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Acupuncture for Quality of Life in Gastric Cancer Patients Undergoing Adjuvant Chemotherapy

  • Author Footnotes
    # Yan-juan Zhu, Xiao-yu Wu, and Wei Wang contributed equally for this study.
    Yan-juan Zhu
    Footnotes
    # Yan-juan Zhu, Xiao-yu Wu, and Wei Wang contributed equally for this study.
    Affiliations
    Department of Oncology (Y.J.Z., X.S.C., D.D.Z., Y.D.C., H.B.Z.), Guangdong Provincial Hospital of Traditional Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China

    Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome (Y.J.Z., H.B.Z.), Guangzhou, China

    Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research (Y.J.Z., H.B.Z.), Guangzhou University of Chinese Medicine, Guangzhou, China
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  • Author Footnotes
    # Yan-juan Zhu, Xiao-yu Wu, and Wei Wang contributed equally for this study.
    Xiao-yu Wu
    Footnotes
    # Yan-juan Zhu, Xiao-yu Wu, and Wei Wang contributed equally for this study.
    Affiliations
    Gastrointestinal Surgery (X.Y.W., G.N.W.), Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, China
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  • Author Footnotes
    # Yan-juan Zhu, Xiao-yu Wu, and Wei Wang contributed equally for this study.
    Wei Wang
    Footnotes
    # Yan-juan Zhu, Xiao-yu Wu, and Wei Wang contributed equally for this study.
    Affiliations
    Gastrointestinal Surgery, Guangdong Provincial Hospital of Traditional Chinese Medicine (W.W., D.C.D., J.W.), the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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  • Xue-song Chang
    Affiliations
    Department of Oncology (Y.J.Z., X.S.C., D.D.Z., Y.D.C., H.B.Z.), Guangdong Provincial Hospital of Traditional Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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  • Dan-dan Zhan
    Affiliations
    Department of Oncology (Y.J.Z., X.S.C., D.D.Z., Y.D.C., H.B.Z.), Guangdong Provincial Hospital of Traditional Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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  • De-chang Diao
    Affiliations
    Gastrointestinal Surgery, Guangdong Provincial Hospital of Traditional Chinese Medicine (W.W., D.C.D., J.W.), the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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  • Jian Xiao
    Affiliations
    Medical Oncology, the Sixth Affiliated Hospital (J.X., T.Y.C., X.H.Z.), Sun Yat-sen University, Guangzhou, China
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  • Yong Li
    Affiliations
    Gastrointestinal Surgery (Y.L.), Guangdong Provincial People's Hospital, Guangzhou, China
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  • Dong Ma
    Affiliations
    Gastrointestinal Oncology (D.M.), Guangdong Provincial People's Hospital, Guangzhou, China
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  • Ming Hu
    Affiliations
    Gastrointestinal Surgery (M.H., C.F.K.), the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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  • Jian-chang Li
    Affiliations
    Gastrointestinal Surgery (J.C.L., Z.L.H.), Cancer Center of Guangzhou Medical University, Guangzhou, China
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  • Jin Wan
    Affiliations
    Gastrointestinal Surgery, Guangdong Provincial Hospital of Traditional Chinese Medicine (W.W., D.C.D., J.W.), the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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  • Guan-nan Wu
    Affiliations
    Gastrointestinal Surgery (X.Y.W., G.N.W.), Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, China
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  • Chuan-feng Ke
    Affiliations
    Gastrointestinal Surgery (M.H., C.F.K.), the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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  • Kai-yu Sun
    Affiliations
    Gastrointestinal Surgery (K.U.S., J.J.P.), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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  • Zhi-liang Huang
    Affiliations
    Gastrointestinal Surgery (J.C.L., Z.L.H.), Cancer Center of Guangzhou Medical University, Guangzhou, China
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  • Tai-yuan Cao
    Affiliations
    Medical Oncology, the Sixth Affiliated Hospital (J.X., T.Y.C., X.H.Z.), Sun Yat-sen University, Guangzhou, China
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  • Xiao-hui Zhai
    Affiliations
    Medical Oncology, the Sixth Affiliated Hospital (J.X., T.Y.C., X.H.Z.), Sun Yat-sen University, Guangzhou, China
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  • Ya-dong Chen
    Affiliations
    Department of Oncology (Y.J.Z., X.S.C., D.D.Z., Y.D.C., H.B.Z.), Guangdong Provincial Hospital of Traditional Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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  • Jian-jun Peng
    Correspondence
    Jian-jun Peng, Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, Guangdong, China 510080.
    Affiliations
    Gastrointestinal Surgery (K.U.S., J.J.P.), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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  • Jun J. Mao
    Correspondence
    Jun J. Mao, Bendheim Integrative Medicine Center, Memorial Sloan Kettering Cancer Center, 1429 First Avenue, New York, NY, 10021.
    Affiliations
    Department of Medicine (J.J.M.), Memorial Sloan Kettering Cancer Center, New York, NY, USA
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  • Hai-bo Zhang
    Correspondence
    Address correspondence to: Hai-bo Zhang, Department of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine, No. 111, Dade Road, Guangzhou, Guangdong, 510120, China.
    Affiliations
    Department of Oncology (Y.J.Z., X.S.C., D.D.Z., Y.D.C., H.B.Z.), Guangdong Provincial Hospital of Traditional Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China

    Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome (Y.J.Z., H.B.Z.), Guangzhou, China

    Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research (Y.J.Z., H.B.Z.), Guangzhou University of Chinese Medicine, Guangzhou, China

    State Key Laboratory of Dampness Syndrome of Chinese Medicine (H.B.Z.), the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou China
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  • Author Footnotes
    # Yan-juan Zhu, Xiao-yu Wu, and Wei Wang contributed equally for this study.
Open AccessPublished:September 23, 2021DOI:https://doi.org/10.1016/j.jpainsymman.2021.09.009

      Abstract

      Context

      Patients with gastric cancer experience health-related quality of life (HRQOL) decline during adjuvant chemotherapy following gastrectomy.

