy Making Inroads in Oncology

Minesh Mehta, MD

The patient begins by shaving his head. He then places the 4 transducer arrays to his skull and turns on the low-voltage current, which courses through his brain for as long as the device is worn, with the recommendation being at least 18 hours a day, every day.

It may sound like dystopian science fiction, but the Optune system, with its tumor-treating electromagnetic fields, is actually one of the biggest advances in glioblastoma treatment in more than a decade.

It is also a particularly innovative example of a novel class of products for patients with cancer: wearable therapeutic devices.

Such devices have taken a comparatively long time to make any impact on oncology. Global sales of wearable health products, which were virtually nonexistent in 2010, reached $3.2 billion in 2015, according to industry analysts at Mordor Intelligence.¹

Oncology-related devices were such a small portion of the total, however, that the healthcare analyst at one market research firm said in an email that he had never separated cancer from the rest of the field and that he doubted any of his counterparts would bother breaking out such a “niche” segment at this point.

Tumor-Treating Field for Brain Cancer

The relative paucity of cancer wearables in past years stemmed from a variety of factors, but such products have begun to arrive in numbers that just might merit quantification by 2020, when Mordor expects wearable medical device sales to reach $7.9 billion.For the moment, the Optune system occupies a unique position. It is the only wearable product designed and approved to fight cancer directly rather than fighting the effects of the disease or the effects of cancer treatment regimens. The FDA has approved the device for patients with recurrent and newly diagnosed glioblastoma.

Yet although the Optune system is an entirely new category of cancer treatment, it operates upon a surprisingly simple principle.

Strands of DNA are dipoles; they have positive electric charges at one end and negative electric charges at the other. As a result, it is possible to make them line up in an orderly fashion—with all the positively charged ends facing the same direction and all the negatively charged ends facing the opposite direction—simply by running a current through them. Better still, it turns out, tumor DNA cannot divide normally and produce daughter cells when it is lined up in this manner.

Translating this observation into a product took far more time and effort than using better Bluetooth standards to build a stylish heart rate monitor. Nearly 15 years elapsed between the time when Israeli researcher Yoram Palti, MD, PhD, first hypothesized that low-voltage current could hinder tumor growth and the approval of the Optune system.

“A lot of people were pretty skeptical when they first heard the idea, but there’s just no ignoring the results.

In what’s known as the EF-14 study² on patients with newly diagnosed glioblastoma, using the NovoTTF-100A in addition to chemotherapy after surgery and radiotherapy was associated with an approximate 5-month increase in median survival time,” said Minesh Mehta, MD, deputy director and chief of radiation oncology at the Miami Cancer Institute.

“It has been considerably more than a decade since any new treatment showed anything like that big an effect in glioblastoma patients,” he added. Of course, glioblastoma is a relatively rare tumor type, but tumor-treating fields may eventually help a large percentage of patients with cancer. The Optune system is being evaluated in clinical trials in other types of brain cancer,³ Mehta noted, as well as in early-stage trials in lung cancer⁴ and other tumors located in the chest.

Cooling Caps to Prevent Hair Loss

“It is exciting to think that it could prove to be an entirely new weapon that works against a wide variety of tumor types, particularly because it is so well tolerated compared with other cancer treatments,” Mehta said. “It doesn’t cause pain other than some skin irritation. It doesn’t induce nausea. It doesn’t make patients weak. It just requires patients to apply a few transducer pads to the skin and carry a 3-pound device around. It obviously looks dramatic when it’s used on the head, but can be covered using hairpieces or headgear.”Unlike the Optune system, which requires users to sacrifice their hair, other wearable devices are designed to prevent patients with cancer from losing their hair while they undergo a more common type of treatment, chemotherapy.

There are a number of different products available, but they all work in the same basic way. Patients wear rubbery skull caps that keep their heads cold every time they go in for chemotherapy. Treatment generally begins an hour or so before the start of an infusion and continues for at least an hour after the infusion is over. The Penguin Cold Cap system has patients chill multiple caps in dry ice before treatment begins and then use each cap for 30 minutes before switching to a fresh cap. It has been available for monthly rental in the United States for several years now, but Penguin says it cannot sell the system to patients or market it as a medical device because it has never been approved by the FDA.

The was true for all cold cap systems until December 2015, when the FDA approved the DigniCap system from the Swedish company Dignitana AB on the strength of a clinical trial performed on 106 patients with breast cancer in the United States.⁵ (A similar system called the Paxman Scalp Cooling System is currently undergoing a phase III clinical trial.)⁶

“About 70% of the trial patients, who tended to be using protocols that would produce partial but not total hair loss, kept enough hair that they did not feel the need to wear a wig or scarf. The threshold for that is usually about 50% hair loss, but it depends on how much hair you start with,” said Susan A. Melin, MD, an oncologist-hematologist at the Wake Forest Baptist Cancer Center who helped run the DigniCap trial.

