We aimed to evaluate the short-term preventive effect of local cooling using cooling patches on HFS caused by chemotherapy with PLD. Female breast cancer patients (n = 101) were selected who underwent PLD in two breast wards at our department from February 2020 to February 2021. The patients were randomly divided into the cooling group (51 patients) and the control group (50 patients).

Patients enrolled in the experiment met the following eligibility criteria: (1) Patients who had been diagnosed with breast cancer by pathology or cytology; (2) Patients aged between 20 and 75 years, and who could cooperate with investigators and complete the scale by themselves; (3) At least 4 cycles of PLD were administered; and (4) Patients agreed to sign the informed consent. Patients with the following conditions were excluded: (1) Breast cancer patients suffering from other serious heart, brain, kidney, or serious metabolic diseases; (2) Those with local bleeding, ulcers, and infection tendency; (3) Those with impaired consciousness, unable to communicate normally; (4) Patients who do not understand the meaning of the terms of the scale; and (5) Patients who refused to participate in the study. Two chemotherapy regimens were administered in this study, including chemotherapy plan 1 (PLD + 0.6 mg/m² cyclophosphamide) and chemotherapy plan 2 (PLD + 0.6 mg/m² cyclophosphamide and sequential 80-100 mg/m² docetaxel treatment). Most patients received 30-35 mg/m² PLD. Briefly, chemotherapy plan 1 included 4 cycles, chemotherapy plan 2 also included 4 cycles of sequential docetaxel treatment based on chemotherapy plan 1. We only discussed the effect of the use of cooling patches on HFS during the first 4 cycles of chemotherapy.

In the control group, patients received routine care, including: (1) Wearing loose shoes, socks, and gloves to avoid frequent friction and excessive pressure on the hands and feet, and they avoided heavy physical labor and intense exercise; (2) Sun protection was advised to avoid direct sunlight on the skin; (3) Sitting or lying on a soft surface with legs as high as possible; and (4) For patients with abnormal skin sensations, contact with too cold, hot, sharp, and irritating objects was avoided. In the cooling group, patients applied cooling patches based on routine care. In addition, all patients received the corresponding dose of dexamethasone orally one day before, on the day of chemotherapy, and one day after chemotherapy, according to the doctor's advice. Supportive therapy was given when necessary.

We explained the purpose and method of the investigation to the patients. The survey method was face-to-face data collection. The patients voluntarily participated in the research and completed the questionnaire according to the actual situation. We only explained unclear points but did not interfere with the patient's selection. The questionnaire was handed out before each chemotherapy cycle. A higher score of the Hand-Foot Skin Reaction and Quality of Life Questionnaire (HF-QOL) indicates poorer QOL or worsening symptoms[15]. Self-efficacy plays a positive role in the psychological resilience of breast cancer patients after surgery[16], which positively correlated with QOL[17]. To understand QOL and self-efficacy of the patients, we also conducted scale assessments, including HF-QOL and the general self-efficacy scale (GSES).

The main components of the cooling patch (50 mm × 110 mm) were pure water (77%), hydrophilic polymer gel, and mint extract (Japan DIA Pharmaceutical Co., Ltd). The cooling patch absorbs the heat from the skin through the polymer hydrogel layer and uses vaporization to dissipate heat so that the local skin is continuously cooled. Cooling patches were applied to the palm and back (avoiding the needle hole for intravenous infusion) of the hands 15 min before infusion of chemotherapy, and the cooling effect was maintained for 10 h. Routine care was applied to the feet without cooling treatment. Each patient used four cooling patches per chemotherapy cycle. If skin ulcers or symptoms were too severe to apply the cooling patches during treatment, local cold therapy was terminated.

When symptoms first appeared on the hands, we evaluated the symptoms and classified HFS before each chemotherapy cycle (starting from the second chemotherapy cycle). Patients with corresponding symptoms in one or both hands were classified as HFS. Evaluation of the occurrence of HFS continued until 2 or 3 cycles after the 4th cycle due to the medicinal properties of PLD.

SPSS version 23.0 was used for statistical analysis of the data in this study. The occurrence and severity of HFS were analyzed by the Mann-Whitney U test, and the Student's t test was used to analyze the scores of the scales. A P value < 0.05 was regarded as statistically significant.

One hundred and one female patients who met the criteria were enrolled, and all of them were treated with intravenous PLD in our department. None of these patients had received previous chemotherapy, and all followed the research protocol.

Moreover, there were no significant differences between the two groups of patients in terms of some baseline. However, there were significant differences between the two groups in terms of character traits, such as facing major events in life, and attitudes to suffering from breast cancer (Table 1). However, multivariate analysis of variance indicated that these three items were not independent influencing factors on the occurrence of HFS, and their main effects and interaction effects did not affect the HF-QOL and GSES scores (P > 0.05) (Table 2).

The incidence of HFS was 40% in the control group and 2% in the cooling group, with a statistically significant difference (P < 0.0001) (Table 3). In the control group, the incidence of Grade 1 and Grade 2 HFS was 38% and 2%, respectively. However, up to the end of the 5th course of treatment, only one patient in the cooling group developed Grade 1 HFS. None of the patients developed Grade 3 HFS in either group. Most patients developed HFS after the 3rd or 4th course of treatment, and two patients developed HFS after the 5th course of treatment.