      Objectives

      This pilot study aimed to evaluate the preliminary effect and feasibility of electro-acupuncture (EA) for HRQOL and symptom burden in these patients.

      Methods

      In this open-label, multicenter, parallel controlled trial, gastric cancer patients who planned to receive adjuvant chemotherapy were randomly assigned to receive high-dose EA (seven times each chemotherapy cycle for three cycles), low-dose EA (three times each chemotherapy cycle), or usual care only. The acupoints prescription consisted of bilateral ST36, PC6, SP4, and DU20, EX-HN3, and selected Back-shu points. Patients completed the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) weekly, and the Edmonton Symptom Assessment System (ESAS). The primary outcome was the difference among the groups on the gastric cancer subscale (GaCS) of the FACT-Ga.

      Results

      Of the 66 randomized patients, 58 were analyzed according to intention-to-treat principle, and 45 were in the per-protocol set (PPS). The average scores in PPS of GaCS were 52.12±9.71, 51.85±12.36, and 45.37±8.61 in high-dose EA, low-dose EA, and control groups, respectively. EA was significantly associated with improved average GaCS scores when compared with control group (51.98±10.91 vs. 45.37±8.61, P = 0.039). EA treatment also produced ESAS relief at the end of intervention (14.36 ± 12.28 vs. 23.91 ± 15.52, P = 0.027). Participants in EA groups had fewer grade ≥3 leukopenia (0% vs. 15.79%, P = 0.031) and neutropenia (2.56% vs. 26.31%, P = 0.012).

      Conclusion

      EA showed promising effects in improving HRQOL, controlling symptom burden, and reducing toxicity during adjuvant chemotherapy in gastric cancer patients. Future adequately powered trials are feasible and needed to confirm the specific effect of EA.

      Key Words

      Key message

      This article describes a multi-center randomized clinical trial with 58 gastric cancer patients undergoing adjuvant chemotherapy after gastrectomy. The results indicate that electro-acupuncture was associated with improved quality of life, controlled symptom burden, and reduced toxicity of chemotherapy in these patients.

      Background

      Gastric cancer is the fifth most frequently diagnosed cancer and the fourth leading cause of cancer-related death worldwide.
      • Sung H
      • Ferlay J
      • Siegel RL
      • et al.
      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      Gastrectomy followed by adjuvant chemotherapy remains the preferred strategy for treatment of local gastric cancer, resulting in improved long-term survival rates. However, the sequelae of gastrectomy and the toxicities of adjuvant chemotherapy lead to a significant decline in health-related quality of life (HRQOL). This is of particular concern during the first three months after gastrectomy when the most common symptoms are nausea, early satiety, reflux, and pain.
      • Munene G
      • Francis W
      • Garland SN
      • et al.
      The quality of life trajectory of resected gastric cancer.
      These symptoms can even lead to discontinuation of chemotherapy. Thus, identifying interventions to control symptom burden and improve HRQOL during adjuvant chemotherapy has important clinical significance.
      Acupuncture, a component of Traditional Chinese Medicine (TCM), is a popular integrative medicine intervention in oncology settings.
      • Yun H
      • Sun L
      • Mao JJ.
      Growth of integrative medicine at leading cancer centers between 2009 and 2016: a systematic analysis of NCI-Designated comprehensive cancer center websites.
      ,
      • Zia FZ
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      • et al.
      The national cancer institute's conference on acupuncture for symptom management in oncology: state of the science, evidence, and research gaps.
      Acupuncture has been found to reduce various symptoms and treatment-related toxicities in cancer patients,
      • Zia FZ
      • Olaku O
      • Bao T
      • et al.
      The national cancer institute's conference on acupuncture for symptom management in oncology: state of the science, evidence, and research gaps.
      including pain,
      • He YH
      • Guo XF
      • May BH
      • et al.
      Clinical evidence for association of acupuncture and acupressure with improved cancer pain a systematic review and meta-analysis.
      ,
      • Mao JJ
      • Liou KT
      • Baser RE
      • et al.
      Effectiveness of electroacupuncture or auricular acupuncture vs usual care for chronic musculoskeletal pain among cancer survivors: the PEACE randomized clinical trial.
      fatigue,
      • Molassiotis A
      • Bardy J
      • Finnegan-John J
      • et al.
      Acupuncture for cancer-related fatigue in patients with breast cancer: a pragmatic randomized controlled trial.
      nausea and/or vomiting,
      • Naeim A
      • Dy SM
      • Lorenz KA
      • et al.
      Evidence-based recommendations for cancer nausea and vomiting.
      and peripheral neuropathy,
      • Bao T
      • Seidman AD
      • Piulson L
      • et al.
      A phase IIA trial of acupuncture to reduce chemotherapy-induced peripheral neuropathy severity during neoadjuvant or adjuvant weekly paclitaxel chemotherapy in breast cancer patients.
      which are also common in postoperative gastric cancer patients. Therefore, we hypothesized that acupuncture may also help to control symptom burden and improve HRQOL of gastric cancer patients undergoing adjuvant chemotherapy. However, efficacy of acupuncture for these patients has never been reported.
      The objectives of this pilot study included: 1) To estimate the effect size of electro-acupuncture (EA) on HRQOL and symptom burden in gastric cancer patients undergoing adjuvant chemotherapy. In order to improve the generalizability of our results, EA, with unified electrical stimulation parameters, rather than manual acupuncture, was used in this study. 2) To refine an optimal EA frequency for future trials, since evidences for optimal acupuncture dosage in oncology settings are still lack. Therefore, two EA groups, high-dose and low dose, were set in this study. 3) To assess the feasibility and refine the logistics in planning for a larger clinical trial, EA and questionnaire completion rates in this study were also evaluated.

