A randomized adaptive sequential selection trial of cryotherapy, compression therapy, and placebo to prevent taxane inducted peripheral neuropathy in patients with breast cancer

Abstract Background: Taxane-induced peripheral neuropathy (TIPN) is one of the most common and debilitating adverse effects of taxane therapy for early-stage breast cancer (ESBC). TIPN is difficult to treat, and there are no known effective prevention strategies. Small non-randomized studies in patients with ESBC, have suggested both cryotherapy and compression therapy to the hands and feet may be effective for TIPN prevention. However, is unknown which therapy, if either, is more effective at prevention of TIPN compared to placebo. Methods: We conducted a randomized phase IIB adaptive sequential selection trial of cryotherapy vs. compression therapy vs. placebo among participants with ESBC during taxane chemotherapy (NCT03873272). Participants were randomized in triplets to either frozen gloves/socks [NatraCure] refrigerated for at least 3 hours to -25 to -30°C prior to use (cryotherapy); compression gloves/socks [Sigvaris] with a pressure of 20-30 mmHg on the upper extremity, 20-30 mmHg on the lower leger, and 15 mmHg on the toes/feet (compression therapy); or “loose” gloves/socks [Sigvaris] with a maximum pressure of 3 mmHg on the upper/lower extremities (placebo arm). All garments were worn for a total of 90-120 minutes, beginning 15 minutes prior to the start of taxane infusion and until 15 minutes after completion of the taxane infusion. The primary goal was to select the best intervention to be carried forward to a larger phase III trial, with a high probability of correct selection if one intervention is truly superior using a novel sequential design based on the Levin-Robbins-Leu family of sequential selection procedures. The primary endpoint was change in Functional Assessment of Cancer Therapy Neurotoxicity (FACT-NTX) at 12-weeks; success was defined as <5-point decrease from baseline (minimal TIPN). The tally of success was compared starting from the 15th triplet. An arm would be eliminated if it had ≥4 successes less than the leading arm. The trial stopped the first time two arms were eliminated. Secondary endpoints included staff assessed adherence (defined as wearing study garments for ≥80% of infusions) and patient reported comfort (4-point Likert scale) to the study intervention. Results: Between 4/2019-4/2021 64 patients were randomized (n=20 cryotherapy; n=22 compression therapy; n=22 placebo). The stopping criterion was met after the 17th triplet (51 patients) had been evaluated for the primary endpoint. For the 51 patients, the median age was 50 years (range, 28-78), and the majority of patients (58.8%) were treated with docetaxel every 3-weeks, whereas 41.2% were treated with weekly paclitaxel. Success (i.e., minimal TIPN) at 12-weeks occurred in 11 (64.7%) patients treated with compression therapy, 7 (41.1%) patients treated with cryotherapy, and 7 (41.1%) patients treated with placebo. Adherence to the study intervention occurred in 82.4% of patients treated with compression therapy, 29.4% of patients treated with cryotherapy, and 76.5% treated with placebo. In regards to comfort, 87.4% of patients treated with compression therapy reported being satisfied/very satisfied with the study garments, compared to 56.3% treated with cryotherapy, and 73.3% treated with placebo. Conclusion: Compression therapy was found to be the most effective and tolerable intervention in this phase IIB selection trial to prevent TIPN, and has the greatest probability of being a successful intervention to prevent TIPN in a future randomized phase III study. Cryotherapy was not successful, which is likely related to poor tolerability due to the cold, which resulted in poor adherence to the study garments. Compression therapy for the prevention of TIPN should be further evaluated in a larger randomized phase III study. Citation Format: Melissa K Accordino, Shing Lee, Cheng-Shiun Leu, Meghna S Trivedi, Katherine D Crew, Kevin M Kalinsky, Rohit Rajhunathan, Alessandra Taboada, Lauren Franks, Erin Honan, Erik Harden, Cynthia Law, Dawn L Hershman. A randomized adaptive sequential selection trial of cryotherapy, compression therapy, and placebo to prevent taxane inducted peripheral neuropathy in patients with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-04.