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A Randomized Assessor-Blinded Wait-List-Controlled Trial to Assess the Effectiveness of Acupuncture in the Management of Chemotherapy-Induced Peripheral Neuropathy

A Randomized Assessor-Blinded Wait-List-Controlled Trial to Assess the Effectiveness of... Purpose: Chemotherapy-induced peripheral neuropathy is a complex side effect with few available treatment options. The aim of the study was to test the effectiveness of an 8-week course of acupuncture in the management of chemotherapy- induced peripheral neuropathy in cancer patients who were receiving or had received neurotoxic chemotherapy. Methods: Randomized assessor-blinded controlled trial with 2 arms; one arm received acupuncture twice weekly for 8 weeks, while the other arm was a wait-list control group receiving only standard care. Primary outcome was pain intensity and interference over the past week using the Brief Pain Inventory at the end of the intervention. Secondary outcomes included clinical assessment (CTCAE [Common Toxicity Criteria for Adverse Events] grading and Total Neuropathy Score–Clinical Version) and nerve conduction studies; and patient-reported outcome measures (Functional Assessment of Cancer Therapy–Gynecologic Oncology Group–Neurotoxicity Quality of Life scale and Symptom Distress Scale) assessed at baseline, end of treatment (8 weeks), week 14, and week 20 from the beginning of treatment. Results: Eighty-seven patients were randomized to the experimental arm (n = 44) and to the standard care wait-list control arm (n = 43). Significant changes at 8 weeks were detected in relation to primary outcome (pain), the clinical neurological assessment, quality of life domains, and symptom distress (all P < .05). Improvements in pain interference, neurotoxicity-related symptoms, and functional aspects of quality of life were sustained in the 14-week assessment (P < .05), as were physical and functional well-being at the 20-week assessment (P < .05). Conclusions: Acupuncture is an effective intervention for treating chemotherapy-induced peripheral neuropathy and improving patients’ quality of life and experience with neurotoxicity-related symptoms with longer term effects evident. Keywords acupuncture, chemotherapy-induced peripheral neuropathy, cancer, neurotoxicity, quality of life, pain Submitted October 24, 2018; revised February 3, 2019; accepted February 13, 2019 alkaloids, ie, vincristine, or taxanes, ie, paclitaxel) can ensue. Introduction The overall incidence of CIPN is not clear, but it is estimated Chemotherapy-induced peripheral neuropathy (CIPN) is a derangement in structure and function of peripheral motor, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR sensory, and autonomic neurons, causing peripheral neuro- Prince of Wales Hospital, Sha Tin, Hong Kong SAR pathic signs and symptoms. Depending on the chemother- Corresponding Author: apy used, a pure sensory and painful neuropathy (with Alexander Molassiotis, School of Nursing, The Hong Kong Polytechnic platinum analogues, ie, cisplatin, oxaliplatin, and carbopla- University, No. 11 Yuk Choi Road, Hung Hom, Kowloon, Hong Kong tin) or a mixed sensory motor neuropathy with or without SAR. involvement of the autonomic nervous system (with vinca Email: alex.molasiotis@polyu.edu.hk Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Integrative Cancer Therapies to occur in 10% to 20% of patients during treatment and it Participants and Settings may be as high as 100%, depending on the chemotherapy Patients with breast, head and neck, colorectal, multiple drug, dose intensity, cumulative dose, and other as yet 1-4 myeloma, or gynecological cancer receiving taxane-based, unidentified risk factors. The implications of CIPN on the bortezomib, capecitabine, or platinum-based chemotherapy quality of life of cancer patients are significant, including experiencing CIPN during or after the end of chemotherapy dysfunction in daily activities, social well-being, work rein- 5 were recruited. The study took place in 2 large cancer cen- tegration, and physical impairments including pain. There ters in the Hong Kong territory. is a considerable impact on health care resource utilization too, with those experiencing CIPN having more frequent outpatient visits and medication use, estimated to be at Inclusion Criteria US$17 000 more in patients with CIPN than non-CIPN can- 6 •• Patients with diagnosis of breast, gynecological, cer patients. colorectal, or head and neck cancer, and multiple Attempts to manage this complex symptom with any myeloma with life expectancy (as judged by the cli- interventions have been largely unsuccessful with low level 7 nician) longer than 5 months. of evidence, and interventional research for this symptom •• Patients with cancer stages I to IV; Karnofsky is currently minimal. The American Society of Clinical Performance score 80 to 100. Oncology guidelines provide no recommendation for pre- •• Currently receiving or having received neurotoxic venting CIPN, a moderate recommendation for duloxetine chemotherapy (taxanes, cisplatin, oxaliplatin, bort- in the treatment of CIPN, and a few treatment options that ezomib, etc). have inconclusive evidence for CIPN, but which are consid- •• Reporting tingling in hands or feet and other clinical ered on the basis of their effect on other neuropathic pain 7 indications of CIPN after initiation of cancer treat- conditions. In this clinical area of limited treatment options, ments, confirmed to be indicative of CIPN by a med- acupuncture may be considered for treating CIPN, with ical consultant, often through brief neurological small-scale pilot studies (N < 30) or case series providing examination but at times based only on clinical signs. some initial evidence of effect, particularly in decreasing 8-14 •• Not using any medication for the prevention or treat- neuropathic pain. A systematic review identified 3 such ment of CIPN for the past 3 months. trials, which all used a different approach (acupuncture, •• Willing to participate and be randomized to one of auricular acupuncture, and acupuncture with moxibus- 15 the study groups. tion). Although these mostly uncontrolled or underpow- •• No previously established peripheral neuropathy. ered studies are positive and encouraging, they suggest that acupuncture could be an option for these patients and that controlled trials using validated patient-reported outcome Exclusion Criteria measures are justified. Patients with needle phobia; patients with low platelet count (<50 000); comorbidity with a bleeding disorder or coagu- Aims lopathy; pregnancy, or having received acupuncture treat- ment in the past 3 months; patients with lymphedematous The aim of the study is to test the effectiveness (in terms of limbs or who have undergone axillary dissection; and neuropathic pain, other neurological sensations, and overall patients with metastatic bone disease or metastatic involve- quality of life) of an 8-week course of acupuncture in the ment of the neural system. management of CIPN in cancer patients who are receiving or have received neurotoxic chemotherapy. Recruitment Methods Potential subjects were identified (through clinic lists and databases of patients who were undergoing treatment or Design attending follow-up visits), were approached initially by the The design of the study involves a pragmatic randomized relevant clinical team, and then screened by research staff. assessor-blinded controlled trial. Clinicians, researchers, and those assessing the patients and obtaining patient data Randomization were blinded to the allocation (but not the patients nor the acupuncturists). A 2-group design is used with the experi- Patients were allocated to study groups through computer- mental group receiving a course of acupuncture in addition generated randomization carried out by the Prince of Wales to standard care and a wait-list control arm receiving stan- Hospital clinical trials unit in Hong Kong. Randomization dard care only. consisted of minimization with a random element (stochastic Molassiotis et al 3 minimization), balancing for the treatment types (taxanes or Standard Care platinum analogues or bortezomib/thalidomide received). The comparison arm was a standard care control arm that received pain medication, vitamin B /B , or other medica- 12 6 Intervention tion as deemed necessary by the doctor. This group was offered acupuncture for their CIPN