      Methods

      Study Participants

      We conducted a multicenter, three-arm (high-dose EA, low-dose EA, and control), parallel randomized clinical trial from January 2019 through February 2020 at seven hospitals in China. This study was approved by the ethics committees of each hospital before participant enrollment at each site, including Guangdong Provincial Hospital of Traditional Chinese Medicine (BF2018-118), the First Affiliated Hospital of Sun Yat-sen University (2019–091), Affiliated Hospital of Nanjing University of Traditional Chinese Medicine (2018NL-172), the Sixth Affiliated Hospital of Sun Yat-sen University (2020ZSLYEC-029), Guangdong Provincial People's Hospital (GDREC2019339H), Affiliated Cancer Hospital & Institute of Guangzhou Medical University (2019-1), and the First Affiliated Hospital of Guangzhou Medical University (2019–43). All participants provided informed consent before randomization. This study has been registered in ClinicalTrials (NCT03753399), and was first released on November 27, 2018. We conducted and reported this study according to the Consolidated Standards of Reporting Trials (CONSORT) 2010 checklist with extension for pilot trials
      • Eldridge SM
      • Chan CL
      • Campbell MJ
      • et al.
      CONSORT 2010 statement: extension to randomised pilot and feasibility trials.
      and the STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) 2010 extension
      • MacPherson H
      • Altman DG
      • Hammerschlag R
      • et al.
      Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA): extending the CONSORT statement.
      (Table S1) .
      Study inclusion criteria included patients: 1) who were pathologically diagnosed with stage Ⅱ/Ⅲ gastric or esophagogastric junction cancer after R0 resection and D2 lymph node dissection; 2) without tumor recurrence confirmed by image examination; 3) without chemotherapy after resection and planning to accept at least 3 cycles of adjuvant chemotherapy; 4) 18–75 years old; 5) with ECOG score≤2; 6) with normal organs function, defined as absolute neutrophil count ≥1.5 × 109/L, platelet ≥100 × 109/ L,hemoglobin ≥90 g/L, serum creatinine ≤1.5 mg/dl (133μmol/L), or creatinine clearance rate ≥60ml/min, total bilirubin ≤1.5 × upper limit of normal value (ULN), alanine transaminase ≤2.5 × ULN, and aspartate transaminase ≤2.5 × ULN; and 7) who can understand the study well and complete the study questionnaires. Exclusion criteria included patients: 1) unable to finish the baseline assessment, 2) with needle phobia; 3) currently diagnosed with psychiatric disorders (e.g., severe depression, obsessive-compulsive disorder, or schizophrenia); 4) with a history of autoimmune diseases, hematological diseases or organ transplantation, or long term use of hormones or immunosuppressors; 5) implanted with heart pacemaker; 6) with neoadjuvant radiotherapy before surgery; 7) with plans of adjuvant radiotherapy during the next three cycles of chemotherapy; 8) with current active infection; 9) who had acupuncture treatment within the previous six weeks; and 10) who were pregnant or breast-feeding.

      Randomization

      Participants were randomly assigned to a high-dose EA group, a low-dose EA group, or a control group (1:1:1) using the central randomization system, allowing for full allocation concealment, provided by the Institute of Clinical Pharmacology of Xiyuan Hospital, China Academy of Chinese Medical Sciences. Random assignment was stratified by resection extent (total/proximal or distal gastrectomy) and neoadjuvant chemotherapy status (yes or no).

      Interventions

      All participants were treated with adjuvant chemotherapy with the CapeOx or SOX regimen. The CapeOx regimen consisted of 130 mg/m2 of oxaliplatin intravenously on the first day and 1000mg/m2 of capecitabine twice daily for 14 consecutive days, every 21 days. The SOX regimen consisted of 130 mg/m2 of oxaliplatin intravenously on the first day and S-1 twice daily for 14 consecutive days, every 21 days. The dose of S-1 was also calculated according to body surface area (BSA): BSA <1.25m2, 80 mg/day; 1.25m2 ≤BSA <1.5m2, 100 mg/day; BSA >1.5m2, 120 mg/day.
      Participants in the high-dose group received EA treatment seven times during each chemotherapy cycle (three times in the first week, twice per week in the next two weeks), for a total of 21 sessions during the first three chemotherapy cycles. Those in the low-dose group received EA treatment three times during each chemotherapy cycle (once per week), for a total of nine sessions during the first three chemotherapy cycles. The acupoints prescription consisted of standard points and selected points. Standard points included bilateral ST36 (Zusanli), bilateral PC6 (Neiguan), bilateral SP4 (Gongsun), DU20 (Baihui), and EX-HN3 (Yintang). Selected points were Back-shu points, in the urinary bladder meridian, chosen according to TCM differentiation (see Supplementary method). The acupoints prescription was designed according to TCM theory and our clinical experience, focusing on tonifying Qi,
      • Chang S.
      The meridian system and mechanism of acupuncture: a comparative review. Part 3: mechanisms of acupuncture therapies.
      considering gastrointestinal symptoms as most common in gastric cancer patients during chemotherapy after gastrectomy.
      • Munene G
      • Francis W
      • Garland SN
      • et al.
      The quality of life trajectory of resected gastric cancer.
      Licensed acupuncturists with at least 2 years of experience, from 11 acupuncture sites, performed the EA interventions. Before treating study participants with EA, all of the acupuncturists received training on the specific protocol and completed study checklists, and XSC checked documentation and provided feedback to ensure treatment fidelity. Acupuncturists inserted and manipulated the needles (25 mm or 40 mm and 0.25 mm gauge; Hanyi Medical Instrument Co., Ltd, Beijing) until patients reported De Qi, a sensation of soreness, warmth, tingling, or heaviness. For EA, participants were in sitting, prone, or in a lateral position. The acupuncture needles were inserted perpendicular, to a depth of approximately 20-30 mm for ST36, 10–20 mm for SP4 and PC6 from the skin surface. For DU20, EX-HN3, and Back-shu points, we inserted acupuncture needles 10–15 mm deep at an angle of 30 degrees to the skin. A bilateral 2-Hz current was connected to the ST36 and PC6 points, using an electrical stimulator (G6805-1 EA apparatus; Xinsheng Industrial Co., Ltd, Qingdao, China). The needles were retained for 20 minutes.

