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Figure.  CONSORT Diagram of Participant Flow Through the Study
CONSORT Diagram of Participant Flow Through the Study

The number of participants who completed treatment at weeks 8 and 12 were included in the analysis for those weeks. CIPN indicates chemotherapy-induced peripheral neuropathy.

Table.  Mean Change in Chemotherapy-Induced Peripheral Neuropathy Symptom Scores at Week 8
Mean Change in Chemotherapy-Induced Peripheral Neuropathy Symptom Scores at Week 8
1.
Hershman  DL, Lacchetti  C, Dworkin  RH,  et al; American Society of Clinical Oncology.  Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline.  J Clin Oncol. 2014;32(18):1941-1967. doi:10.1200/JCO.2013.54.0914PubMedGoogle ScholarCrossref
2.
Bao  T, Goloubeva  O, Pelser  C,  et al.  A pilot study of acupuncture in treating bortezomib-induced peripheral neuropathy in patients with multiple myeloma.  Integr Cancer Ther. 2014;13(5):396-404. doi:10.1177/1534735414534729PubMedGoogle ScholarCrossref
3.
Downie  WW, Leatham  PA, Rhind  VM, Wright  V, Branco  JA, Anderson  JA.  Studies with pain rating scales.  Ann Rheum Dis. 1978;37(4):378-381. doi:10.1136/ard.37.4.378PubMedGoogle ScholarCrossref
4.
Ferraz  MB, Quaresma  MR, Aquino  LR, Atra  E, Tugwell  P, Goldsmith  CH.  Reliability of pain scales in the assessment of literate and illiterate patients with rheumatoid arthritis.  J Rheumatol. 1990;17(8):1022-1024.PubMedGoogle Scholar
5.
D’Alessandro  EG, Nebuloni Nagy  DR, de Brito  CMM, Almeida  EPM, Battistella  LR, Cecatto  RB.  Acupuncture for chemotherapy-induced peripheral neuropathy: a randomised controlled pilot study  [published online June 29, 2019].  BMJ Support Palliat Care. doi:10.1136/bmjspcare-2018-001542PubMedGoogle Scholar
6.
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.  Eur J Cancer. 2018;101:12-19. doi:10.1016/j.ejca.2018.06.008PubMedGoogle ScholarCrossref
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    1 Comment for this article
    EXPAND ALL
    Would Be Nice To Compare This Rather Intensive Protocol To Something Less So
    Michael Barr, MSc, DAOM, LAc | Private practice
    First of all, congratulations to the team for even daring to compare sham acupuncture to verum acupuncture-- and then for achieving a statistically significant difference. I can't help wondering though if all these needles (and even the e-stim) are really necessary. Even in my school clinic days, we achieved (albeit patient self-report and clearly not a randomized trial) amelioration in chemotherapy-induced neuropathy symptoms with what I am remembering was an eight needle protocol and without electrical stimulation. I realize that culturally, this kind of aggressive approach is warmly embraced, but I cannot help but wonder if a simpler and less jarring to the patient protocol of something as simple as Four Gates, P6 and ear Shen Men might produce the same or even better results. 
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Research Letter
    Oncology
    March 11, 2020

    Effect of Acupuncture vs Sham Procedure on Chemotherapy-Induced Peripheral Neuropathy Symptoms: A Randomized Clinical Trial

    Author Affiliations
    • 1Integrative Medicine Service, Memorial Sloan Kettering Cancer Center, New York, New York
    • 2Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
    • 3Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, New York
    JAMA Netw Open. 2020;3(3):e200681. doi:10.1001/jamanetworkopen.2020.0681
    Introduction

    Chemotherapy-induced peripheral neuropathy (CIPN) is the most common and debilitating long-term adverse effect of neurotoxic chemotherapy that significantly worsens cancer survivors’ quality of life. Well-tolerated, evidence-based interventions for CIPN are needed.1

    Methods

    This pilot randomized clinical trial compared the effect of 8 weeks of real acupuncture vs sham acupuncture or usual care to treat CIPN. The trial protocol (Supplement 1) was approved by the institutional review board of Memorial Sloan Kettering Cancer Center and follows the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure). Written informed consent was obtained from all study participants. Patients with solid tumors with persistent moderate to severe CIPN (symptoms of numbness, tingling, or pain rated ≥4 on a numeric rating scale [NRS]) who had completed 3 or more months of chemotherapy prior to study enrollment and were not taking stable neuropathic medication were eligible. Patients were allocated 1:1:1 to real acupuncture, sham acupuncture, or usual care through computer-generated randomization conducted by the Clinical Research Database in randomly permuted blocks.