at the end of the trial The acupuncture intervention is described below based on after they completed week 20 assessments. Treatment was the STRICTA (Standards for Reporting Interventions in given as per in the intervention group above. Clinical Trials of Acupuncture) recommendations for reporting acupuncture trials. In the acupuncture group, patients received, in addition to standard care, a standard- Study Duration ized 30-minute acupuncture session needling specific Treatment duration was 8 weeks. The duration of each body points; there was flexibility in case some points patient’s involvement in the study was 20 weeks (5 months) could not be punctured (ie, in case of lymphedema), and with assessments at baseline, end of 8-week treatment, 14 alternative points (as in routine practice) were selected by weeks, and 20 weeks (the latter 2 to assess possible longer the therapists using their discretion to maintain an equal term effects). dose of treatment to all patients. The points were stan- dardized according to the clinical manifestations of the Outcome Measures subjects: if upper limbs were involved, we used LI4, LI11, PC7, TE5, and/or Baxie points (Ex-UE9; since the Primary outcome at 8 weeks (end of acupuncture treat- effect of Ex-UE9, PC7, and TE5 are similar, only 1 out of ment): pain: “worst pain during past week” was measured the 3 was chosen); if lower limbs were affected (most using the Brief Pain Inventory (BPI). The BPI measures common), we used SP6, ST36, LV3, ST41, and/or Bafeng pain intensity (worst pain; pain in last 24 hours; average (Ex-LE10; since the effect of LV3, Ex-LE10, and ST41 pain; and pain right now) on a 10-point scale (from 0-10) are similar, only 1 out of the 3 was chosen) reflecting a and its interference with 7 functions (ie, sleep or walking traditional Chinese medicine diagnosis of “blood and qi ability) also on a 10-point scale. Higher scores indicate stagnation and accumulation of dampness.” If the pain worse pain intensity and/or interference. threshold of the patients was low, TE5 for upper limbs and/or ST41 for lower limbs were chosen. An equal Secondary Outcomes “dose” of points was used for all patients (4 points bilater- •• Functional Assessment of Cancer Therapy/Gynecologic ally). Stimulation of the acupoints to achieve de qi sensa- Oncology Group–Neurotoxicity (FACT/GOG-Ntx) is tion was done manually through rotation of the needle a 38-item self-reported questionnaire: the 27-item backward and forward for a few seconds, done twice dur- general assessment of Quality of Life scale (FACT-G) ing each treatment session (just after inserting the needle alongside its 11-item neurotoxicity-specific module. and before removing the needle). This approach to treat- Higher scores indicate better quality of life outcomes. ment mimics current acupuncture practices and is based •• The presence of other related symptoms (ie, fatigue, 12,13,16 on the literature ; we have discussed this with expe- sleep, etc) was assessed using the 10-item Symptom 13 19 rienced acupuncturists and used earlier data and experi- Distress scale. Higher scores indicate more distress ence from the acupuncturists in the trial team. Acupuncture with symptoms. sessions were carried out twice weekly for 8 weeks (= a total of 16 sessions). Points were punctured to a depth of Completion of the self-report questionnaires was done at 0.5 to 1.2 cm depending on the patients’ size, sensitivity, home and these were posted back to the researchers using and state of health. The needles were Hwato sterile nee- prepaid envelopes. dles for single use, size 0.25 × 40 mm. Each session was Neurotoxicity examination: baseline and at the end of based on a strict protocol followed by all therapists. acupuncture course. Immediately after each session, the therapist completed A nurse not involved in the study and without knowing an intervention monitoring form verifying the exact treat- the patient allocation performed the neurological assess- ment given and any other issues that needed to be reported ment. This was the same person for all patients, and training (ie, any side effects). Forms were checked regularly by was provided for neurological assessments. the investigators for consistency across therapists. No other complementary therapy use was recommended dur- •• The 7-domain Total Neuropathy Score–Clinical ing the course of acupuncture. Therapists were Chinese Version (TNSc). The TNSc provides a composite medicine practitioners, registered with their professional score based on clinical neurological examination body in Hong Kong and had a minimum of 2 years’ expe- obtained from grading of symptoms (including auto- rience in working with patients. nomic ones), signs, and quantitative sensory tests 4 Integrative Cancer Therapies (tendon reflexes; strength; vibration sensibility, pin Sample Size sensibility; and 10-g monofilament), and provides a 20 Based on a randomized control trial on auricular acupunc- single measure to quantify neuropathy. ture for cancer chronic peripheral or central neuropathic •• The National Cancer Institute–Common Toxicity pain, a 30-day trial could reduce the pain intensity of the Criteria for Adverse Events (CTCAE) v.4.0, is a cancer patients from a Visual Analogue score (0-100) of physician-rated grading system that includes crite- 58 to 44 (standard deviation = 19). This effect corresponds ria and definitions for quantifying and grading to a Cohen’s d of 0.74, and 39 patients per arm were CIPN (both neurosensory and neuromotor compo- required to achieve significance level of .05 and power of nents) utilizing a 5-point scale ranging from grade 0.90. It is prudent to inflate this figure further as follows: 1 to grade 5. (1) the score distributions are likely to be fairly skewed •• Neurophysiological testing included a detailed and a Wilcoxon rank sum test may be more appropriate motor nerve conduction study (NCS) in a subsam- than a t test; (2) some dropout is likely, and though appro- ple of the patients of the following nerves on the priate to use a last value carried forward (LVCF) approach, affected limbs: for upper limbs, the test included a completers analysis is also likely to be performed. Taking median nerve (bilateral) and ulnar nerve (bilateral). these 2 factors into account indicates aiming for a sample For lower limbs, the test included peroneal nerve size of 44 in each arm. (bilateral) and tibial nerve (bilateral). There was provision of the most sensitive parameters to regis- Data Analysis ter any axonopathy or demyelination. Distal laten- cies, amplitudes, and conduction velocities were Analyses included descriptive statistics to summarize the measured as well as F-waves. For the sensory nerve data, analysis of variance to assess between-groups differ- conduction part of the neurophysiological assess- ences for primary and each of the secondary outcomes, and ment (NCS), the following nerves were studied: for generalized linear model (analysis of covariance upper limbs, the test included median nerve (bilat- [ANCOVA]) using the baseline pain score as covariate. eral) and ulnar nerve (bilateral). For lower limbs, it Ninety-five percent confidence intervals were also calcu- included sural nerve (bilateral). Neurophysiological lated. In more detail, while a t test is adequate for analysis, testing was offered to each patient before and after ANCOVA was used with the baseline score for each depen- treatment but only a subgroup of patients could dent variable as a covariate, and center and trial arm as attend one or all of the sessions owing to the con- grouping factors. Dropout cases and nonrespondents were current need of chemotherapy, acupuncture treat- asked to complete the primary outcome scale (1 item) and ment, discomfort from the assessment, and travel the 2 items of the CTCAE scale on CIPN in order to capture logistic issues. outcomes in as many patients as possible, and if this was not •• Sociodemographic and treatment characteristics feasible, we used data imputation (LVCF). An intention-to- were obtained from the patients’ records or patients treat analysis was carried out. Sensitivity analysis in the pri- themselves. Patients were asked at baseline about mary outcome variables (where there were missing values) treatment expectations, how much they believed repeating the ANCOVA after using LVCF was also carried this method will help them alleviate their neuropa- out as well as with GEE (generalized