The GSES and HF-QOL scores are shown in Figure 1A and B, respectively. We also performed intra-group comparisons (Table 4). In the third assessment in the control group, the GSES score was significantly different to the baseline score (the first evaluation). Several subsequent scores were also significantly different from the baseline. In the cooling group, the GSES score was significantly different from the baseline score in the second evaluation, and the difference persisted until the fourth evaluation. Compared with the baseline scores, the GSES scores showed a difference in the fourth evaluation in both the control group (19.48 ± 5.88 vs 17.22 ± 5.16, P = 0.012) and the cooling group (21.61 ± 6.13 vs 19.63 ± 6.42, P = 0.008), and the mean value of both groups was low, indicating that most patients had a lower sense of self-efficacy (the total score was 40 points, and below 24 points was regarded as low self-efficacy). A comparison between the two groups was then performed (Table 5). No significant difference in GSES scores between the two groups in the first assessment (19.48 ± 5.88 vs 21.61 ± 6.13, P = 0.078) was observed. And 78% of patients had low self-efficacy in the control group, and 64.7% of patients had low self-efficacy in the cooling group. In the third evaluation, there were no significant differences in GSES scores between the two groups. In the fourth assessment, although mean GSES scores were low in the cooling group, they were still significantly higher than those in the control group (17.22 ± 5.16 vs 19.63 ± 6.42, P = 0.041). Low self-efficacy was observed in 94% of patients in the control group, and in 78.4% of patients in the cooling group.

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Figure 1 Box plots of raw data for Hand-Foot Skin Reaction and Quality of Life Questionnaire and general self-efficacy scale score before the 1^st, 2^nd, 3^rd and 4^th cycle of chemotherapy. A: Hand-Foot Skin Reaction and Quality of Life Questionnaire scores; B: General self-efficacy scale scores. Data are outliers (dots), adjacent values (whiskers), median (central line), and interquartile range (box margins). HF-QOL: Hand-Foot Skin Reaction and Quality of Life Questionnaire; GSES: General self-efficacy scale.

At baseline, there were no significant differences in HF-QOL scores between the two groups (39.14 ± 10.29 vs 39.06 ± 8.56, P = 0.966) (Table 6). From the second evaluation, the HF-QOL scores in the two groups were significantly different, and this difference persisted until the fourth evaluation. In the fourth evaluation, the HF-QOL scores showed very significant differences (18.08 ± 7.01 vs 14.20 ± 7.39, P = 0.008) between the two groups, and compared with the control group, the median HF-QOL score in the cooling group was significantly lower. In the intra-group comparisons (Table 7), in both groups in the second evaluation, the HF-QOL score was significantly different from baseline. Several subsequent scores were also significantly different from baseline. There were significant differences in HF-QOL scores before the 1st chemotherapy and the 4th chemotherapy in both the cooling group (39.06 ± 8.56 vs 14.20 ± 7.39, P < 0.05) and the control group (39.14 ± 10.29 vs 18.08 ± 7.01, P < 0.05).

In order to identify the factors that may have caused HFS, univariate analysis of the factors that may affect the occurrence of HFS was performed (Table 4). The results showed that occupation, albumin level, and whether the patient had a long-term medication history were the factors that may have caused HFS. However, after binary logistic regression analysis, none of these factors were found to be associated with the occurrence of HFS. Moreover, character traits, such as facing major events in life, attitudes toward cancer, body mass index (BMI), age, PLD dose, and body surface area were not significantly associated with the incidence of HFS (Table 8).

Hand-foot syndrome (HFS) is one of the most common skin toxicities of pegylated liposomal doxorubicin (PLD). When patients develop HFS, they may be at risk for dose adjustment (or withdrawal) and limitation of activities of daily living due to physical pain, even lead to limited social activities due to psychological disorders. Although cold therapy as a non-drug therapy to prevent and treat HFS has been effective in previous studies, there is room for improvement. If local cold therapy has the advantages of good effect, easy operation, and low price, it will be a huge benefit for patients with HFS.

Current methods of preventing chemotherapy-induced HFS are mostly pharmacological prevention, and local cooling as a non-drug therapy is effective in previous studies, but has disadvantages such as cumbersome implementation steps, low patient tolerance, and high shedding rate.

The main goal is to study the efficacy of the cooling patch in preventing HFS caused by PLD in the short term (for the prevention of hand symptoms). Improve the current situation that patients face the risks of restricted activities of daily living due to physical pain caused by HFS and limited social activities due to psychological disorders. We apply a cooling patch originally used to reduce fever in infants and children to prevent HFS caused by PLD in breast cancer patients to make up for some of the shortcomings of ice packs, ice gloves, and ice socks.

This study was a retrospective cohort study in which using purposive sampling to select the research objects. The research objects answered the questions in the scale regularly, and we distributed and collected the scale.

The cooling patch can effectively reduce the frequency and severity of HFS in the short-term. Before the fourth chemotherapy cycle, although general self-efficacy scale scores in the cooling group were low, they were still significantly higher than those in the control group. Compared with the control group, the mean Hand-Foot Skin Reaction and Quality of Life Questionnaire score in the cooling group was significantly lower. We have used the cooling patch to prevent PLD-induced HFS with good results with higher comfort of patients and a shedding rate of 0.

The cooling patch can effectively reduce the frequency and severity of HFS caused by PLD in the short term. In addition, it may help to improve patients' quality of life and delay the decline of their self-efficacy. The cooling patch is often applied to treat fever in infants and young children. We use it to prevent HFS caused by PLD chemotherapy in breast cancer patients.

In the future, we will study whether the cooling patch also has a good effect on the feet, underarms, and other parts that may be affected and conduct more rigorous randomized controlled studies to clarify the optimal duration, temperature, and effectiveness of local cooling.