Researchers have long realized that cold temperatures reduce the impact of most chemotherapies, and they first considered using cold caps to prevent hair loss for patients with leukemia in the 1970s. The idea was not tested in any systematic way, Melin said, because of concerns that using ice to reduce the impact of chemotherapy on the scalp might make the head a sanctuary site for blood-borne cancers.

The concept resurfaced in the 1990s, when cold caps became available in Europe for patientswith solid tumors. (They still are not used for hematological cancers because of lingering concerns that they might reduce chemotherapy’s effect against such cancers.) Cold caps finally reached the United States several years ago, but the lack of FDA approval greatly restricted product advertisement and eliminated any chance of insurance coverage.

Since the FDA gave DigniCap its blessing, Dignitana has had the right to advertise the device as a safe and effective tool for reducing chemotherapy- related hair loss. The company also has built up trial data to convince skeptics. What it still lacks, though, is widespread acceptance by insurers. Dignitana says it is negotiating with insurers over the treatment, which costs $500 for each cycle of chemotherapy at Wake Forest.

“The hospital has not filed directly with insurers to receive reimbursement for DigniCap treatment. I have asked patients to check with their insurers to see if they'll cover the treatment now that it's FDA approved. I’m hoping that quality-of-life research scheduled to be presented in San Antonio is enough to secure full payment,” said Melin, who noted that hair loss is common in patients with many tumor types (ovarian, lung, testicular, etc) and that she has had male patients ask about (but not purchase) DigniCap treatment.

“Chemotherapy-induced hair loss is a declaration to yourself and the world that you really are sick. Research consistently shows that it affects how patients feel and act, and that it affects how others treat them,” she said. “It is a devastating side effect, and if there’s a way we can allow a significant number of people to avoid it, that’s a good thing.”

The trial data demonstrating that temperature can reduce the effects of chemotherapy on the hair have also inspired other researchers to look at how temperature can influence chemotherapy’s effects elsewhere. “An exciting idea is that people have been empowered to use cooling devices to try and prevent peripheral neuropathy,” said Hope S. Rugo, MD, a clinical professor of hematology and oncology and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco. She led the DigniCap trial.

More Ideas in Works

“There’s also been much interest in preventing nail changes with cooling, but the nail changes go away. Neuropathy is a different area. One of my colleagues in Japan presented some fascinating data at ASCO, looking at frozen gloves. The glove was used on the dominant side, both hand and foot, and no glove was used on the other; it showed that you had much less neuropathy on the frozen side.”Another wearable product that may lessen the effects that cancer (or cancer treatment) has on patients comes from a suburban Boston company called NeuroMetrix. That company’s Quell device wraps around the calf and uses low-frequency electricity to stimulate sensory nerves and induce the brain to block pain signals.

The company has teamed up with researchers at Scripps Translational Science Institute in San Diego to run a small trial in 40 adults who suffer chronic pain related to metastatic breast, prostate, or colorectal cancer.⁷ The trial will assess patient response every 2 weeks for a total of 10 weeks, keeping a particular eye on whether any significant number of patients reduce their opioid use by at least 20%.

Patients who wish to try the device for themselves need not wait for study results or FDA approval. NeuroMetrix already sells the Quell system, which includes a smart phone app that tracks sleep quality and other metrics, for $249. The overall market for wearable health technology focuses more on diagnosis than treatment. Last year, according to research from Technavio, global sales of wearable diagnostic products totaled $2.25 billion⁸—or about 68% of all wearable health product revenue.

Most of those dollars went to relatively simple products that monitor vital signs or track user sleep and activity. Such products can spot a number of conditions such as hypertension or atrial fibrillation, but they have little apparent use in cancer diagnosis. That said, there are at least a few companies that believe wearable technology has a valuable role to play in cancer prevention and detection.

Among the simplest of those products are wearable monitors designed to track sun exposure. L’Oréal and MC10 unveiled the My UV Patch at the 2016 Consumer Electronics Show in Los Vegas.⁹

Users stick the patch, which measures about a single square inch, onto any bit of exposed skin. The patch works with a smartphone app that tells users their cumulative sun exposure at any point in the day. Patches can be purchased at a retail price of $30 apiece, but they only last 3 to 5 days, so using the product consistently would be a significant expense. (Users who got an average of 4 days out of every patch would spend approximately $2700 a year.)

A company called Ultra may soon offer a cheaper solution, at least in the long run. Ultra, which already offers a smartphone app designed to help users track sun exposure, says it will soon sell a clip-on UV monitor that will provide precise exposure data to the app.¹⁰

The software from both L’Oréal and Ultra considers information about the user’s skin tone before making recommendations about when to get more sun (for vitamin D), when to use sunscreen, and when to get out of the sun. Neither company claims in its marketing materials that its product will reduce the risk of skin cancer, but both of them note that about 1 in 5 Americans will eventually develop skin cancer, largely because of excessive sun exposure.