      Outcome Measures

      We used the Chinese version of Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) questionnaire (https://www.facit.org/) to assess HRQOL,
      • Garland SN
      • Pelletier G
      • Lawe A
      • et al.
      Prospective evaluation of the reliability, validity, and minimally important difference of the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) Quality-of-Life Instrument.
      which has been validated in Chinese population with excellent reliability, construct validity, and sensitivity to distinguish changes in responsible to different clinical characteristics and interventions.
      • Zhou HJ
      • So JB
      • Yong WP
      • et al.
      Validation of the functional assessment of cancer therapy-gastric module for the Chinese population.
      The FACT-Ga consists of five subscales, including physical well-being (PWB, seven items), social/family well-being (SWB, seven items), emotional well-being (EWB, six items), functional well-being (FWB, seven items), and the gastric cancer subscale (GaCS, 19 items). A higher score indicates better HRQOL. Patients completed the FACT-Ga before chemotherapy and then once a week during the study duration (three weeks/cycle × three cycles of chemotherapy, ten times in total) using a patient diary. The GaCS subscale was the main indicator of HRQOL in this pilot study since it is specific to gastric cancer.
      We used the Chinese version of Edmonton Symptom Assessment System (ESAS) to assess the symptom burden.
      • Dong Y
      • Chen H
      • Zheng Y
      • et al.
      Psychometric validation of the edmonton symptom assessment system in Chinese patients.
      In the Chinese version of ESAS, 11 symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite loss, nonwellbeing, itching, breath shortness, and other problems, were scored using a numeric rating scale (NRS), ranging from 0 to 10. Higher scores indicate greater symptom severity. Since the itching symptom was specific for patients with jaundice, which is not common in our participants, and are not included in other versions of ESAS,
      • Hui D
      • Bruera E.
      The Edmonton Symptom Assessment System 25 Years Later: past, present, and future developments.
      we didn't score the itching symptom; therefore, only 10 symptoms were recorded, and the total ESAS score ranges from 0 to 100 in this study.
      The primary outcome was the average of the GaCS scores during the three cycles of chemotherapy. We chose this as the primary outcome because the effect of EA on HRQOL should persist throughout the entire phase of the intervention rather than at any specific time point.
      • Fairclough DL.
      Summary measures and statistics for comparison of quality of life in a clinical trial of cancer therapy.
      ,
      • Sprangers MAG
      • Moinpour CM
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      • et al.
      Assessing meaningful change in quality of life over time: a users' guide for clinicians.
      Secondary outcomes included the average scores of trial outcome index variables (TOI = PWB + FWB + GaCS), FACT-Ga total scores (PWB + SWB + EWB + FWB + GaCS), and ESAS total scores. Research staff, not blinded to treatment groups, monitored adverse events (AEs) according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTC AE, V4.0) before each cycle of chemotherapy.

      Statistical Analysis

      According to the statistics analysis plan for this study, primary outcomes should be compared according to the intention-to-treat (ITT) principle. However, due to the COVID-19 pandemic, 13.79% of participants did not complete the treatments per protocol. Therefore, we modified our analyses to compare the outcomes in per-protocol set (PPS) population; we also compared the differences in the ITT population as sensitivity analysis. Missing data were imputed using the worst observation carried forward (WOCF) method. We used student's t test, analysis of variance (ANOVA) with least significant difference (LSD) for post hoc test, χ2 test, or Fisher's exact test to test the differences among groups. ANOVA for repeated measures was used to test the within-subject differences during the intervention and among each cycle of chemotherapy. Data were analyzed using SPSS (version 16.0). The Statistician was not blinded to the treatment groups.
      We postulated that the GaCS average score would be 40 in the control group, with a standard deviation of 10, according to the trajectory investigation by Munene G et al.
      • Munene G
      • Francis W
      • Garland SN
      • et al.
      The quality of life trajectory of resected gastric cancer.
      As a pilot study, we planned to enroll a total of 54 patients, randomizing 36 in EA groups (18 in the high-dose group and 18 in the low-dose group), and 18 in control group, allowing for an 81% power to detect a difference of 8.2 in GaCS between EA and control groups, the minimally important difference (MID) for GaCS,
      • Garland SN
      • Pelletier G
      • Lawe A
      • et al.
      Prospective evaluation of the reliability, validity, and minimally important difference of the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) Quality-of-Life Instrument.
      using a two side hypothesis test at a significance level of 0.05. We hoped that more than 90% of participants would complete the intervention per-protocol and answer all of the questionnaires, determining a good feasibility for a larger trial. Therefore, we assumed a 10% dropout rate, and a total of 60 subjects (20 per arm) were needed.

      Results

      Feasibility Outcomes

      A total of 167 patients were assessed for eligibility, and 66 patients were randomized. Eight patients refused to participate after randomization or baseline data collection. Finally, a total of 58 patients, including 5 (8.62%) with missing FACT-Ga or ESAS data during the treatment, were analyzed as ITT population (Fig. 1).
      Fig 1
      Fig. 1Participants recruitment diagram for this study. Hb = hemoglobin; EA = electro-acupuncture; ITT = intention to treat; PPS = per-protocol set.
      A total of 10 patients did not complete the acupuncture per protocol; for 6 patients, this was due to the COVID-19 pandemic. Two other patients refused the third cycle of adjuvant chemotherapy also due to the COVID-19 pandemic. In addition, one patient in the control group did not complete the FACT-Ga or ESAS data during the study. Finally, a total of 45 patients were analyzed as PPS population (Fig. 1). Regardless of the impact of COVID-19 pandemic (8/58, 13.79%), the dropout rate was 8.62% (5/58).