estimating equation) thy/pain, and how much faith they have in acu- for all variables. puncture (10-point Visual Analogue Score scales), alongside information if they have used any com- Results plementary therapies in the past and how much faith they have on complementary therapies. Sample Characteristics Chemotherapy dosage documentation (cumulative dosage received, completed number of cycles, and Eighty-seven Chinese patients with CIPN were recruited, chemotherapy type) were also collected. Adverse 43 randomized to the control arm and 44 to the acupunc- effects were monitored at each clinic visit for the ture arm. Their mean age was 57.1 years (SD = 7.7 years). duration of the acupuncture treatment (although The majority (72.4%) were females, had breast (42.5%) or none reported). colorectal (34.5%) cancer, were off treatment (90%), and an average of 15.3 months experiencing CIPN (range = Ethical approval from the Human Research Ethics 1-81 months). Detailed characteristics are shown in Table Review Committee of the Hong Kong Polytechnic 1. There were no differences in sample characteristics University (HSEARS20141011004) and the study hospi- between the 2 groups at inclusion. The CONSORT tals (CREC Ref. 2014.529-T) was obtained. All patients (Consolidated Standards of Reporting Trials) diagram of signed a consent form. the patients’ participation to the trial is shown in Figure 1. Molassiotis et al 5 Table 1. Sample Characteristics. Control Arm Intervention Arm Overall Variable (N = 43), n (%) (N = 44), n (%) (N = 87), n (%) Sex (P = .13) Male 15 (34.9%) 9 (20.5%) 24 (27.6%) Female 28 (65.1%) 35 (79.5%) 63 (72.4%) Marital status (P = .997) Never married 7 (16.3%) 8 (18.2%) 15 (17.2%) Married 31 (72.1%) 31 (70.5%) 62 (71.3%) Widower/widow 1 (2.3%) 1 (2.3%) 2 (2.3%) Divorced 4 (9.3%) 4 (9.1%) 8 (9.2%) Education level (P = .30) Nil 2 (4.7%) 0 (0.0%) 2 (2.3%) Primary 13 (30.2%) 9 (20.5%) 22 (25.3%) Secondary 23 (53.5%) 30 (68.2%) 53 (60.9%) Post-secondary 5 (11.6%) 5 (11.4%) 10 (11.5%) Economic status (P = .79) Full-time worker 21 (48.8%) 22 (50.0%) 43 (49.4%) Taking care of family 11 (25.6%) 11 (25.0%) 22 (25.3%) Retired 11 (25.6%) 10 (22.7%) 21 (24.1%) Others 0 (0.0%) 1 (2.3%) 1 (1.1%) Major income source (P = .12) Government 4 (9.3%) 1 (2.3%) 5 (5.7%) Family 23 (53.5%) 19 (43.2%) 42 (48.3%) Personal income 16 (37.2%) 21 (47.7%) 37 (42.5%) Savings 0 (0.0%) 3 (6.8%) 3 (3.4%) Personal monthly income (HK$, 1 US$ = 7.8 HK$) <$10 000 27 (62.7%) 29 (65.9%) 56 (62.5%) $10 000-$19 999 10 (23.3%) 10 (22.7%) 20 (22.9%) $20 000 or above 6 (14.0%) 5 (11.4%) 11 (12.6%) Diabetes (P = .97) Yes 4 (9.3%) 4 (9.1%) 8 (9.2%) Cancer stage (P = .30) I 10 (23.3%) 4 (9.1%) 14 (16.1%) II 10 (23.3%) 15 (34.1%) 25 (28.7%) III 20 (46.5%) 22 (50.0%) 42 (48.3%) IV 3 (7.0%) 3 (6.8%) 6 (6.9%) Type of cancer (P = .74) Ovarian 8 (18.6%) 4 (9.1%) 12 (13.8%) Head and neck 3 (7.0%) 3 (6.8%) 6 (6.9%) Breast 16 (37.2%) 21 (47.7%) 37 (42.5%) Colorectal 15 (34.9%) 15 (34.1%) 30 (34.5%) Myeloma 1 (2.3%) 1 (2.3%) 2 (2.3%) Currently receiving chemotherapy 4 (9.2%) 5 (11.4%) 9 (10.3%) Post chemotherapy 40 (90.8%) 38 (88.6%) 78 (89.7%) N; Mean (SD) N, Mean (SD) N, Mean (SD) Chemotherapy received and cumulative dose Oxaliplatin-based regimens (mg/m ) (P = .42) N = 14; 945.1 (78.3) N = 15; 900.1 (192.7) N = 29; 921.8 (148.1) Carboplatin and total area under the curve (P = .34) N = 8; 29.4 (3.2) N = 5; 25.0 (12.4) N = 13; 27.7 (7.8) Cisplatin-based regimens (mg/m ) (P = .29) N = 4; 639.0 (198.0) N = 3; 500.0 (40.0) N = 7; 579.4 (160.2) ) (P = .15) N = 12; 878.1 (279.3) N = 17; 760.1 (151.9) N = 29; 809.0 (217.5) Paclitaxel-based regimen (mg/m Docetaxel-based regimens (mg/m ) (P = .51) N = 12; 350.0 (52.2) N = 8; 367.8 (65.5) N = 20; 357.1 (56.9) Capecitabine (mg/m ) (P = .97) N = 15; 122826.7 (34820.2) N = 14; 123372.0 (42613.4) N = 29; 123089.9 (38071.0) Bortezomib (mg/m ) N = 1; 10.4 N = 1; 36.0 N = 2; 23.2 (18.1) Number of chemotherapy cycles received (P = .81) 6.0 (1.9) 6.1 (3.3) 6.0 (2.7) Number of chemotherapy cycles received (oral chemotherapy) (P = .77) N = 15; 8.1 (1.7) N = 14; 7.9 (0.3) N = 29; 8.0 (1.2) Days since the last chemotherapy cycle (P = .54), mean (SD) 459 (399) 401 (176) 430 (438) Used complementary therapies in the past (P = .32); yes, N (%) 27 (62.8%) 23 (52.3%) 50 (57.5%) Belief that acupuncture will help you manage your problem (10-point 6.9 (1.8) 6.6 (2.1) 6.7 (2.0) scale) (P = .56), mean (SD) How much faith do you have in complementary therapies in general? 6.7 (2.2) 6.4 (2.3) 6.6 (2.3) (10-point scale) (P = .43), mean (SD) 6 Integrative Cancer Therapies Figure 1. CONSORT diagram of the trial flow. The vast majority had moderate/severe CIPN (56/87 medication for CIPN at week 8 was minimal and included 6 patients with signs of sensory neuropathy and 63/87 participants in the control arm and 3 participants in the patients with signs of motor neuropathy as per CTCAE experimental group, 1 massaging hands, 1 using Panadol, scale at entry to trial). and traditional Chinese medicine. The TNSc (combination of sensory tests/neurological assessment, signs and symptoms) was significantly Outcomes improved at the end of the intervention in the acupuncture Detailed outcome analysis is shown in Table 2. The primary arm (P < .05). Also, significant improvements were seen in outcome (pain intensity and pain interference) was signifi- the sensory CTCAE item (P < .05) but not the motor item, cantly better at the end of the intervention in the acupunc- although the latter had a 17% difference in prevalence at ture arm than the control arm (P < .05 and P < .01, week 8 between the 2 groups (or 22% difference from respectively). Pain intensity remained lower in the acu- baseline), with the lower prevalence being in the acupunc- puncture arm at the 14-week assessment (P < .05; see Figure ture group. 2). Statistically significant differences were still present in Quality of life was also significantly better in the acu- pain interference (P < .01) at 14 weeks. At week 20, the BPI puncture arm at the end of the intervention, particularly in score had a 0.7-point difference from the control group, but terms of physical well-being (P < .01), functional well- this did not reach statistical significance as less than half of being (P < .05), neurotoxicity subscale score (P < .01), the the patients actually reported pain. Use of concomitant FACT/GOG-Ntx Trial Outcome Index (TOI; P < .001), the Molassiotis et al 7 Table 2. Trial Outcomes Between Control and Intervention Groups Over Time . b b b Baseline 8 Weeks P 14 Weeks P 20 Weeks P Brief Pain Inventory Pain intensity Control group 1.3 (0.4) 1.7 (0.4) .31 2.2 (0.4) .06 2.3 (0.4) .03 (worst pain; P for group by time Intervention group 2.1 (0.5) 1.0 (0.3) .008 1.5 (0.4) .13 1.8 (0.3) .49 interaction .03) Effect size 0.26 0.26 0.17 P value .20 .14 .18 .35 Pain intensity (mild pain or more severe; Control group N = 10 (23%) N = 16 (37%) .07 N = 21 (51%) .001 N = 22 (55%) <.001 P for group by time interaction .01) Intervention group N = 15 (34%) N = 8 (18%) .03 N = 13 (32%) .76 N = 20 (46%) .13 P value .26 .04 .07 .44 Pain interference Control group 0.9 (0.3) 1.3 (0.3) .33 1.7 (0.3) .04 2.0 (0.4) .007 (P for group by time interaction .04) Intervention group 1.5 (0.3) 0.5 (0.2) .001 1.5 (0.4) .94 1.6 (0.3) .75 Effect size 0.36 0.11 0.19 P value .25 .04 .66 .42 Pain interference (mild pain or more severe) Control group N = 9 (21%) N = 16 (37%) .04 N = 24 (48%) .001 N = 22 (55%) <.001 (P for group by time interaction .02) Intervention group N = 5 (34%) N = 8 (18%) .03 N = 20 (32%) .76 N = 19 (44%) .21 P value .16 .04 .12 .32 FACT Physical well-being Control group 21.6 (0.8) 20.9 (0.8) .37 20.1 (0.9) .047 19.1 (0.9) .007 (P for group by time interaction .006) Intervention group 20.5 (0.8) 23.5 (0.5) <.001 21.7 (0.8) .22 21.6 (0.7) .21 Effect size 0.46 0.28 0.46 P value .38 .01 .19 .02 Social/family well-being Control group 20.7 (1.0) 20.3 (0.9) .63 18.5 (0.9) .05 18.4 (1.2) .03 (P for group by time interaction .53) Intervention group 20.0 (0.7) 20.5 (0.7) .49 19.7 (0.9) .69 19.3 (0.8) .40 Effect size 0.03 0.21 0.16 P value .55 .87 .35 .51 Emotional well-being Control group 13.3 (0.6) 13.2 (0.7) .86 13.0 (0.6) .61 13.1 (0.7) .77 (P for group by time interaction .86) Intervention group 14.0 (0.6) 13.9 (0.5) .90 13.8 (0.6) .76 13.3 (0.7) .25 Effect size 0.18 0.20 0.04 P value .41 .41 .39 .87 Functional well-being Control group 17.3 (0.9) 16.3 (0.8) .26 