Introduction
Chemotherapy-induced nausea and vomiting (CINV) significantly impacts the quality of life (QoL) of cancer patients and is a major side effect of chemotherapy. The pathophysiology of CINV involves the peripheral and central nervous system, with acute CINV triggered by serotonin release through chemotherapeutic agents, and delayed CINV involving substance P [
1‐
4]. Chemotherapeutic agents are categorized by emetogenic potential: high (> 90% incidence of CINV), moderate (30–90%), low (10–30%), and minimal (< 10%) emetic risks [
5]. Despite advancements in antiemetics, CINV prevention is not fully achievable, and side effects like constipation and dizziness remain issues [
6].
Various alternative treatments and rescue medications have been explored to alleviate CINV [
7,
8]. Among non-pharmacological therapies, massage therapy has been investigated as a non-invasive option and has shown benefits in reducing depression, stress, anxiety, and nausea in cancer patients [
9]. As an alternative to human massage therapists, mechanical devices are becoming increasingly popular [
10], driven by the need for healing and comfort in modern society. The surge in caregiving service demand, due to the rise in single-person households and healthcare labor costs, has led to a push for replacing cancer care for palliation with machines. Among these mechanical options, the electric massage chair (EMC) is designed to automatically massage the user’s entire body using digital and mechanical tools. Additionally, modern EMCs offer mental care through natural sounds and relaxing music. A previous study found that combining soothing massage and music therapy effectively reduced physical/mental fatigue and enhanced cognitive function in healthy adults [
11‐
14].
Given this background, administering chemotherapy in an EMC could positively impact distressed cancer patients, particularly those suffering from CINV. However, the clinical efficacy of EMC remains largely unexplored. This study was conducted as an open-label, randomized trial to assess the effectiveness of an EMC in preventing CINV in cancer patients.
Methods
Study design
Sample size calculation
Under both a significance level of 5% and a power of 80%, the number of patients required to show that the proportion of patients reaching an INVR (Rhodes Index of Nausea, Vomiting, and Retching) score of less than 9 increased by 35% when using an EMC was at least 30 patients per group (60 patients in total). The expected reach rate of 75% for the group using the EMC and 40% for the group not using the EMC was assumed, and this 35% difference was assumed to be the minimal clinically important difference. Assuming a 10% dropout rate, 68 patients (34 patients per group) were planned.
Study protocol
This study was designed as an open-label, phase 2 clinical trial conducted at the Korea University Anam Hospital. Between June 2020 and July 2021, solid cancer patients scheduled to receive HEC or MEC for the first time in their life were screened. Those who had disseminated or extensive bone metastasis or were taking anticoagulant agents were excluded. To prevent bias, patients already using EMC at home were also excluded. When the patients met all the inclusion and exclusion criteria, they were enrolled in the study and randomized into two groups: Group A or Group B. The randomization process was conducted independently by the research team using computer software that generated the random sequence. Patients in Group A received chemotherapy on a general ward bed, while those in Group B received chemotherapy in an EMC during the first cycle of treatment. At the 2nd cycle of chemotherapy, participants crossed the other group. We assumed that at least 10 days after receiving an EMC treatment was enough to wash out the clinical effect of massage, and that there might be no carry-over effect on the next cycle of chemotherapy. Standard prophylactic antiemetics were prescribed according to each chemotherapy regimen, and rescue medicines were also added according to patients’ needs and investigators’ decisions. Acute CINV was evaluated on the second day of each chemotherapy cycle according to the CTCAE v5.0 [
9]. Information regarding rescue medication for CINV and QoL surveillance was also collected. The study protocol was reviewed and approved by the Institutional Review Board of Korea University Anam Hospital (No. 2020AN0054).
Goal of the study
Primary endpoint of the study was an INVR score for two groups in the acute (0–24 h) phase of chemotherapy. Secondary endpoints included complete response (CR: no emesis, no rescue medication) rate during the acute (0–24 h) and delayed (24–120 h) phase defined by previous study [
15], and QoL scale assessed by EORTC-QLQ-C30.
The intervention – EMC
The intervention group underwent mechanical massage using automatic EMCs (Phantom Medical, BFR-M8030, Bodyfriend Inc., Seoul, Korea). The EMC was approved as a medical device certified by the Ministry of Food and Drug Safety and induced muscle relaxation through whole-body massage, including the neck, shoulders, arms, hands, waist, hip, calf, and soles of the feet. Physical force was applied to the soft tissue of the body through massage modules, calf and foot rollers, and airbags. The device was equipped with medical modes with up to 38 kneading and 560 tapping functions per minute of massage.