      Patient Characteristics and Treatments

      Baseline characteristics of the study population were balanced well among the groups (Table 1). The mean age was 55.95±11.23 years. Thirty-six patients (62.07%) were male, and 40 (68.97%) were diagnosed with stage Ⅲ disease. Most patients had an ECOG physical status (PS) score of 1 (86.21%, 50/58), and only one patient had a PS score of 2 (in the low-dose EA group). Thirty-two patients (55.17%) were treated with distal gastrectomy, 22 (37.93%) with total gastrectomy, and only 4 (6.90%) with proximal gastrectomy. Twenty-eight patients (48.28%) underwent laparoscopic surgery, and the others underwent open surgery. Only eight patients (13.79%) accepted neoadjuvant chemotherapy. The median time from surgery to the first cycle of adjuvant chemotherapy was 30 days (25%–75% percentile, 25–38 days). Most patients (87.93%, 51/58) were treated with the CapeOx regimen, and five (8.62%) were treated with CapeOx at first, but then changed to other oxaliplatin-containing regimens. The other two patients were treated with the SOX regimen. The median number of acupoints of each session was 12, with a range of 10–14.
      Table 1Demographic and Clinical Characteristics of Patients in the Intention to Treat Population
      CharacteristicsHigh-dose EA (n = 19)Low-dose EA (n = 20)Control Group (n = 19)
      Age (year), mean ± SD55.00±12.4158.75±8.8553.95±12.19
      Gender
       Male15 (78.95%)11 (55.00%)10 (52.63%)
       Female4 (21.05%)9 (45.00%)9 (47.37%)
      ECOG physical status score
       02 (10.53%)2 (10.00%)3 (15.79%)
       (1-2)
      Only 1 patient in low-dose group was with ECOG PS=2.
      17 (89.47%)18 (90.00%)16 (84.21%)
      Stage
       II5 (26.32%)6 (30.00%)7 (36.84%)
       III14 (73.68%)14 (70.00%)12 (63.16%)
      Resection extent
       Total/proximal gastrectomy9 (47.37%)9 (45.00%)8 (42.11%)
       Distal gastrectomy10 (52.63%)11 (55.00%)11 (57.89%)
      Surgical approach
       Laparoscope9 (47.37%)10 (50.00%)9 (47.37%)
       Open surgery10 (52.63%)10 (50.00%)10 (52.63%)
      Neo-adjuvant chemotherapy
       Yes4 (21.05%)2 (10.00%)2 (10.53%)
       No15 (78.95%)18 (90.00%)17 (89.47)
      Days from surgery to adjuvant
      chemotherapy, median (range)29 (20-58)30 (22-65)34 (19-52)
      Number of acupoints, median (range)12 (10-14)12 (10-13)-
      Abbreviations: EA = electro-acupuncture; SD = standard deviation; ECOG = Eastern Cooperative Oncology Group.
      low asterisk Only 1 patient in low-dose group was with ECOG PS=2.

      EA Significantly Improved Quality of Life

      Expectedly, the GaCS (P < 0.001), TOI (P < 0.001), and FACT-Ga (P < 0.001) scores were significantly different during the intervention, with the worst scores on the day7 of each chemotherapy cycle (Fig. 2a). Differences of GaCS (P = 0.320), TOI (P = 0.403), or FACT-Ga (P = 0.525) among each cycle of chemotherapy were not significant. Average scores of GaCS (51.98 ± 10.91 vs. 45.37 ± 8.61, P = 0.039) and TOI (85.71 ± 19.47 vs. 75.51 ± 13.30, P = 0.043) during the chemotherapy for patients in EA groups were significantly higher than those in control group (Fig. 2a, Table S2). EA treatment also produced a trend of better average scores, yet not statistically significant, of FACT-Ga (P = 0.067) and other subscales (Fig. 2a, Fig. S1a). Similar trend of changes on GaCS (P = 0.058), TOI (P = 0.069), and total FACT-Ga (P = 0.070) scores between EA and control groups, although not significantly different, were also indicated in the sensitivity analysis using ITT population (Fig. 2b).
      Fig 2
      Fig. 2Scores of Gastric Cancer Subscale (GaCS), Trial Outcome Index (TOI), and the total Functional Assessment of Cancer Therapy-Gastric (FACT-Ga), the higher, the better, for patients in EA and control groups in per-protocol set (2a) and intention to treat (2b) populations. Data were shown as mean ± standard error (SE) in the figures and mean ± standard derivation (SD) in the tables. EA = electro-acupuncture; PPS = per-protocol set; ITT = intention to treat.