16.8 (0.9) .51 16.0 (1.0) .23 (P for group by time interaction .12) Intervention group 17.0 (0.6) 18.8 (0.7) .03 17.6 (0.7) .48 17.9 (0.9) .36 Effect size 0.51 0.16 0.38 P value .78 .02 .50 .16 Neurotoxicity subscale Control group 26.5 (1.2) 28.2 (1.1) .06 27.4 (1.0) .30 28.0 (1.1) .18 (P for group by time interaction .04) Intervention group 27.4 (0.9) 32.2 (1.1) <.001 30.6 (1.2) <.001 30.3 (1.3) .003 Effect size 0.56 0.45 0.32 P value .56 .01 .04 .18 FACT/GOG-Ntx Trial Outcome Index Control group 65.3 (2.4) 65.4 (2.2) .98 64.4 (2.0) .60 63.1 (2.4) .34 (P for group by time interaction 0.001) Intervention group 64.9 (1.8) 74.5 (1.8) <.001 69.9 (2.3) .006 69.8 (2.4) .01 Effect size 0.65 0.39 0.48 P value .88 .001 .07 .047 FACT-G total score Control group 72.9 (2.4) 70.7 (2.5) .27 68.4 (2.4) .03 66.8 (2.2) .02 (P for group by time interaction .049) Intervention group 71.5 (1.8) 76.7 (1.7) .004 73.4 (1.9) .54 72.4 (2.1) .79 Effect size 0.42 0.31 0.38 P value .64 .045 .19 .12 FACT/GOGNtx_total Control group 99.4 (3.1) 98.9 (3.1) .85 96.0 (2.9) .18 94.7 (3.3) .15 (P for group by time interaction .01) Intervention group 98.9 (2.3) 108.9 (2.2) <.001 103.3 (3.0) .06 102.4 (3.1) .16 Effect size 0.55 0.41 0.42 P value .90 .009 .08 .09 Symptom Distress Scale total score Control group 17.6 (0.9) 17.6 (0.9) .995 18.4 (0.9) .28 19.4 (0.9) .06 (P for group by time interaction .15) Intervention group 16.6 (0.7) 14.6 (0.6) .001 17.1 (0.9) .49 18.5 (0.9) .004 Effect size 0.54 0.24 0.16 P value .42 .009 .29 .49 Total Neuropathy Score Control group 7.6 (0.5) 7.6 (0.6) .92 — — (P for group by time interaction .01) Intervention group 8.1 (0.5) 6.2 (0.5) <.001 Effect size 0.42 P value .43 .10 NCI-CTCAE-sensory (moderate/severe) Control group N = 27 (63%) N = 26 (62%) .91 — — (P for group by time interaction 0.046) Intervention group N = 29 (66%) N = 16 (37%) .001 P value .76 .02 NCI-CTCAE motor (moderate/severe) Control group N = 30 (70%) N = 28 (67%) .62 — — (P for group by time interaction .07) Intervention group N = 33 (75%) N = 21 (50%) .003 P value .59 .11 Abbreviations: FACT/GOG-Ntx, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity; NCI-CTCAE, National Cancer Institute–Common Toxicity Criteria for Adverse Events. Marginal mean (standard error) estimated with ANCOVA and GEE. Comparison with baseline. Control versus intervention group comparison. 8 Integrative Cancer Therapies Figure 2. Worst pain intensity score changes over time. Figure 3. FACT-G Neurotoxicity scale (total score) changes over time. FACT-G total score (P < .01), and the total score for the some significant effects in the ANCOVA model became FACT/GOG-Ntx scale (P < .01; see Figure 3). The neuro- insignificant in the GEE model. toxicity subscale score, the FACT/GOG-Ntx TOI score, and The NCS showed values largely within the normal FACT/GOG-Ntx total score remained significantly better in ranges or borderline ones for all parameters at baseline the acupuncture arm at the 14-week assessment, and at 20 (Table 3). At 8 weeks, there was no significant difference weeks, physical well-being and FACT/GOG-Ntx TOI score from baseline. continued to remain better in the acupuncture arm (Table 2 We examined if there was a correlation between out- and Figure 4). Overall symptom distress was also lower in comes and expectations, faith in the treatment, and faith in the acupuncture arm at the end of the intervention (P < .01). complementary therapies. There were no significant correla- Sensitivity analysis showed that the results were sus- tions in any of the outcome variables and these beliefs, tained when LVCF was used. The effect size estimation except in the case of symptom distress score at 14 weeks, from ANCOVA and GEE were also similar, although the which was correlated with faith in complementary therapies GEE had larger standard error (due to its complexity) hence (r = 0.31, P < .05) and also had an inverse correlation with Molassiotis et al 9 Table 3. Median Values of Nerve Conduction Studies for Combined Right and Left Foot at Week 8 Between Control and Experimental Groups. Control Intervention Variable (n = 8) (n = 9) P Sum of both foots in peroneal, motor (extensor digitorum brevis)—distal latency (ms) 6.6 7.1 .83 Sum of both foots in peroneal, motor (extensor digitorum brevis)—amplitude (µV)—first recording 13.8 16.1 .68 Sum of both foots in peroneal, motor (extensor digitorum brevis)—amplitude (µV)—second recording 12.6 14.7 .63 Sum of both foots in peroneal, motor (extensor digitorum brevis)—velocity (m/s) 90.5 93.0 .75 Sum of both foots in tibial, motor (abductor hallucis brevis)—distal latency (ms) 8.6 9.2 .82 Sum of both foots in tibial, motor (abductor hallucis brevis)—amplitude (µV)—first recording 27.2 33.3 .30 Sum of both foots in tibial, motor (abductor hallucis brevis)—amplitude (µV)—second recording 20.2 26.2 .06 Sum of both foots in tibial, motor (abductor hallucis brevis)—velocity (m/s) 89.5 93.0 .33 Sum of both foots in sural, sensory (behind malleolus)—distal latency(ms) 4.2 4.4 .25 Sum of both foots in sural, sensory (behind malleolus)—amplitude (µV) 14.0 13.0 .71 Sum of both foots in sural, sensory (behind malleolus)—velocity (m/s) 100.0 87.0 .27 Adjusted for baseline scores. P = .04 when only the values for the right foot were assessed. Figure 4. FACT/COG-Ntx Trial Outcome Index changes over time. expectations (r = −0.32, P < .05). Furthermore, no adverse exciting as there are limited treatment options available for effects were reported after checking the therapists’ records. managing CIPN. Clinical assessment that combines touch perceptions and deep nerve impairment at week 8 (primary outcome assess- Discussion ment) by blinded assessors clearly shows significant This is the first fully powered trial using acupuncture to improvements. This is further supported by the clinician- treat CIPN, showing, both through patient-reported out- rated CTCAE where significant sensory changes were also comes and clinical neurological assessment, that it signifi- detected. For the CTCAE motor item, statistically signifi- cantly improved CIPN in the acupuncture group compared cant differences were not shown, although the numeric dif- with the standard care wait-list control group. The current ference in favor of the acupuncture group was 22%; when findings alongside available small-scale pilot/feasibility tri- we assessed individual limb score changes, the left hand 8-14 als or uncontrolled trials and case series confirm the ben- motor impairment was also improved in the acupuncture eficial effect of acupuncture in treating CIPN. This is group (P < .05). This may also indicate that acupuncture 10 Integrative Cancer Therapies may be more effective in dealing with sensory impairment is expensive as well as uncomfortable and time-consum- than motor. ing for the patients, hence we allowed this part of the Pain intensity and pain interference with daily life were study to be on a voluntary basis. significantly better in the acupuncture arm, despite the There is debate in the literature if the results of acu- small number of patients who experienced (mostly mild) puncture are due to placebo effects and the need for a pain in the overall sample, suggesting a strong effect. The sham group in acupuncture trials. The current study change in intensity in the acupuncture group was 38% from answers an effectiveness research question using a prag- baseline, whereas in the control group, pain intensity matic trial design. The decision not to use a sham-control slightly increased. The impact of the improvement was methods in this study was not taken lightly and considered notable, as most patient-reported outcomes in the study, a number of aspects, including the difficulty in masking including overall quality of life, neurotoxicity-related acupuncture in very “acupuncture-experienced” people symptoms (ie. tingling/numbness in the hands/feet), physi- like the Chinese and the ethics of using shams and having cal well-being, and functional well-being, were enhanced to attend for treatment for 8 weeks while still continuing to in the acupuncture group. The change in pain interference experience discomfort. Also, a crucial question is whether (1 point in the acupuncture group) is also consistent with various sham methods can elicit a therapeutic effect and minimal clinically important differences (MCIDs) reported criticisms of shams in acupuncture trials have been previ- 26 27,28 in past studies of 0.5 