A Prevention Strategy for Chemotherapy-Induced Peripheral Neuropathy in Patients with Breast Cancer May Be in Sight

For patients with breast cancer, chemotherapy-induced peripheral neuropathy (CIPN) is a common, long-lasting toxicity of many of the antineoplastic therapies given during treatment that can greatly impact their quality of life, Melissa Kate Accordino, MD, MS, explained during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. In the recently reported S1714 large cohort study (NCT03939481) that included more than 1000 patients starting taxane therapy, up to 68% developed clinically meaningful CIPN.¹

“There’s currently no effective pharmacologic agent for CIPN prevention, and the current strategy when patients develop CIPN is to dose-reduce their taxane therapy, which raises the concern of potentially impacting efficacy and long-term outcomes,” Accordino, director of the Hematology and Medical Oncology Fellowship Program, director of quality and patient safety in the Division of Hematology and Oncology, and associate professor of medicine at Columbia University Irving Medical Center in New York, New York, said during her presentation. “There are very limited options for treatment.”¹

Additionally, although there have been promising preliminary data for nonpharmacologic therapies, such as compression therapy and cryotherapy, the studies were small, nonrandomized, and self-controlled, according to Accordino. There have also been notable tolerability concerns with cryotherapy.¹

Accordino noted that ASCO does provide treatment recommendations for CIPN; however, the only intervention listed is duloxetine (Cymbalta, Lilly), which is noted as having moderate benefits with moderate recommendation of strength for use.^1,2

“This is really only for the treatment of painful CIPN, not numbness or tingling,” Accordino said. “So this really calls out that it’s important for us to find effective prevention therapies. Many pharmacologic agents have been tried and many have not been successful. In fact, several of these have caused our patients harm.”¹

Nonpharmacologic agents can offer an alternative mechanism and are often more accepted by patients than taking another pill, Accordino explained. These alternative therapies include acupuncture, exercise, compression therapy, and cryotherapy. Accordino noted that compression therapy and cryotherapy in particular are worth discussing further, both with the same mechanism of action in that they reduce vasoconstriction to prevent drug delivery to the extremities.¹

ASCO notes that the current data available for compression therapy and cryotherapy are insufficient to support a recommendation for their use outside the context of a clinical trial. However, ASCO additionally notes that more rigorous phase 3 studies are needed to further assess these nonpharmacologic agents.¹

Furthermore, the origins of cryotherapy for CIPN prevention are accidental, Accordino explained. In a study conducted in Denmark of over 1700 patients with early-stage breast cancer who were randomlyassigned to 1 of 2 chemotherapy regimens—epirubicin/cyclophosphamide/docetaxel or cyclophosphamide/docetaxel—participants were offered frozen gloves or socks to try to reduce nail toxicity related to taxane chemotherapy. Patient-reported peripheral neuropathy (PN) was also collected as one of the study end points.1

“In an exploratory analysis, participants who wore the frozen gloves or socks had a 44% reduced likelihood of developing neuropathy compared to participants who did not wear frozen gloves or socks,” Accordino said. “These data were hypothesis generating and led to some pilot studies. One of the first was the Hanai et al study [in Kyoto, Japan].”^1,2

In the nonrandomized Hanai et al study (UMIN000013398), 40 patients with breast cancer were treated with weekly paclitaxel. Study participants wore frozen Elasto-Gel gloves and socks on their dominant hand and foot. The nondominant side of patients’ hands and feet were the untreated control, Accordino explained.¹

“Patients had reduced risk of CIPN development both by tactile disturbance evaluated by monofilament and also by patient-reported outcomes [PRO],” Accordino said.¹

Following this study, a small, randomized, phase 2 trial was conducted that investigated cryotherapy for CIPN in patients with breast cancer who were given weekly paclitaxel. Patients in this study were randomlyassigned 1:1 to receive frozen Elasto-Gel gloves and socks for 15 minutes before, during, and 15 minutes after treatment, or receive untreated control. The primary end point of the trial was a decrease of FACT/GOG-NTX of 10%, which was considered a clinically meaningful reduction. The secondary end points were PRO PNQ, CTCAE G2+ sensory/motor PN, FACTTaxane, and tolerability.^1,3

“In terms of results, the patients who were treated with frozen gloves or socks had statistically significantly less development of CIPN: 73% of patients who were in the control arm developed clinically meaningful CIPN, while 41%—which is still a relatively large number—developed clinically meaningful CIPN in the cryotherapy arm,” Accordino said. “Of note, about 32% of patients in the treatment arm were nonadherent with the cryotherapy, and these were largely due to concerns related to tolerability.”¹