      EA Helped to Reduce Symptom Burden

      Again, the ESAS scores were significantly different during the intervention (P < 0.001), with the worst symptom burden in the first weeks after each cycle of chemotherapy (Fig. 3a). Differences of ESAS scores among each cycle of chemotherapy were not significant (P = 0.572). The average ESAS scores during intervention in the EA and control groups were not significantly different (22.21±15.49 vs. 28.81±15.18, P = 0.170). Nevertheless, the last reported ESAS scores, reported at the end of intervention, in the EA group were significantly lower than those in control group (14.36±12.28 vs. 23.91±15.52, P = 0.027, Table S2), suggesting a promising effect of EA treatment to reduce total ESAS scores (Fig. 3a). No significant differences on symptom scores recorded in ESAS questionnaire between the EA and control groups were indicated, except for the last reported feeling of nonwellbeing (2.18±1.95 vs. 3.47±2.27, P = 0.049), pain (0.82±1.25 vs. 1.76±1.82, P = 0.045), and shortness of breath (0.82±1.28 vs. 1.88±1.69, P = 0.021, Fig. S2). Similar trend of changes on total ESAS scores between EA and control groups, although not significantly different, was also indicated in the sensitivity analysis using ITT population (Fig. 3b).
      Fig 3
      Fig. 3Scores of total Edmonton Symptom Assessment System (ESAS), the lower, the better, for patients in EA and control groups in per-protocol set (3a) and intention to treat (3b) populations. Data were shown as mean± derivation (SD). EA = electro-acupuncture; PPS = per-protocol set; ITT = intention to treat.

      Association of EA Dose and Efficacy

      No significant differences on GaCS (p=0.945), TOI (P = 0.855), FACT-Ga (P = 0.677), ESAS (P = 0.717, Fig. 4), or other FACT-Ga subscales (Fig. S1b) between the high-dose and low-dose EA groups were indicated. Interestingly, in the symptom and psychology-associated PWB (P = 0.702), and EWB (P = 0.707) subscales, efficacy of EA was very similar between the high-dose and low-dose groups (Fig. S1b). However, in the social-associated SWB (P = 0.268) and FWB (P = 0.311) domains, high-dose EA even produced a trend of worse scores when comparing with low-dose EA, although the differences were not significant (Fig. S1b).
      Fig 4
      Fig. 4Scores of Gastric Cancer Subscale (GaCS), Trial Outcome Index (TOI), the total Functional Assessment of Cancer Therapy-Gastric (FACT-Ga), the higher, the better, and the total Edmonton Symptom Assessment System (ESAS), the lower, the better, for patients in high-dose EA, low-dose EA, and control groups in per-protocol set. Data were shown as mean±derivation (SD). EA = electro-acupuncture; PPS = per-protocol set; H vs. L = high-dose vs. low-dose EA; H vs. C = high-dose EA vs. control; L vs. C = low-dose EA vs. control.

      Safety Data

      Treatment-related AEs occurred in 94.74% (grade 3–4, 15.79%), 95.00% (grade 3–4, 15.00%), and 100.00% (grade 3–4, 31.58%) of patients in high-dose EA group, low-dose EA group, and control group, respectively (Table 2). The most common AEs were nausea (75.86%), neutropenia (60.34%), leukopenia (50.00%), peripheral sensory neuropathy (46.55%), vomiting (39.66%), anemia (39.66%), diarrhea (34.48%), and increased ALT/AST (34.48%). The most common grade 3–4 AEs was neutropenia (10.34%), vomiting (8.62%), nausea (6.90%), and leukopenia (5.17%). EA was associated with reduced grade 3–4 leukopenia (0% vs. 15.79%, P = 0.031) and neutropenia (2.56% vs. 26.31%, P = 0.012). In addition, trends of reduced grade 3–4 AEs (15.38% vs. 31.58%, P = 0.153), all grade of neutropenia (30.77% vs. 68.42%, P = 0.380) and vomiting (33.33% vs. 52.63%, P = 0.159) were indicated in EA group, although the differences were not significant.
      Table 2Treatment-related Adverse Events of Patients in the Intention to Treat Population
      CharacteristicsEA (n = 39)Control Group (n = 19)P
      Any GradeGrade 3-4Any GradeGrade 3-4Any GradeGrade 3-4
      Any adverse event37 (94.87%)6 (15.38%)19 (100%)6 (31.58%)1.000
      Fisher's exact test.
      0.153
      χ2 test.
      Leukopenia19 (48.72%)0 (0%)10 (52.63%)3 (15.79%)0.780
      χ2 test.
      0.031
      Fisher's exact test.
      Neutropenia22 (30.77%)1 (2.56%)13 (68.42%)5 (26.31%)0.380
      χ2 test.
      0.012
      Fisher's exact test.
      Thrombocytopenia7 (17.95%)0 (0%)2 (10.53%)0 (0%)0.703
      Fisher's exact test.
      -
      Anemia14 (35.90%)0 (0%)9 (47.37%)0 (0%)0.402
      χ2 test.
      -
      ALT/AST increased11 (28.21%)0 (0%)9 (47.37%)0 (0%)0.150
      χ2 test.
      -
      Bilirubin increased2 (5.13%)0 (0%)0 (0%)0 (0%)1.000
      Fisher's exact test.
      -
      Creatinine increased1 (2.56%)0 (0%)0 (0%)0 (0%)1.000
      Fisher's exact test.
      -
      Nausea28 (71.79%)3 (7.69%)14 (73.68%)1 (5.26%)0.880
      χ2 test.
      1.000
      Fisher's exact test.
      Vomiting13 (33.33%)3 (7.69%)10 (52.63%)2 (10.53%)0.159
      χ2 test.
      1.000
      Fisher's exact test.
      Diarrhea16 (41.03%)2 (5.13%)4 (21.05%)0 (0%)0.155
      Fisher's exact test.
      1.000
      Fisher's exact test.
      Constipation2 (5.13%)0 (0%)1 (5.26%)0 (0%)1.000
      Fisher's exact test.
      -
      Oral mucositis3 (7.69%)0 (0%)0 (0%)0 (0%)0.544
      Fisher's exact test.
      -
      Foot-hand syndrome8 (20.51%)0 (0%)3 (15.79%)0 (0%)1.000
      Fisher's exact test.
      -
      Peripheral sensory neuropathy18 (46.15%)0 (0%)9 (47.37%)0 (0%)0.931
      χ2 test.
      -
      Abbreviations: EA = electroacupuncture; ALT = alanine aminotransferase; AST = aspartate aminotransferase.
      Significant differences are shown in bold.
      a Fisher's exact test.
      b χ2 test.