to 1 point in a group of patients with ously discussed by ourselves and other researchers. bone metastasis showing improvement (although MCIDs In the revised CONSORT standards for reporting acu- for those deteriorating were 1.4-2.3 points). However, puncture trials, it is also highlighted that sham needling another study on bone metastasis patients showed that techniques may evoke neurophysiological and other MCID for pain interference is 2 to 3.5 points in those with responses, an area for which we have lack of knowledge, complete/partial response or 0.5 to 2.2 points in those with leading to compromises in the interpretation of results. indeterminate response, and in our study the change was 1 Until this debate is resolved, we should not deny patients point only. Quality of life indicators, such as neurotoxic- from the opportunity of symptom improvement using acu- ity subscales, neurotoxicity TOI, physical well-being, and puncture, if they prefer or have access to use it. In the cur- functional well-being, also showed highly statistically sig- rent trial, we decreased placebo effects by minimizing nificant improvements in the acupuncture group. Published interactions and communication between the therapist and MCIDs for the FACT physical well-being and functional the patients, using a wait-list control arm, assessing the well-being are around 2 to 3 points of change, and our role of patient expectations from treatment and using both data showed change of 3 and 1.8, respectively, at the end of objective and subjective outcome measures. intervention, although there are no established MCID val- Study limitations may include the small sample size ues for neurotoxicity subscale scores. It is interesting to see (although this was a fully powered trial), the use of CTCAE that symptom distress from multiple symptoms also as one of the objective measures that has been criticized as improved, suggesting that acupuncture for CIPN can a scale that can misdiagnose CIPN, the lack of sham- or impact on a wider range of symptoms, perhaps as a result attention-control methods, and use of multiple secondary of some acupoints used not being specific only to CIPN. outcomes at multiple time-points. Also, it is not clear if the Improvements were sustained for longer term albeit not in duration of effect can extend beyond 20 weeks, as we have all outcomes assessed, but primarily in physical and func- not used “booster sessions,” a common practice in acupunc- tional well-being and neurotoxicity-related symptoms. It ture treatments. However, our previous research in relation may be prudent to provide patients with additional less fre- to cancer-related fatigue showed that such booster sessions quent “boosting” sessions to maintain the initial effect, a may not enhance or extend the acupuncture effect. Pain, common practice among therapists, although this may need as an outcome for CIPN trials, may also not be the most testing in the future. appropriate primary endpoint as highlighted in the litera- The NCS was not a useful test in this study, as most ture, as the CIPN experience is wider than pain and patients had no evidence of neurophysiological impair- involves many other sensations that are more commonly ment, with values in the nerves assessed being often present in CIPN. Indeed, in our trial pain was not the most within normal ranges. Perhaps CIPN affects more small frequently reported experience, with less than half the nerve fibers (ie, A-delta fibers or C fibers), whereas NCS patients experiencing mild-to-moderate pain. Also, the neu- is able to measure primarily large nerve fibers with rou- rotoxicity-related (secondary) outcomes were the ones to tine electrodiagnostic tests being mostly normal in show consistently and more long-term improvements after patients with small fiber neuropathies. The role of NCS the intervention. and other neurophysiological tests in the diagnosis of Acupuncture can be a treatment option for patients expe- CIPN needs further investigation. The small number of riencing CIPN, although access to such a service and costs patients undergoing NCS is a limitation; however, the test for private treatments may affect the uptake of acupuncture Molassiotis et al 11 from patients. Specific attention should be paid to the adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32:1941-1967. “dose” and duration of treatment and the specific acupoints 8. Bao T, Goloubeva O, Pelser C, et al. A pilot study of acu- used. Further trials in a wide range of participants should be puncture in treating bortezomib-induced peripheral neuropa- carried out to confirm the results of the present study. thy in patients with multiple myeloma. Integr Cancer Ther. 2014;13:396-404. Acknowledgments 9. Garcia MK, Cohen L, Guo Y, et al. Electroacupuncture for We thank Dr Radha Raghupathy, Dr Annette Poon, and Dr Ashley thalidomide/bortezomib-induced peripheral neuropathy in CY Wong from Clinical Oncology, Prince of Wales Hospital, multiple myeloma: a feasibility study. J Hematol Oncol. Hong Kong; Dr Yu Chung Li, Dr Anthony Kwun To Leung, and 2014;7:41. doi:10.1186/1756-8722-7-41 Dr Kam Hung Wong from Clinical Oncology, Queen Elisabeth 10. Wong R, Major P, Sagar S. Phase 2 study of acupuncture-like Hospital, Hong Kong; and Dr Janice Ho, Dr Jerry Yeung, Ms transcutaneous nerve stimulation for chemotherapy-induced Echo Lau, and Mr Hon-fat Wong, Integrative Health Clinic, peripheral neuropathy. Integr Cancer Ther. 2016;15: School of Nursing, The Hong Kong Polytechnic University, for 153-164. their contributions to the study. 11. Greenlee H, Crew KD, Capodice J, et al. Randomized sham-controlled pilot trial of weekly electro-acupuncture Declaration of Conflicting Interests for the prevention of taxane-induced peripheral neuropathy in women with early stage breast cancer. Breast Cancer Res The author(s) declared no potential conflicts of interest with respect Treat. 2016;156:453-464. to the research, authorship, and/or publication of this article. 12. Schroeder S, Meyer-Hamme G, Epplée S. Acupuncture for chemotherapy-induced peripheral neuropathy (CIPN): a pilot Funding study using neurography. Acupunct Med. 2012;30:4-7. 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Ocean AJ, Vahdat LT. Chemotherapy-induced peripheral China: Foreign Languages Press; 1999. neuropathy: pathogenesis and emerging therapies. Support 17. Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treat- Care Cancer. 2004;12:619-625. ment in outpatients with metastatic cancer. N Engl J Med. 3. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of car- 1994;330:592-596. boplatin and paclitaxel compared with cisplatin and pacli- 18. Huang HQ, Brady MF, Cella D, Fleming G. Validation taxel in patients with optimally resected stage III ovarian and reduction of FACT/GOG-Ntx subscale for platinum/ cancer: a Gynecologic Oncology Group study. J Clin Oncol. paclitaxel-induced neurologic symptoms: a Gynecologic 2003;21:3194-3200. Oncology Group Study. Int J Gynecol Cancer. 2007;17: 4. Armstrong T, Almadrones L, Gilbert MR. Chemotherapy- 387-393. induced peripheral neuropathy. Oncol Nurs Forum. 19. McCorkle R, Cooley ME, Shea JA. 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A Randomized Assessor-Blinded Wait-List-Controlled Trial to Assess the Effectiveness of Acupuncture in the Management of Chemotherapy-Induced Peripheral Neuropathy

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Pubmed Central
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© The Author(s) 2019
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1534-7354
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1552-695X
DOI
10.1177/1534735419836501
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Abstract