In a larger, randomized, multicenter study of 180 patients with an expanded set of regimens, including oxaliplatin, docetaxel, or paclitaxel, patients were randomly assigned 1:1 to receive frozen gloves (15 minutes before, during, and 15 minutes after treatment) or untreated control. The primary end point was PRO using the CIPN20 questionnaire—designed to supplement the core quality of life questionnaire of the European Organization for Research and Treatment of Cancer—in terms of subscale differences, with secondary end points being quality of life, tolerance, and dose reduction.¹

“This time, there was no treatment to the lower extremities, just the hands,” Accordino said. “The results showed no difference in the primary end point, which was patient-reported CIPN via the CIPN20 subscales. Specifically for CIPN20, one of the scales we’re most interested in is the sensory scale, and this was statistically not significantly different.”¹

When investigators looked at the responses to individual questions on the CIPN20, they found that participants did have significant differences pertaining to some of the questions around CIPN development in the hands, Accordino explained. Additionally, in this study 34% of patients discontinued treatment, primarily because of discomfort (65%).¹

“Switching gears to compression therapy, which again has the same mechanism of action as cryotherapy, but instead of using cold to obtain vasoconstriction, compression with pressure is used,” Accordino said. “This first pilot study for compression therapy, which is very similar to the first pilot study for cryotherapy, has 43 patients with breast cancer treated with nabpaclitaxel who were not randomized.”¹

In this Tsuyuki et al study (UMIN000024836), participants wore 2 surgical gloves 1 size smaller than their hand on their dominant side, with their nondominant side the untreated control. The primary end point was incidence of PN G2 or higher on CTCAE both sensory and motor neuropathy, with secondary end points of PRO PNQ and change in temperature of fingertips using thermography.^1,4

“In terms of their primary end point, there was statistically significantly less development of grade 2 or higher sensory or motor neuropathy, which was promising,” Accordino said.¹

The next study investigating compression was a double-blinded study of 56 patients with breast cancer who were treated with weekly paclitaxel and had no history of PN or taxane exposure. Patients were randomly assigned to receive the intervention of 2 surgical gloves 1 size smaller than their hand to either their right or left hand, or receive 2 gloves that were the normal size for their hands.¹

“So patients did serve as their own control,” Accordino said. “In this study, there was no difference in grade 2 or higher sensory or motor neuropathy.”¹

In terms of studies evaluating which intervention may be the preferred intervention between compression or cryotherapy, there are limited data, Accordino explained. However, research has been conducted in this area. For example, in a self-controlled pilot study investigating compression vs cryotherapy, investigators enrolled 38 patients with breast cancer who were treated with 260 mg/m2 of nab-paclitaxel and have no history of PN. Patients were then randomly assigned to receive either a frozen Elasto-Gel glove or 2 surgical gloves 1 size smaller than their hand on their dominant hand. The primary end point was incidence of PN G2 or higher on CTCAE both sensory and motor neuropathy, with secondary end points of PRO PNQ, FACT-Taxane, and temperature changes.¹

“The unit of randomization for this trial was what intervention went to the dominant hand,” Accordino said. “In terms of what they found, there was no difference in investigator-assessed or patient-reported CIPN. In terms of tolerability, 2 patients withdrew from the cryotherapy due to intolerance, and 1 patient withdrew from the compression due to the development of a latex allergy.”¹

In a pilot CONTRoL study (NCT03873272) conducted by Accordino, the lead author on the study, and her colleagues at Columbia University Irving Medical Center, they assessed cryotherapy vs compression therapy vs placebo in patients with early-stage breast cancer.¹

“It’s an adaptive sequential design, or as we call it, a ‘pick the winner’ design, so it’s very different from what we’ve seen so far. The goal was to determine which of these 3 interventions has the highest probability of success in a future randomized phase 3 study,” Accordino said. “Patients were randomized in triplets to cryotherapy with frozen gloves and socks, compression therapy with Sigvaris compression devices to the upper and lower extremities, or to placebo, which consisted of loose gloves and socks.”¹

The primary end point was change in FACT/GOG-NTX from baseline, with a good outcome being less than 5 and a poor outcome being 5 or greater, dose reduction, or early discontinuation due to CIPN from taxane-based therapy. Patients were followed and assessed at 12 weeks, with outcomes tallied, proportions evaluated, and arms eliminated based on the number of successful or unsuccessful outcomes until there was a winner remaining.¹