      Discussion

      Gastrectomy and perioperative chemotherapy has improved survival in patients with stage Ⅱ-Ⅲ gastric cancer.
      • Bang YJ
      • Kim YW
      • Yang HK
      • et al.
      Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial.
      ,
      • Noh SH
      • Park SR
      • Yang HK
      • et al.
      Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial.
      However, the sequelae of gastrectomy exacerbate the symptoms and decline the HRQOL, especially within the first three months.
      • Munene G
      • Francis W
      • Garland SN
      • et al.
      The quality of life trajectory of resected gastric cancer.
      ,
      • Shan B
      • Shan L
      • Morris D
      • Golani S
      • Saxena A.
      Systematic review on quality of life outcomes after gastrectomy for gastric carcinoma.
      ,
      • Hu YN
      • Vos EL
      • Baser RE
      • et al.
      Longitudinal analysis of quality-of-life recovery after gastrectomy for cancer.
      Furthermore, toxicity of adjuvant chemotherapy during this period aggravates the HRQOL. Unfortunately, there is a lack of effective therapies to control the symptoms and improve HRQOL when undergoing adjuvant chemotherapy. To our knowledge, this trial is the first study focusing on the use of acupuncture on symptom control and HRQOL during this specific and challenging period for patients with gastric cancer.
      The best oncology clinical care should not only focus on prolonging survival, but also improving HRQOL for patients during treatment and survivorship. Increasing evidence showing the effect of acupuncture on cancer-related symptoms
      • Yun H
      • Sun L
      • Mao JJ.
      Growth of integrative medicine at leading cancer centers between 2009 and 2016: a systematic analysis of NCI-Designated comprehensive cancer center websites.
      ,
      • Zia FZ
      • Olaku O
      • Bao T
      • et al.
      The national cancer institute's conference on acupuncture for symptom management in oncology: state of the science, evidence, and research gaps.
      led us to investigate its role for patients with gastric cancer. In a clinical trial with 56 advanced gastric cancer patients, acupuncture helped to reduce gastrointestinal symptoms during chemotherapy, including nausea, vomiting, abdominal pain, and diarrhea.
      • Zhou J
      • Fang L
      • Wu WY
      • et al.
      The effect of acupuncture on chemotherapy-associated gastrointestinal symptoms in gastric cancer.
      In addition, it has also been reported that acupuncture can help to prevent or reduce postoperative ileus in gastric cancer patients after gastrectomy.
      • Jung SY
      • Chae HD
      • Kang UR
      • Kwak MA
      • Kim IH.
      Effect of acupuncture on postoperative ileus after distal gastrectomy for gastric cancer.
      • Chae HD
      • Kwak MA
      • Kim IH.
      Effect of acupuncture on reducing duration of postoperative ileus after gastrectomy in patients with gastric cancer: a pilot study using sitz marker.
      • You XL
      • Wang YJ
      • Wu J
      • et al.
      Zusanli (ST36) Acupoint injection with neostigmine for paralytic postoperative ileus following radical gastrectomy for gastric cancer: a randomized clinical trial.
      Consistent with these findings on specific symptoms, our data contributes promising effect of EA for improving HRQOL during the hard period of postoperative adjuvant chemotherapy. Regardless of the impact of COVID-19 pandemic, the dropout rate of less than 10% indicated good feasibility for a larger clinical trial. If the preliminary observation can be confirmed in future large clinical trials, acupuncture can potentially be integrated into oncological care delivery to improve HRQOL for patients with gastric cancer during this challenging period.
      Theoretically, acupuncture dosage is as important for effectiveness as that of pharmacological agents. Yet, acupuncture frequency in oncology settings varies from daily
      • Zhou J
      • Fang L
      • Wu WY
      • et al.
      The effect of acupuncture on chemotherapy-associated gastrointestinal symptoms in gastric cancer.
      to weekly,
      • Bao T
      • Seidman AD
      • Piulson L
      • et al.
      A phase IIA trial of acupuncture to reduce chemotherapy-induced peripheral neuropathy severity during neoadjuvant or adjuvant weekly paclitaxel chemotherapy in breast cancer patients.
      depending mainly on the experiences of acupuncturists rather than evidences from clinical trials, suggesting that dosage is a crucial research area for acupuncture. An individual patient meta-analysis indicates that more acupuncture sessions appeared to be associated with better outcomes in patients with chronic pain.
      • MacPherson H
      • Maschino AC
      • Lewith G
      • et al.
      Characteristics of acupuncture treatment associated with outcome: an individual patient meta-analysis of 17,922 patients with chronic pain in randomised controlled trials.
      However, this may not be the case in oncology settings, since our data indicated that high-dose EA (2–3 times per week) was not more efficacious than low-dose EA (once per week) in improving HRQOL. Cancer patients undergoing chemotherapy are often suffering from increased travel and financial burdens due to frequent antitumor therapies; high dose acupuncture requires more time and increases cost. This may partially explain our data that in the social-associated SWB and FWB domains (Fig. S1b), as well as depression (P = 0.337) and anxiety (P = 0.358) symptoms (not reported), high-dose EA acted worse, although not significantly, than low-dose EA. In addition, for health systems, high dose acupuncture also requires more demands on staffing and space. Therefore, once weekly acupuncture appears to be the optimal dosing for future trials, nevertheless, more confirmation is needed.
      Our data suggests EA not only improved subjective HRQOL, but also reduced objective high-grade leukopenia and neutropenia. A prior exploratory meta-analysis also indicates that acupuncture use was associated with an increase in leukocytes in patients during chemotherapy or chemoradiotherapy.
      • Lu W
      • Hu D
      • Dean-Clower E
      • et al.
      Acupuncture for chemotherapy-induced leukopenia: exploratory meta-analysis of randomized controlled trials.
      A clinically-relevant trend of higher white blood cell count for acupuncture use was also observed in a pilot randomized, sham-controlled clinical trial in gynecologic malignancy patients undergoing chemotherapy.
      • Lu WD
      • Matulonis UA
      • Doherty-Gilman A
      • et al.
      Acupuncture for chemotherapy-induced neutropenia in patients with gynecologic malignancies: a pilot randomized, sham-controlled clinical trial.
      Recently, Zhang Y, et al. reported that acupuncture promoted typical Th1 cells drifting, increased IFNγ and decreased IL-4 and IL-6 levels in peripheral blood mononuclear cells and plasma in advanced stage gastric cancer patients.
      • Zhang YJ
      • Min Q
      • Huang Y
      • et al.
      Efficacy of acupuncture and moxibustion as a subsequent treatment after second-line chemotherapy in advanced gastric cancer.
      All these results, as well as our data, indicated that acupuncture may have effects on modulating the immune system in cancer patients, while basic research in animal models suggested that this may be via vagal modulation.
      • Torres-Rosas R
      • Yehia G
      • Pena G
      • et al.
      Dopamine mediates vagal modulation of the immune system by electroacupuncture.
      ,
      • Zhang Q
      • Xu CC
      • Lin SQ
      • et al.
      Synergistic immunoreaction of acupuncture-like dissolving microneedles containing thymopentin at acupoints in immune-suppressed rats.
      If future clinical trial confirms that electroacupuncture can prevent grade 3 leukopnea and neutropenia, it can potentially increase the tolerability of chemotherapy thereby increase the long term survival for patients with gastric cancer.
      This study has some limitations. First, we did not use sham acupuncture as a control. This trial focused on determining the preliminary effect size of electroacupuncture for improving HRQOL for gastric cancer patients undergoing adjuvant chemotherapy. The placebo effect of acupuncture cannot be ruled out and should be further explored. Second, due to the COVID-19 pandemic and the relatively high drop-out rate, we modified our analysis approach in the PPS population, where the ITT data was used as the sensitivity analysis. Furthermore, investigators and the statistician were not blinded to treatment groups, with potential risk of bias, even though we used the WOCF method to imput missing data for the bias risk reduction. Therefore, our findings should be interpreted as preliminary rather than definitive. Lastly, this study was conducted in China and may need to be repeated in health care settings in other regions of the world to determine generalizability of findings.