Purpose: Chemotherapy-induced peripheral neuropathy is a complex side effect with few available treatment options. The aim of the study was to test the effectiveness of an 8-week course of acupuncture in the management of chemotherapy- induced peripheral neuropathy in cancer patients who were receiving or had received neurotoxic chemotherapy. Methods: Randomized assessor-blinded controlled trial with 2 arms; one arm received acupuncture twice weekly for 8 weeks, while the other arm was a wait-list control group receiving only standard care. Primary outcome was pain intensity and interference over the past week using the Brief Pain Inventory at the end of the intervention. Secondary outcomes included clinical assessment (CTCAE [Common Toxicity Criteria for Adverse Events] grading and Total Neuropathy Score–Clinical Version) and nerve conduction studies; and patient-reported outcome measures (Functional Assessment of Cancer Therapy–Gynecologic Oncology Group–Neurotoxicity Quality of Life scale and Symptom Distress Scale) assessed at baseline, end of treatment (8 weeks), week 14, and week 20 from the beginning of treatment. Results: Eighty-seven patients were randomized to the experimental arm (n = 44) and to the standard care wait-list control arm (n = 43). Significant changes at 8 weeks were detected in relation to primary outcome (pain), the clinical neurological assessment, quality of life domains, and symptom distress (all P < .05). Improvements in pain interference, neurotoxicity-related symptoms, and functional aspects of quality of life were sustained in the 14-week assessment (P < .05), as were physical and functional well-being at the 20-week assessment (P < .05). Conclusions: Acupuncture is an effective intervention for treating chemotherapy-induced peripheral neuropathy and improving patients’ quality of life and experience with neurotoxicity-related symptoms with longer term effects evident. Keywords acupuncture, chemotherapy-induced peripheral neuropathy, cancer, neurotoxicity, quality of life, pain Submitted October 24, 2018; revised February 3, 2019; accepted February 13, 2019 alkaloids, ie, vincristine, or taxanes, ie, paclitaxel) can ensue. Introduction The overall incidence of CIPN is not clear, but it is estimated Chemotherapy-induced peripheral neuropathy (CIPN) is a derangement in structure and function of peripheral motor, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR sensory, and autonomic neurons, causing peripheral neuro- Prince of Wales Hospital, Sha Tin, Hong Kong SAR pathic signs and symptoms. Depending on the chemother- Corresponding Author: apy used, a pure sensory and painful neuropathy (with Alexander Molassiotis, School of Nursing, The Hong Kong Polytechnic platinum analogues, ie, cisplatin, oxaliplatin, and carbopla- University, No. 11 Yuk Choi Road, Hung Hom, Kowloon, Hong Kong tin) or a mixed sensory motor neuropathy with or without SAR. involvement of the autonomic nervous system (with vinca Email: alex.molasiotis@polyu.edu.hk Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Integrative Cancer Therapies to occur in 10% to 20% of patients during treatment and it Participants and Settings may be as high as 100%, depending on the chemotherapy Patients with breast, head and neck, colorectal, multiple drug, dose intensity, cumulative dose, and other as yet 1-4 myeloma, or gynecological cancer receiving taxane-based, unidentified risk factors. The implications of CIPN on the bortezomib, capecitabine, or platinum-based chemotherapy quality of life of cancer patients are significant, including experiencing CIPN during or after the end of chemotherapy dysfunction in daily activities, social well-being, work rein- 5 were recruited. The study took place in 2 large cancer cen- tegration, and physical impairments including pain. There ters in the Hong Kong territory. is a considerable impact on health care resource utilization too, with those experiencing CIPN having more frequent outpatient visits and medication use, estimated to be at Inclusion Criteria US$17 000 more in patients with CIPN than non-CIPN can- 6 •• Patients with diagnosis of breast, gynecological, cer patients. colorectal, or head and neck cancer, and multiple Attempts to manage this complex symptom with any myeloma with life expectancy (as judged by the cli- interventions have been largely unsuccessful with low level 7 nician) longer than 5 months. of evidence, and interventional research for this symptom •• Patients with cancer stages I to IV; Karnofsky is currently minimal. The American Society of Clinical Performance score 80 to 100. Oncology guidelines provide no recommendation for pre- •• Currently receiving or having received neurotoxic venting CIPN, a moderate recommendation for duloxetine chemotherapy (taxanes, cisplatin, oxaliplatin, bort- in the treatment of CIPN, and a few treatment options that ezomib, etc). have inconclusive evidence for CIPN, but which are consid- •• Reporting tingling in hands or feet and other clinical ered on the basis of their effect on other neuropathic pain 7 indications of CIPN after initiation of cancer treat- conditions. In this clinical area of limited treatment options, ments, confirmed to be indicative of CIPN by a med- acupuncture may be considered for treating CIPN, with ical consultant, often through brief neurological small-scale pilot studies (N < 30) or case series providing examination but at times based only on clinical signs. some initial evidence of effect, particularly in decreasing 8-14 •• Not using any medication for the prevention or treat- neuropathic pain. A systematic review identified 3 such ment of CIPN for the past 3 months. trials, which all used a different approach (acupuncture, •• Willing to participate and be randomized to one of auricular acupuncture, and acupuncture with moxibus- 15 the study groups. tion). Although these mostly uncontrolled or underpow- •• No previously established peripheral neuropathy. ered studies are positive and encouraging, they suggest that acupuncture could be an option for these patients and that controlled trials using validated patient-reported outcome Exclusion Criteria measures are justified. Patients with needle phobia; patients with low platelet count (<50 000); comorbidity with a bleeding disorder or coagu- Aims lopathy; pregnancy, or having received acupuncture treat- ment in the past 3 months; patients with lymphedematous The aim of the study is to test the effectiveness (in terms of limbs or who have undergone axillary dissection; and neuropathic pain, other neurological sensations, and overall patients with metastatic bone disease or metastatic involve- quality of life) of an 8-week course of acupuncture in the ment of the neural system. management of CIPN in cancer patients who are receiving or have received neurotoxic chemotherapy. Recruitment Methods Potential subjects were identified (through clinic lists and databases of patients who were undergoing treatment or Design attending follow-up visits), were approached initially by the The design of the study involves a pragmatic randomized relevant clinical team, and then screened by research staff. assessor-blinded controlled trial. Clinicians, researchers, and those assessing the patients and obtaining patient data Randomization were blinded to the allocation (but not the patients nor the acupuncturists). A 2-group design is used with the experi- Patients were allocated to study groups through computer- mental group receiving a course of acupuncture in addition generated randomization carried out by the Prince of Wales to standard care and a wait-list control arm receiving stan- Hospital clinical trials unit in Hong Kong. Randomization dard care only. consisted of minimization with a random element (stochastic Molassiotis et al 3 minimization), balancing for the treatment types (taxanes or Standard Care platinum analogues or bortezomib/thalidomide received). The comparison arm was a standard care control arm that received pain medication, vitamin B /B , or other medica- 12 6 Intervention tion as deemed necessary by the doctor. This group was offered acupuncture for their CIPN at the end of the trial The acupuncture intervention is described below based on after they completed week 20 assessments. Treatment was the STRICTA (Standards for Reporting Interventions in given as per in the intervention group above. Clinical Trials of Acupuncture) recommendations for reporting acupuncture trials. In the acupuncture group, patients received, in addition to standard care, a standard- Study Duration ized 30-minute acupuncture session needling specific Treatment duration was 8 weeks. The duration of each body points; there was flexibility in case some points patient’s involvement in the study was 20 weeks (5 months) could not be punctured (ie, in case of lymphedema), and with assessments at baseline, end of 8-week treatment, 14 alternative points (as in routine practice) were selected by weeks, and 20 weeks (the latter 2 to assess possible longer the therapists using their discretion to maintain an equal term effects). dose of treatment to all patients. The points were stan- dardized according