“Once 51 patients were evaluable for our primary endpoint of 12 weeks, compression was deemed the winner due to the higher success rate [of 11/17 patients] in the compression arm, with both the cryotherapy [success rate of 7/17 patients] and placebo [success rate of 7/17 patients] arms closing at the same time [both 0.41 (0.18-0.67)],” Accordino said.¹

While this was occurring, 63 patients were also enrolled and followed, with all patients assessed for the primary end point at 12 weeks. In this cohort, compression therapy still had the highest proportion of success.¹

“We learned a lot from this study, potentially about why cryotherapy was not as successful as compression therapy in this study compared to some of the earlier work. One of the things that we found was a signal for tolerability concerns. We asked patients about their satisfaction with the study garments at week 12 and week 24,” Accordino said. “The majority of patients in the placebo and compression groups were generally satisfied with their interventions, while there was a high proportion of the cryotherapy group who were not satisfied.”¹

Specifically, only 35% of patients were adherent to the cryotherapy, while 73% were adherent to the compression therapy and 76% were adherent to the placebo.¹

“Of note, this study was conducted at the height of the COVID-19 pandemic, so there was a period of time where we were not able to place garments on patients due to concerns about getting too close to others, but this affected all 3 arms equally, and you can see there was a big difference in the cryotherapy arm.”¹

Accordino explained that going forward, a potential intervention strategy could be cryocompression therapy to overcome the limitations observed with cryotherapy.¹

“The premise is to use cryotherapy using continuous flow cooling, and to add cyclic compression. The theory behind this is the gate control theory of pain. [In this theory,] the addition of low cyclic compression can help improve the tolerability,” Accordino said.

In a proof-of-concept study of 13 patients who received 142 cycles of taxane chemotherapy, when nerve conduction studies were done, the patients who received cryocompression had a higher degree of preservation of their motor amplitudes compared with historical controls who received just cooling alone or control.

“This was largely due to being able to get the skin to cooler temperatures—patients receiving cryocompression were able to get to lower skin temperatures than the historical controls,” Accordino said.¹

In terms of tolerability, patients were also able to tolerate the cryocompression well, with only 1 patient requiring an intracycle temperature increase of 1 °F and no patients discontinuing treatment because of tolerability concerns.¹

Overall, these data have led to the phase 3 SWOGS2205 ICE COMPRESS trial (NCT05642611) that was recently activated through the National Cancer Institute’s National Clinical Trials Network, according to Accordino.¹

“I believe we enrolled our first patient very recently and we’re very excited about that,” Accordino said. “This study is for patients starting 1 of 4 taxane-based regimens. They are randomized in a 1:1:1 fashion to receive either cryocompression, continuous compression, or low cyclic compression.”¹

Accordino explained that all of the compressions will be delivered by a novel Paxman Limb Cryocompression System, which will deliver the intervention to all 4 extremities.¹

“A lot of work has been done in trying to find a successful prevention strategy for CIPN development. There have been some successes along the way, and some unsuccessful outcomes,” Accordino said. “It’s apparent, though, that work is still needed to be done, and hopefully this phase 3, randomized study can help find a definitive strategy to help prevent CIPN.”¹

References

1. Accordino MK. Mitigating neuropathy: cooling down and other options. Presented at: 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Accessed June 11, 2023. https://meetings. asco.org/2023-asco-annual-meeting/15064?presentation=215018#215018

2. Hanai A, Ishiguro H, Sozu T, et al. Effects of cryotherapy on objective and subjective symptoms of paclitaxel-induced neuropathy: prospective self-controlled trial. J Natl Cancer Inst. 2018;110(2):141-148. doi:10.1093/jnci/djx178

3. Shigematsu H, Hirata T, Nishina M, Yasui D, Ozaki S. Cryotherapy for the prevention of weekly paclitaxel-induced peripheral adverse events in breast cancer patients. Support Care Cancer. 2020;28(10):5005-5011. doi:10.1007/s00520-020-05345-9

4. Tsuyuki S, Yamagami K, Yoshibayashi H, et al. Effectiveness and safety of surgical glove compression therapy as a prophylactic method against nanoparticle albumin-bound-paclitaxelinduced peripheral neuropathy. Breast. 2019;47:22-27. doi:10.1016/j.breast.2019.06.008