      Conclusions

      We presented preliminary evidence that EA is associated with promising effects in improving HRQOL, controlling symptom burden, and reducing toxicity during adjuvant chemotherapy in gastric cancer patients. Future adequately powered trials are feasible and needed to confirm the specific effect of EA.

      Disclosures and Acknowledgments

      The work was original research that has not been published previously, except that some results were presented as a Poster (1843P) at the 2020 ESMO (European Society for Medical Oncology) Annual Meeting. Dr. Jun J. Mao has received grants from Tibet Cheezheng Tibetan Medicine Co Ltd for work performed outside of the current study. All other authors declare no conflicts of interest. We thank all the patients who participated in this study and their families. We thank Wen-wei Ou-yang from Guangdong Provinicial Hospital of Traditional Chinese Medicine for help with statistical analysis. We thank Qiao-ning Yang from Xiyuan Hospital, China Academy of Chinese Medical Sciences for the help with data monitoring. We thank Jie-shan Zhang from Zengcheng Hospital of TCM, Hai-peng Li from Central Hospital of Guangdong Nongken, Zhao-hong Li from Foshan Hospital of TCM, Jun-yi Cai from the Second People's Hospital of Guangdong Shanwei, Li-zhen Zou from Heyuan Hospital of TCM, Zi-qian Zhang and Gui-yuan Li from the First Affiliated Hospital of Guangzhou Medical University, Li-na Yang from Shenzhen Traditional Chinese Medicine Hospital, Yi-fen Wu from Dongguan People's Hospital, and Cheng-yun Wang from Maoming Hospital of Traditional Chinese Medicine, for performing the acupuncture.

      Funding

      This study was funded by the National Key Research and Development Program of China (2017YFC1700603), and the Science and Technology Planning Project of Guangdong Province (2017A020213021). Dr. Mao is supported in part by a grant from the National Institutes of Health/National Cancer Institute Cancer Center (P30 CA008748) and by the Translational and Integrative Medicine Research Fund at Memorial Sloan Kettering Cancer Center.

      Data Statement

      Dr. Hai-bo Zhang has full control of all primary data. All data relevant to the study are available in the department of Scientific Research Management of Guangdong Provincial Hospital of Traditional Chinese Medicine. Data and the protocol for this study may be available upon reasonable request, after the permission from Ministry of Science and Technology of the People's Republic of China.

      Appendix. Supplementary materials

      • Fig. S1. Scores of FACT-Ga subscales, the higher the better, for patients in per-protocol set (PPS) populations. 1a. Differences between the EA and control groups. Data were shown as mean ± standard error (SE). P value represents the differences on average scores during the chemotherapy between the EA and control groups. 1b. Differences among the high-dose EA, low-dose EA, and control groups. P value represents the differences on average scores during the chemotherapy between the high-dose and low-dose EA groups. EA: electro-acupuncture; PWB: physical well-being subscale of Functional Assessment of Cancer Therapy-Gastric (FACT-Ga); SWB: social/family well-being subscale of FACT-Ga; EWB: emotional well-being subscale of FACT-Ga; FWB: functional well-being subscale of FACT-Ga.

      • Fig. S2. Scores of each symptom in the Edmonton Symptom Assessment System (ESAS), the lower, the better, for patients in electro-acupuncture (EA) and control groups in per-protocol set (PPS) populations.

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