In the present study, the massage module was set to gently knead the soft tissue of the body around the neck and back during the session. Leg massage was provided through calf and foot rollers and airbags at mild intensity. Each massage session lasted of a total of 20 min. Initially, it offers neck and shoulder kneading, rolling massage, and comforting music for muscle relaxation and stability over the first 5 min. Then, for 10 min, it provides bilateral stimulation and a narrative approach with psychiatric healing messages, aimed at transforming negative emotions into positive ones. The final 5 min focus on soothing the entire body to relax tense muscles.
The intervention group received at least one massage session per day. Unless side effects were reported, the massage session was continued for another 20 min. Reclining and tilting of the massage chair were included to enhance the effect of the mechanical massage. Upper extremity airbags were provided only in the arm where the intravenous line was not administered.
Along with physical massage, the EMC also provided audio to the patients. Comforting New Age-style music without lyrics followed by a narrative message of hope and courage, orchestrated by a psychiatrist, was presented during the intervention.
Assessment of CINV
The degree of acute CINV was measured on the second day after chemotherapy initiation. To assess the severity of acute CINV, we adopted the Korean version of the INVR, which was translated from the English version and validated previously [
10]. The INVR scores range from 0 to 32 and the higher the score, the greater the severity of nausea and vomiting. Along with INVR, we also collected the patients’ subjective CINV rating scales. The CINV score ranged from 0 (no symptoms) to 10 (worst imaginable symptoms). A higher score indicated greater CINV intensity. For the assessment CINV, we measured timepoints based on guidelines established in previous studies [
15]: the acute phase (0–24 h) and the delayed phase (24–120 h). Additionally, following the protocol of the two-week interval triplet chemotherapy, we conducted another check on day 10.
After chemotherapy, rescue medication was permitted to treat refractory CINV and the timing of rescue medicine was collected by the study coordinator to calculate the CR. Information on rescue medication in the acute phase (0–24 h) was collected using the electronic prescription system. Information during the delayed phase was self-reported by the patients.
QoL assessment
Patient-reported outcomes were obtained before starting chemotherapy, the day before the starting 2nd cycle (completing the 1st cycle), and the day before starting the 3rd cycle (completing 2nd cycle). We adopted the Korean version of the EORTC-QLQ-C30 to assess patient QoL. The EORTC-QLQ-C30 is a survey form that incorporates a 30-item cancer-specific questionnaire to assess the health-related QoL of cancer patients
11. The questionnaire comprises five functional scales (physical, role, cognitive-emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), and a global health and QoL scale. All items are scored on a 4-point Likert scale ranging from 1 “not at all” to 4 as “very much”, with the exception of two items in the global health/QoL scale, which uses modified 7-point linear analog scales [
16]. The Korean EORTC-QLQ-C30 was developed by the EORTC group and was validated by Yun et al. in 2003 [
17].
Statistical analysis
Continuous data are indicated as median (interquartile range) or mean (standard deviation, SD) using Student’s t-test. Categorical data are presented as percentages and compared using a chi-squared test. The treatment effect or period effect was assessed by a paired t-test considering the cross-over design. A p-value less than 0.05 was accepted as the threshold to discriminate significant from non-significant. All statistical analyses were performed the SAS version 9.4 software (SAS Institute Inc., Cary, NC, USA).
Discussion
We conducted an open-label, randomized, cross-over phase II trial to assess the clinical efficacy of an EMC in preventing CINV. Fifty-nine patients receiving MEC or HEC for the first time were randomized and analyzed. Overall, no significant difference was observed in the prevention of CINV between patients treated with or without the EMC, in terms of INVR score (2.76 vs. 3.63, p-value = 0.5367) or CINV severity (1.48 vs. 1.63, p-value = 0.0675). However, QoL improvements were noted in patients receiving chemotherapy in the EMC, particularly in those undergoing HEC.
CINV, a major side effect of cancer treatment, can severely compromise patient QoL and compliance, potentially leading to treatment discontinuation. Both physiological and psychological factors influence CINV. A study in Europe found that patients with emotional distress and maladaptive coping experienced more severe CINV [
18], highlighting the role of psychological vulnerability in CINV.