    The real acupuncture group received ear and body acupuncture at Shen Men, point zero, and a third electrodermal active point,2 and bilateral body: LI-4, PC-6, SI-3, LR-3, GB-42, ST-40, Bafeng 2, and Bafeng 3. Electrical acupuncture was also applied bilaterally from LR-3 (negative) to GB-42 (positive) at 2 to 5 Hz for 20 minutes. The sham acupuncture group received a noninsertion procedure on nonacupoints. The usual care group did not receive any interventions throughout the study period. Investigators, study coordinators, and the statistician were blinded to the treatment assignments.

    The primary end point was CIPN symptom severity measured by NRS (11-point scale; 0 = no symptoms and 10 = worst symptom imaginable) at week 8. In prior studies, the NRS had high reliability and validity.3,4 We targeted a sample size of 25 participants in each group. This sample size allowed us to estimate the upper bound of a 1-sided 90% confidence interval for the treatment effect on outcome (eg, sham acupuncture vs real acupuncture or usual care vs real acupuncture) to 0.35-unit SDs. Mixed-effects models with an interaction term between group and assessment time (up to 8 weeks) were fit to examine whether temporal changes in a measure differed by group. The threshold for statistical significance was set at 2-sided P < .05.

    Results

    From July 2017 to June 2018, we enrolled 75 patients with solid tumors with moderate to severe CIPN (median [interquartile range] age, 59.7 [36.3-85.9] years; 60 [80%] female; 55 [73%] white; 40 [53%] with breast cancer and 12 [16%] with colorectal cancer). In all, 24 patients were randomized to real acupuncture, 23 to sham acupuncture, and 21 to usual care. Compared with usual care, NRS-measured pain, tingling, and numbness significantly decreased in real acupuncture at week 8 (Table). From baseline to week 8, mean absolute reduction in CIPN pain was greatest in real acupuncture (−1.75 [95% CI, −2.69 to −0.81]) and least in usual care (−0.19 [95% CI, −1.13 to 0.75]) (Table). At the 8-week assessment, sham acupuncture had a reduction of −0.91 (95% CI, −2.0 to 0.18). At the longer 12-week follow-up, real acupuncture had a mean absolute reduction in NRS-measured pain of −1.74 (95% CI, −2.6 to −0.83) from baseline, while sham treatment had a reduction of −0.34 (−1.3 to 0.61). Adverse events were few and mild.

    Discussion

    We found therapeutic benefit of real acupuncture for neuropathic pain that is consistent with previous pilot acupuncture CIPN trials.5,6 Distinctively, our study is the first, to our knowledge, to incorporate a sham treatment and a nontreatment control to evaluate the efficacy of acupuncture for CIPN. The addition of a sham acupuncture control in an acupuncture clinical trial is difficult owing to the challenge of incorporating a truly inert placebo. In addition, a sham control limits the ability of a small effect size to elucidate a true difference between real and sham acupuncture. Not only did our study demonstrate the feasibility of conducting a sham-controlled acupuncture trial, it generated sufficient pilot data to inform a definitive sham-controlled efficacy trial. Our trial is limited by its small sample size, single center, and short-term follow-up.

    In conclusion, compared with usual care, acupuncture resulted in significant improvement in CIPN symptoms. The effect size observed between real and sham control will inform a rigorous and adequately powered trial to establish the efficacy of acupuncture for CIPN.

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    Article Information

    Accepted for Publication: January 14, 2020.

    Published: March 11, 2020. doi:10.1001/jamanetworkopen.2020.0681

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Bao T et al. JAMA Network Open.