Cyrcadia Health, on the other hand, hopes to be able to make very specific claims about the wearable product that it has developed. The iTBra uses sensors to detect temperature changes in breast tissue.

It then analyzes that information to spot breast cancer at its earliest stages. The product has already undergone a trial at Ohio State University that included more than 200 women, according to the company.¹¹ Results have shown an 87% correlation between the iTBra and clinical diagnoses.

Despite the name, the product is not a bra. It’s a flexible, x-shaped panel of sensors that will slip into any bra cup. Women wear a pair of sensors for 2 to 12 hours a month, every month. The sensors transmit data to the user’s smartphone or computer, which sends it on to Cyrcadia for analysis of temperature changes over time. Particular heat changes are associated with increased cell activity related to tumors.

The sensors are designed to work for all women, but their particular advantage seems to lie in detecting tumors in the roughly 40% of women who are believed to have dense breast tissue. The iTBra is currently being evaluated in a clinical trial to determine whether it can supplement mammography and ultrasound in predicting a breast cancer diagnosis.¹² A secondary goal is to find out whether the iTBra improves screening over mammography for patients with dense breasts.

Cyrcadia has little choice but to underwrite trials and seek FDA approval for a device that does something as complex and specific as diagnosing breast cancer. Other device makers must decide whether to undertake such a long and expensive process or whether to forgo formal trials and market themselves as consumer entertainment rather than true medical technology.

Impetus for Wearable Devices

The cost of trials is not the only drawback of seeking FDA approval. That path also limits how frequently companies can update and improve their products (unless they want to get a new product approved every 6 months). It also means their products have to work far more reliably than many consumer products currently do. However, companies that do the work to receive FDA approval can make claims that other companies cannot and could likely charge premium prices for their products, particularly if insurance companies decide to cover them.The ongoing boom in wearable health products, most of which involves products pitched directly to users, stems more from improvements in communications technology than improvements in medical technology.

Nearly all of the products on the market work with smartphones, which only became popular with the introduction of the iPhone 9 years ago. Even more important was the introduction of Bluetooth 4.0 in 2012. That new standard consumed about 90% less energy than its predecessor, a breakthrough that made it far easier to build a device that could last at least a day (and often far longer) without heavy battery packs.¹³ Looking forward, sales projections are speculative at best. Developers are constantly inventing new uses for these and other technologies.

Indeed, think back to the Optune and DigniCap systems. The first may produce a significant advance in cancer treatment with little more than a battery and some wires while the second can save most users from baldness with coolant and a stretchy cap.

References

1. Global wearable medical devices market—growth, trends and forecasts (2015-2020). Mordor Intelligence website. https://goo.gl/ x5TRaO. Published August 2016. Accessed September 21, 2016.
2. Stupp R, Taillibert S, Kanner AA, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma. JAMA. 2105;314(23):25345-2543.
3. Preliminary phase 2 data demonstrate tumor treating fields is safe in patients with brain metastases originating from non-small cell lung cancer [press release]. St. Helier, NJ: Novocure; December 2, 2015.
4. Novocure to present clinical trial designs and preclinical data on tumor treating fields at the 16th World Conference on Lung Cancer [press release]. St. Helier, NJ: Novocure; September 4, 2015.
5. Rugo HS, Klein P, Melin SA, et al. Clinical performance of the Digni- Cap system, a scalp hypothermia system, in preventing chemotherapy- induced alopecia. J Clin Oncol. 2015;33(suppl; abstr 9518).
6. NIH Clinical Trials.gov website. www.ClinicalTrials.gov. Identifier: NCT01986140.
7. NIH Clinical Trials.gov website. www.ClinicalTrials.gov. Identifier: NCT02809846.
8. Global diagnostic wearable medical devices market. Technavio website. https://goo.gl/DtjJCI. Published June 6, 2016. Accessed September 21, 2016.
9. L’Oréal debuts first-ever stretchable electronic UV monitor at the 2016 Consumer Electronics Show [press release]. Clichy, France: L’Oréal Group; January 6, 2016.
10. Say no to sunburn, say yes to natural vitamin D. Ultra website. https://goo.gl/Rgw9Kx. Accessed September 21, 2016.
11. Core technology. Cyrcadia Health website. https://goo.gl/9AH- 9We. Accessed September 21, 2016.
12. NIH Clinical Trials Registry. www.ClinicalTrials. gov. Identifier: NCT02511301.
13. Bennett B. The power of Bluetooth 4.0: it’ll change your life. Cnet. https://goo.gl/vJiN4j. Published March 2, 2012. Accessed September 21, 2016.