Despite numerous antiemetics, complete CINV remission remains elusive. NEPA, an oral drug combining an NK1 receptor antagonist and a 5HT3 receptor antagonist, has shown efficacy in HEC or MEC patients [
19]. In a recent phase 3 clinical trial, a combination of oral dexamethasone and NEPA, which is considered the most efficacious regimen for preventing CINV, showed a CR of 73.8% during the overall phase in patients received HEC [
20]. The most commonly reported adverse events were constipation (8.0%) and hiccups (2.7%) [
20]. However, even the most effective antiemetic combinations cannot perfectly control CINV.
To address this unmet clinical need, many integrative therapies have been investigated and tested. Among the complementary measures, acupuncture and massage therapy are key alternative methods that have been shown to reduce symptoms [
21]. Although the precise mechanism of action has not been fully elucidated, massage therapy is preferred due to its non-invasiveness, and it has been shown to relieve multiple distressing symptoms in cancer patients, including pain, anxiety, fatigue, and nausea [
22]. Music therapy, encompassing interactive (e.g., improvisation, singing) and receptive (e.g., listening to music) techniques, significantly benefits cancer patients by boosting mood, alleviating stress, pain, and anxiety, and fostering relaxation [
23]. As a crucial component of supportive cancer care, it not only assists during treatment but also sets the stage for successful rehabilitation, ultimately improving wellness, physical and emotional health, and quality of life. Considering the use of New Age style music in our study and the variety of music types in previous research [
24], it’s necessary to explore which type of music is the most effective.
In our study, we combined mechanical massage with relaxing music using EMCs. This approach was as effective as physiotherapy in controlling pain and improving QoL and satisfaction, and more cost-effective than manual massage [
25]. EMCs have also been reported to manage chronic stress effectively [
13] and reduce cortisol levels more than mental training [
26], suggesting their potential as a paramedical option in modern cancer care.
However, our study didn’t meet the primary endpoint of a statistically lower INVR score for C1D2 with EMC therapy. This may be due to the subjective nature of CINV reporting and the novel experience of chemotherapy for participants, complicating symptom description. Ethical considerations required the early prescription of antiemetics, affecting the calculation of CR rates. Our phase II trial’s small size and lack of patient stratification by clinical characteristics also limited our findings.
Subgroup analysis, however, indicated EMC’s potential efficacy in high-risk patients. Along with the chemotherapeutic agent itself, several patient-related factors determine the degree of CINV. A history of CINV, expectancy of CINV, female sex, younger age, history of morning sickness, and low alcohol consumption are important risk factors for CINV [
27]. Prior research indicated that for every year younger in age, the likelihood of experiencing CINV rises by 4%. Female patients face a substantially greater risk compared to male patients, marked by an odds ratio of 2.79. Additionally, having a lower risk associated with alcohol consumption corresponds to an odds ratio of 1.94, while a history of morning sickness correlates with an elevated odds ratio of 1.97. Patients with a history of CINV at earlier treatment were at a significantly higher risk of CINV (summary odds ratio = 1.67, 95% CI 1.41–1.99) [
27]. Having had nausea in the previous cycle could be a risk factor not only for anticipatory nausea but also for acute and delayed nausea [
28]. With this background, we defined high-risk patients as those who presented with severe nausea (INVR score ≥ 3) in the first cycle. Patients who received HEC, younger patients, and non-colorectal cancer patients presented with less severe CINV when an EMC was used. Appropriate integrated medicine, in addition to standard treatment, could be an effective and safe option for high-risk CINV patients.
Our study had several limitations. We enrolled patients who received HEC or MEC, regardless of the tumor type or other clinical factors, including stage. Therefore, participants’ characteristics were heterogeneous. Additive antiemetic agents were administered based on patients’ complaints of symptoms and investigators’ decisions, resulting in a bias in the CR rate. We adopted the standard massage mode inherent in the commercial EMC; whether this is optimal is unknown due to the lack of previous research. Due to the varying body types of participants, it was challenging to pinpoint the exact massage targets of the EMC. Further research is needed to determine the optimal mode for cancer patients. In addition, as a phase II clinical trial with a sample size of less than 70 participants, the statistical meaning should be interpreted with caution.
To our knowledge, this is the first randomized trial assessing EMC’s effect on CINV. While it didn’t conclusively prove EMC’s CINV-reducing effect, high-risk patients tended to experience lower symptom severity and improved QoL with EMC treatment. The rising demand for caregiving and healthcare costs suggests that massage chairs could offer a viable alternative. Collecting more real-world data and further studies are necessary to minimize chemotherapy’s side effects using both medication and medical devices.
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