to the clinical manifestations of the Outcome Measures subjects: if upper limbs were involved, we used LI4, LI11, PC7, TE5, and/or Baxie points (Ex-UE9; since the Primary outcome at 8 weeks (end of acupuncture treat- effect of Ex-UE9, PC7, and TE5 are similar, only 1 out of ment): pain: “worst pain during past week” was measured the 3 was chosen); if lower limbs were affected (most using the Brief Pain Inventory (BPI). The BPI measures common), we used SP6, ST36, LV3, ST41, and/or Bafeng pain intensity (worst pain; pain in last 24 hours; average (Ex-LE10; since the effect of LV3, Ex-LE10, and ST41 pain; and pain right now) on a 10-point scale (from 0-10) are similar, only 1 out of the 3 was chosen) reflecting a and its interference with 7 functions (ie, sleep or walking traditional Chinese medicine diagnosis of “blood and qi ability) also on a 10-point scale. Higher scores indicate stagnation and accumulation of dampness.” If the pain worse pain intensity and/or interference. threshold of the patients was low, TE5 for upper limbs and/or ST41 for lower limbs were chosen. An equal Secondary Outcomes “dose” of points was used for all patients (4 points bilater- •• Functional Assessment of Cancer Therapy/Gynecologic ally). Stimulation of the acupoints to achieve de qi sensa- Oncology Group–Neurotoxicity (FACT/GOG-Ntx) is tion was done manually through rotation of the needle a 38-item self-reported questionnaire: the 27-item backward and forward for a few seconds, done twice dur- general assessment of Quality of Life scale (FACT-G) ing each treatment session (just after inserting the needle alongside its 11-item neurotoxicity-specific module. and before removing the needle). This approach to treat- Higher scores indicate better quality of life outcomes. ment mimics current acupuncture practices and is based •• The presence of other related symptoms (ie, fatigue, 12,13,16 on the literature ; we have discussed this with expe- sleep, etc) was assessed using the 10-item Symptom 13 19 rienced acupuncturists and used earlier data and experi- Distress scale. Higher scores indicate more distress ence from the acupuncturists in the trial team. Acupuncture with symptoms. sessions were carried out twice weekly for 8 weeks (= a total of 16 sessions). Points were punctured to a depth of Completion of the self-report questionnaires was done at 0.5 to 1.2 cm depending on the patients’ size, sensitivity, home and these were posted back to the researchers using and state of health. The needles were Hwato sterile nee- prepaid envelopes. dles for single use, size 0.25 × 40 mm. Each session was Neurotoxicity examination: baseline and at the end of based on a strict protocol followed by all therapists. acupuncture course. Immediately after each session, the therapist completed A nurse not involved in the study and without knowing an intervention monitoring form verifying the exact treat- the patient allocation performed the neurological assess- ment given and any other issues that needed to be reported ment. This was the same person for all patients, and training (ie, any side effects). Forms were checked regularly by was provided for neurological assessments. the investigators for consistency across therapists. No other complementary therapy use was recommended dur- •• The 7-domain Total Neuropathy Score–Clinical ing the course of acupuncture. Therapists were Chinese Version (TNSc). The TNSc provides a composite medicine practitioners, registered with their professional score based on clinical neurological examination body in Hong Kong and had a minimum of 2 years’ expe- obtained from grading of symptoms (including auto- rience in working with patients. nomic ones), signs, and quantitative sensory tests 4 Integrative Cancer Therapies (tendon reflexes; strength; vibration sensibility, pin Sample Size sensibility; and 10-g monofilament), and provides a 20 Based on a randomized control trial on auricular acupunc- single measure to quantify neuropathy. ture for cancer chronic peripheral or central neuropathic •• The National Cancer Institute–Common Toxicity pain, a 30-day trial could reduce the pain intensity of the Criteria for Adverse Events (CTCAE) v.4.0, is a cancer patients from a Visual Analogue score (0-100) of physician-rated grading system that includes crite- 58 to 44 (standard deviation = 19). This effect corresponds ria and definitions for quantifying and grading to a Cohen’s d of 0.74, and 39 patients per arm were CIPN (both neurosensory and neuromotor compo- required to achieve significance level of .05 and power of nents) utilizing a 5-point scale ranging from grade 0.90. It is prudent to inflate this figure further as follows: 1 to grade 5. (1) the score distributions are likely to be fairly skewed •• Neurophysiological testing included a detailed and a Wilcoxon rank sum test may be more appropriate motor nerve conduction study (NCS) in a subsam- than a t test; (2) some dropout is likely, and though appro- ple of the patients of the following nerves on the priate to use a last value carried forward (LVCF) approach, affected limbs: for upper limbs, the test included a completers analysis is also likely to be performed. Taking median nerve (bilateral) and ulnar nerve (bilateral). these 2 factors into account indicates aiming for a sample For lower limbs, the test included peroneal nerve size of 44 in each arm. (bilateral) and tibial nerve (bilateral). There was provision of the most sensitive parameters to regis- Data Analysis ter any axonopathy or demyelination. Distal laten- cies, amplitudes, and conduction velocities were Analyses included descriptive statistics to summarize the measured as well as F-waves. For the sensory nerve data, analysis of variance to assess between-groups differ- conduction part of the neurophysiological assess- ences for primary and each of the secondary outcomes, and ment (NCS), the following nerves were studied: for generalized linear model (analysis of covariance upper limbs, the test included median nerve (bilat- [ANCOVA]) using the baseline pain score as covariate. eral) and ulnar nerve (bilateral). For lower limbs, it Ninety-five percent confidence intervals were also calcu- included sural nerve (bilateral). Neurophysiological lated. In more detail, while a t test is adequate for analysis, testing was offered to each patient before and after ANCOVA was used with the baseline score for each depen- treatment but only a subgroup of patients could dent variable as a covariate, and center and trial arm as attend one or all of the sessions owing to the con- grouping factors. Dropout cases and nonrespondents were current need of chemotherapy, acupuncture treat- asked to complete the primary outcome scale (1 item) and ment, discomfort from the assessment, and travel the 2 items of the CTCAE scale on CIPN in order to capture logistic issues. outcomes in as many patients as possible, and if this was not •• Sociodemographic and treatment characteristics feasible, we used data imputation (LVCF). An intention-to- were obtained from the patients’ records or patients treat analysis was carried out. Sensitivity analysis in the pri- themselves. Patients were asked at baseline about mary outcome variables (where there were missing values) treatment expectations, how much they believed repeating the ANCOVA after using LVCF was also carried this method will help them alleviate their neuropa- out as well as with GEE (generalized estimating equation) thy/pain, and how much faith they have in acu- for all variables. puncture (10-point Visual Analogue Score scales), alongside information if they have used any com- Results plementary therapies in the past and how much faith they have on complementary therapies. Sample Characteristics Chemotherapy dosage documentation (cumulative dosage received, completed number of cycles, and Eighty-seven Chinese patients with CIPN were recruited, chemotherapy type) were also collected. Adverse 43 randomized to the control arm and 44 to the acupunc- effects were monitored at each clinic visit for the ture arm. Their mean age was 57.1 years (SD = 7.7 years). duration of the acupuncture treatment (although The majority (72.4%) were females, had breast (42.5%) or none reported). colorectal (34.5%) cancer, were off treatment (90%), and an average of 15.3 months experiencing CIPN (range = Ethical approval from the Human Research Ethics 1-81 months). Detailed characteristics are shown in Table Review Committee of