    Corresponding Author: Ting Bao, MD, DABMA, MS, Bendheim Integrative Medicine Center, 1429 First Ave, New York, NY 10021 (baot@mskcc.org).

    Author Contributions: Dr Bao had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Bao was the principal investigator.

    Concept and design: Bao, Mao.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Bao, Patil, Chen, Zhi, Piulson.

    Critical revision of the manuscript for important intellectual content: Bao, Patil, Zhi, Li, Mao.

    Statistical analysis: Bao, Patil, Li, Mao.

    Obtained funding: Bao.

    Administrative, technical, or material support: Bao, Piulson.

    Supervision: Bao, Piulson, Mao.

    Conflict of Interest Disclosures: Dr Bao reported receiving grants from the National Institutes of Health/National Cancer Institute during the conduct of the study. Dr Mao reported receiving grants from Tibet Cheezheng Tibetan Medicine Co, Ltd and Zhongke Health International LLC outside the submitted work. No other disclosures were reported.

    Funding/Support: This work was supported in part by a National Institutes of Health/National Cancer Institute Cancer Center grant (P30 CA008748), the Translational and Integrative Medicine Research Fund at Memorial Sloan Kettering Cancer Center, and the Frueauff Foundation.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Trial Registration: ClinicalTrials.gov Identifier: NCT03183037

    Additional Contributions: Yi Chan, Jonathan Siman, Lily Zhang, and Matthew Weitzman (Memorial Sloan Kettering Cancer Center Integrative Medicine Service) provided the acupuncture intervention for this study; Patricia Chen, BA (Memorial Sloan Kettering Cancer Center Integrative Medicine Service), assisted in conducting this study; and Victoria Blinder, MD (Memorial Sloan Kettering Cancer Center Breast Medicine Service), Mark Robson, MD (Memorial Sloan Kettering Cancer Center Breast Medicine Service), Andrew Seidman, MD (Memorial Sloan Kettering Cancer Center Breast Medicine Service), Linda Vahdat, MD (Norwalk Hospital), and Steven Sugarman, MD (Memorial Sloan Kettering Commack), assisted with recruiting patients. None of these individuals were compensated for their contributions. We thank all the cancer survivors in this study for their participation.

    Data Sharing Statement: See Supplement 2.

    References
    1.
    Hershman  DL, Lacchetti  C, Dworkin  RH,  et al; American Society of Clinical Oncology.  Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline.  J Clin Oncol. 2014;32(18):1941-1967. doi:10.1200/JCO.2013.54.0914PubMedGoogle ScholarCrossref
    2.
    Bao  T, Goloubeva  O, Pelser  C,  et al.  A pilot study of acupuncture in treating bortezomib-induced peripheral neuropathy in patients with multiple myeloma.  Integr Cancer Ther. 2014;13(5):396-404. doi:10.1177/1534735414534729PubMedGoogle ScholarCrossref
    3.
    Downie  WW, Leatham  PA, Rhind  VM, Wright  V, Branco  JA, Anderson  JA.  Studies with pain rating scales.  Ann Rheum Dis. 1978;37(4):378-381. doi:10.1136/ard.37.4.378PubMedGoogle ScholarCrossref
    4.
    Ferraz  MB, Quaresma  MR, Aquino  LR, Atra  E, Tugwell  P, Goldsmith  CH.  Reliability of pain scales in the assessment of literate and illiterate patients with rheumatoid arthritis.  J Rheumatol. 1990;17(8):1022-1024.PubMedGoogle Scholar
    5.
    D’Alessandro  EG, Nebuloni Nagy  DR, de Brito  CMM, Almeida  EPM, Battistella  LR, Cecatto  RB.  Acupuncture for chemotherapy-induced peripheral neuropathy: a randomised controlled pilot study  [published online June 29, 2019].  BMJ Support Palliat Care. doi:10.1136/bmjspcare-2018-001542PubMedGoogle Scholar
    6.
    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.  Eur J Cancer. 2018;101:12-19. doi:10.1016/j.ejca.2018.06.008PubMedGoogle ScholarCrossref
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