A meta-analysis studying the utility of cryotherapy in the prevention of peripheral neuropathy in breast cancer patients receiving paclitaxel and nab-paclitaxel.
Authors: Ashok Kumar Prashanth , Sampat Parth J , Suresh Kumar Vishnu Charan , Smith Abigail , Wang Dongliang , Huang Danning , Sivapiragasam Abirami 
Published: June 2023

12025 Background: Debilitating Peripheral Neuropathy (PN) caused by paclitaxel adversely impacts the quality of life in Breast Cancer (BC) patients. Cryotherapy using cooling devices during taxane infusion is a non-invasive strategy to prevent PN, but its efficacy has not been established. We hope to answer this question through our meta-analysis. Methods: A systematic search with keywords and controlled vocabulary encompassing BC, antineoplastics, and paclitaxel was conducted in PubMed, CINHAL, Embase, Scopus, Web of Science Collections, and CENTRAL. All databases were searched on March 7, 2022. There were no search restrictions on date, language, status, or outcomes. 405 records were identified, and duplicates were removed using EndNote 20. The remaining 372 records were imported into Covidence, and the titles and abstracts were screened independently by 2 reviewers. 22 out of 63 full texts were relevant to our question of which 14 [12 Randomized control studies and 2 retrospective studies] were included for the meta-analysis using R package meta. Only studies that analyzed cryotherapy use in BC patients who received paclitaxel or nab-paclitaxel were included. Relative risk (RR) derived from random effects model with Mantel-Haenszel method was used to compare the occurrence of PN between cryotherapy vs placebo groups. Results: Pooled incidence of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 PN was 24.85% (81/326) in the cryotherapy arm and 42.35% (72/170) in the placebo arm. Overall RR for CTCAE grade ≥ 2 PN with cryotherapy compared to placebo was 0.45 [0.27,0.77, p = 0.0031]. RR for sensory PN was 0.19 [0.05,0.66, p = 0.009] and for motor PN was 0.18 [0.03,0.99, p = 0.0491]. RR for Patient Neurotoxicity Questionnaire (PNQ) score ≥ D which connotes severe neuropathy was 0.24 [0.09,0.62, p = 0.0035]. Cold intolerance was the predominant adverse effect at 15% (37/247). Fingernail paronychia and skin irritation were reported at 0.8% (2/247) each. 5.1% (15/294) stopped cryotherapy use prior to completion. However, this number was driven by a single study (10/16 patients stopped using cryotherapy due to cold intolerance) and 7/11 studies had no discontinuations. Visual inspection of our funnel plots revealed no publication bias. Conclusions: Use of cryotherapy decreased the occurrence of CTCAE grade ≥ 2 PN by 55% in BC patients getting paclitaxel or nab-paclitaxel. Occurrence of both sensory and motor PN were lower. Cold intolerance was the most frequently reported issue with its use but lead to relatively low discontinuation rates in most studies. Given the lack of any severe adverse effect, cryotherapy use must be encouraged for patients receiving paclitaxel and nab-paclitaxel. Further studies are needed establish a standardized way of applying cryotherapy in terms of the device to use, timing and other logistical factors.