Study design and participants
Of the 44 cases in a randomized trial investigating the preventive effect of cryotherapy on weekly paclitaxel-induced CIPN in breast cancer patients (UMIN000034966), cases that could provide a response to a questionnaire for CIPN at more than one year after completion of paclitaxel treatment were evaluated in this study. Detailed information and results of the randomized trial are described in a previous report . Briefly, the main inclusion criterion was a diagnosis of invasive breast cancer scheduled for 12 weekly doses of paclitaxel-based treatment. HER2 targeting therapy was combined with weekly paclitaxel in HER2-positive breast cancer. Eligible cases were randomly (1:1) assigned to the cryotherapy group or control group. As cryotherapy, patients continuously wore frozen (-20 °C) gloves/socks (Elasto-Gel, mittens, and slippers) on both hands and feet between 15 min before and after paclitaxel infusion (total 90 min). The primary endpoint was incidence of clinical meaningful CIPN after completion of weekly paclitaxel. In total, 38 cases were given a questionnaire for CIPN between April 2020 and October 2020. Six cases were excluded from this survey due to the following reasons: systemic treatment for recurrent breast cancer (2), transfer to different hospital (2), depression (1), and severe neuropathy after meningioma surgery (1) (Fig. 1). This study was approved by the Ethics Committee of the National Hospital Organization of Kure Medical Center and Chugoku Cancer Center (Approval number 28-70) and adhered to the Helsinki Declaration and the ethical principles for clinical research. All patients received a detailed explanation of the study from the primary physician and informed consent was obtained prior to enrollment.
Evaluation of CIPN
Eligible cases were evaluated using a questionnaire survey for Functional Assessment of Cancer Therapy-Neurotoxicity (FACT-NTX) score and Patient Neurotoxicity Questionnaire. FACT-NTX consists of 11 items evaluating CIPN-associated symptoms with a 0 to 4 score and a lower FACT-NTX score reflects worse peripheral neuropathy. A 6-point or more decrease in the total FACT-NTX score from baseline is regarded as clinically significant CIPN. PNQ is a patient-reported questionnaire on sensory and motor neuropathy and how they influence daily activity and quality of life. A PNQ grade ranges from A (no symptoms) to E (severe symptom with significant deterioration of daily activity).
Patient characteristics were assessed by groups using a Fisher's exact test of categorical variables and t-test for continuous variables. A Fisher's exact test was used to compare the incidence of a clinically significant decrease of the FACT-NTX score and the distributions of each FACT-NTX item and PNQ grade between the cryotherapy and control groups. Predictive factors for a clinically significant decrease of the FACT-NTX score were evaluated using logistic regression analysis. A two-sided p value < 0.05 was considered significant. Statistical analyses were performed using JMP software version 13.2.1 (SAS Institute Inc., Cary, USA).
Of 38 cases evaluated for persistent CIPN at more than one year after completion of treatment, 19 cases were from the cryotherapy group and 19 were from the control group. The median time from completion of the weekly paclitaxel treatment to questionnaire for persistent CIPN in this study was 2.3 (1.3-3.1) years. There was no statistical difference in regard to baseline clinicopathological factors, including interval from completion of paclitaxel, PS, age, height, weight, stage, subtype, adjuvant endocrine therapy and radiation therapy between the cryotherapy and control group (Table 1). During weekly paclitaxel treatment, there was significantly lower incidence of a clinically significant decrease in FACT-NTX score (31.6% vs. 73.7%, p = 0.008) and a lower grade of PNQ sensory (p = 0.02) and motor (p = 0.04) in the cryotherapy group compared to the control group.
Effect of cryotherapy on incidence of persistent CIPN
All 38 cases responded to the questionnaire for FACT-NTX and PNQ after completion of weekly paclitaxel treatment. The incidence of a clinically significant decrease in the FACT-NTX score was 15.8% and 36.8% in the cryotherapy and control group, respectively, showing a numerically lower incidence in the cryotherapy group (p = 0.14) (Table 2). Figure 1 shows the distribution of scores for each questionnaire item in FACT-NTX. There was tendency for a lower score for Hand numbness, Foot numbness and Foot discomfort in the cryotherapy group compared with the control group. In the questionnaire for PNQ, there was also a lower grade of sensory (p = 0.02) and motor (p = 0.17) symptoms in the cryotherapy group compared with the control group (Table 2).
Predictive factor for persistent CIPN
Logistic regression analysis was used to evaluate the association between clinicopathological factors and the incidence of significant decrease in the FACT-NTX score. Age 60 years or older had a significantly increased risk of significant decrease in the FACT-NTX score (odds ratio = 26.6, 95%CI = 3.3-574.5, p = 0.001). Cryotherapy was marginally associated with significant decrease in the FACT-NTX score (odds ratio = 4.8 95%CI = 0.7-50.1, p = 0.12). The other baseline clinicopathological factors including age, cryotherapy height, weight, adjuvant endocrine therapy, adjuvant radiation therapy and length of interval, were not associated with significant decrease in the FACT-NTX score.