the Hong Kong Polytechnic 1. There were no differences in sample characteristics University (HSEARS20141011004) and the study hospi- between the 2 groups at inclusion. The CONSORT tals (CREC Ref. 2014.529-T) was obtained. All patients (Consolidated Standards of Reporting Trials) diagram of signed a consent form. the patients’ participation to the trial is shown in Figure 1. Molassiotis et al 5 Table 1. Sample Characteristics. Control Arm Intervention Arm Overall Variable (N = 43), n (%) (N = 44), n (%) (N = 87), n (%) Sex (P = .13) Male 15 (34.9%) 9 (20.5%) 24 (27.6%) Female 28 (65.1%) 35 (79.5%) 63 (72.4%) Marital status (P = .997) Never married 7 (16.3%) 8 (18.2%) 15 (17.2%) Married 31 (72.1%) 31 (70.5%) 62 (71.3%) Widower/widow 1 (2.3%) 1 (2.3%) 2 (2.3%) Divorced 4 (9.3%) 4 (9.1%) 8 (9.2%) Education level (P = .30) Nil 2 (4.7%) 0 (0.0%) 2 (2.3%) Primary 13 (30.2%) 9 (20.5%) 22 (25.3%) Secondary 23 (53.5%) 30 (68.2%) 53 (60.9%) Post-secondary 5 (11.6%) 5 (11.4%) 10 (11.5%) Economic status (P = .79) Full-time worker 21 (48.8%) 22 (50.0%) 43 (49.4%) Taking care of family 11 (25.6%) 11 (25.0%) 22 (25.3%) Retired 11 (25.6%) 10 (22.7%) 21 (24.1%) Others 0 (0.0%) 1 (2.3%) 1 (1.1%) Major income source (P = .12) Government 4 (9.3%) 1 (2.3%) 5 (5.7%) Family 23 (53.5%) 19 (43.2%) 42 (48.3%) Personal income 16 (37.2%) 21 (47.7%) 37 (42.5%) Savings 0 (0.0%) 3 (6.8%) 3 (3.4%) Personal monthly income (HK$, 1 US$ = 7.8 HK$) <$10 000 27 (62.7%) 29 (65.9%) 56 (62.5%) $10 000-$19 999 10 (23.3%) 10 (22.7%) 20 (22.9%) $20 000 or above 6 (14.0%) 5 (11.4%) 11 (12.6%) Diabetes (P = .97) Yes 4 (9.3%) 4 (9.1%) 8 (9.2%) Cancer stage (P = .30) I 10 (23.3%) 4 (9.1%) 14 (16.1%) II 10 (23.3%) 15 (34.1%) 25 (28.7%) III 20 (46.5%) 22 (50.0%) 42 (48.3%) IV 3 (7.0%) 3 (6.8%) 6 (6.9%) Type of cancer (P = .74) Ovarian 8 (18.6%) 4 (9.1%) 12 (13.8%) Head and neck 3 (7.0%) 3 (6.8%) 6 (6.9%) Breast 16 (37.2%) 21 (47.7%) 37 (42.5%) Colorectal 15 (34.9%) 15 (34.1%) 30 (34.5%) Myeloma 1 (2.3%) 1 (2.3%) 2 (2.3%) Currently receiving chemotherapy 4 (9.2%) 5 (11.4%) 9 (10.3%) Post chemotherapy 40 (90.8%) 38 (88.6%) 78 (89.7%) N; Mean (SD) N, Mean (SD) N, Mean (SD) Chemotherapy received and cumulative dose Oxaliplatin-based regimens (mg/m ) (P = .42) N = 14; 945.1 (78.3) N = 15; 900.1 (192.7) N = 29; 921.8 (148.1) Carboplatin and total area under the curve (P = .34) N = 8; 29.4 (3.2) N = 5; 25.0 (12.4) N = 13; 27.7 (7.8) Cisplatin-based regimens (mg/m ) (P = .29) N = 4; 639.0 (198.0) N = 3; 500.0 (40.0) N = 7; 579.4 (160.2) ) (P = .15) N = 12; 878.1 (279.3) N = 17; 760.1 (151.9) N = 29; 809.0 (217.5) Paclitaxel-based regimen (mg/m Docetaxel-based regimens (mg/m ) (P = .51) N = 12; 350.0 (52.2) N = 8; 367.8 (65.5) N = 20; 357.1 (56.9) Capecitabine (mg/m ) (P = .97) N = 15; 122826.7 (34820.2) N = 14; 123372.0 (42613.4) N = 29; 123089.9 (38071.0) Bortezomib (mg/m ) N = 1; 10.4 N = 1; 36.0 N = 2; 23.2 (18.1) Number of chemotherapy cycles received (P = .81) 6.0 (1.9) 6.1 (3.3) 6.0 (2.7) Number of chemotherapy cycles received (oral chemotherapy) (P = .77) N = 15; 8.1 (1.7) N = 14; 7.9 (0.3) N = 29; 8.0 (1.2) Days since the last chemotherapy cycle (P = .54), mean (SD) 459 (399) 401 (176) 430 (438) Used complementary therapies in the past (P = .32); yes, N (%) 27 (62.8%) 23 (52.3%) 50 (57.5%) Belief that acupuncture will help you manage your problem (10-point 6.9 (1.8) 6.6 (2.1) 6.7 (2.0) scale) (P = .56), mean (SD) How much faith do you have in complementary therapies in general? 6.7 (2.2) 6.4 (2.3) 6.6 (2.3) (10-point scale) (P = .43), mean (SD) 6 Integrative Cancer Therapies Figure 1. CONSORT diagram of the trial flow. The vast majority had moderate/severe CIPN (56/87 medication for CIPN at week 8 was minimal and included 6 patients with signs of sensory neuropathy and 63/87 participants in the control arm and 3 participants in the patients with signs of motor neuropathy as per CTCAE experimental group, 1 massaging hands, 1 using Panadol, scale at entry to trial). and traditional Chinese medicine. The TNSc (combination of sensory tests/neurological assessment, signs and symptoms) was significantly Outcomes improved at the end of the intervention in the acupuncture Detailed outcome analysis is shown in Table 2. The primary arm (P < .05). Also, significant improvements were seen in outcome (pain intensity and pain interference) was signifi- the sensory CTCAE item (P < .05) but not the motor item, cantly better at the end of the intervention in the acupunc- although the latter had a 17% difference in prevalence at ture arm than the control arm (P < .05 and P < .01, week 8 between the 2 groups (or 22% difference from respectively). Pain intensity remained lower in the acu- baseline), with the lower prevalence being in the acupunc- puncture arm at the 14-week assessment (P < .05; see Figure ture group. 2). Statistically significant differences were still present in Quality of life was also significantly better in the acu- pain interference (P < .01) at 14 weeks. At week 20, the BPI puncture arm at the end of the intervention, particularly in score had a 0.7-point difference from the control group, but terms of physical well-being (P < .01), functional well- this did not reach statistical significance as less than half of being (P < .05), neurotoxicity subscale score (P < .01), the the patients actually reported pain. Use of concomitant FACT/GOG-Ntx Trial Outcome Index (TOI; P < .001), the Molassiotis et al 7 Table 2. Trial Outcomes Between Control and Intervention Groups Over Time . b b b Baseline 8 Weeks P 14 Weeks P 20 Weeks P Brief Pain Inventory Pain intensity Control group 1.3 (0.4) 1.7 (0.4) .31 2.2 (0.4) .06 2.3 (0.4) .03 (worst pain; P for group by time Intervention group 2.1 (0.5) 1.0 (0.3) .008 1.5 (0.4) .13 1.8 (0.3) .49 interaction .03) Effect size 0.26 0.26 0.17 P value .20 .14 .18 .35 Pain intensity (mild pain or more severe; Control group N = 10 (23%) N = 16 (37%) .07 N = 21 (51%) .001 N = 22 (55%) <.001 P for group by time interaction .01) Intervention group N = 15 (34%) N = 8 (18%) .03 N = 13 (32%) .76 N = 20 (46%) .13 P value .26 .04 .07 .44 Pain interference Control group 0.9 (0.3) 1.3 (0.3) .33 1.7 (0.3) .04 2.0 (0.4) .007 (P for group by time interaction .04) Intervention group 1.5 (0.3) 0.5 (0.2) .001 1.5 (0.4) .94 1.6 (0.3) .75 Effect size 0.36 0.11 0.19 P value .25 .04 .66 .42 Pain interference (mild pain or more severe) Control group N = 9 (21%) N = 16 (37%) .04 N = 24 (48%) .001 N = 22 (55%) <.001 (P for group by time interaction .02) Intervention group N = 5 (34%) N = 8 (18%) .03 N = 20 (32%) .76 N = 19 (44%) .21 P value .16 .04 .12 .32 FACT Physical well-being Control group 21.6 (0.8) 20.9 (0.8) .37 20.1 (0.9) .047 19.1 (0.9) .007 (P for group by time interaction .006) Intervention group 20.5 (0.8) 23.5 (0.5) <.001 21.7 (0.8) .22 21.6 (0.7) .21 Effect size 0.46 0.28 0.46 P value .38 .01 .19 .02 Social/family well-being Control group 20.7 (1.0) 20.3 (0.9) .63 18.5 (0.9) .05 18.4 (1.2) .03 (P for group by time interaction .53) Intervention group 20.0 (0.7) 20.5 (0.7) .49 19.7 (0.9) .69 19.3 (0.8) .40 Effect size 0.03 0.21 0.16 P value .55 .87 .35 .51 Emotional well-being Control group 13.3 (0.6) 13.2 (0.7) .86 13.0 (0.6) .61 13.1 (0.7) .77 (P for group by time interaction .86) Intervention group 14.0 (0.6) 13.9 (0.5) .90 13.8 (0.6) .76 13.3 (0.7) .25 Effect size 0.18 0.20 0.04 P value .41 .41 .39 .87 Functional well-being Control group 17.3 (0.9) 16.3 (0.8) .26 16.8 (0.9) .51 16.0 (1.0) .23 (P for group by time interaction .12) Intervention group 17.0 (0.6) 18.8 (0.7) .03 17.6 (0.7) .48 17.9 (0.9) .36 Effect size 0.51 0.16 0.38 P value .78 .02 .50 .16 Neurotoxicity subscale Control group 26.5 (1.2) 28.2 (1.1) .06 27.4 (1.0) .30 28.0 (1.1) .18 (P for group by time interaction .04) Intervention group 27.4 (0.9) 32.2 (1.1) <.001 30.6 (1.2) <.001 30.3 (1.3) .003 Effect size 0.56 0.45 0.32 P value .56 .01 .04 .18 FACT/GOG-Ntx Trial Outcome Index Control group 65.3 (2.4) 65.4 (2.2) .98 64.4 (2.0) .60 63.1 (2.4) .34 (P for group by time interaction 0.001) Intervention group 64.9 (1.8) 74.5 (1.8) <.001 69.9 (2.3) .006 69.8 (2.4) .01 Effect size 0.65 0.39 0.48 P value .88 .001 .07 .047 FACT-G total score Control group 72.9 (2.4) 70.7 (2.5) .27 68.4 (2.4) .03 66.8 (2.2) .02 (P for group by time interaction .049) Intervention group 71.5 (1.8) 76.7 (1.7) .004 73.4 (1.9) .54 72.4 (2.1) .79 Effect size 0.42 0.31 0.38 P value .64 .045 .19 .12 FACT/GOGNtx_total Control group 99.4 (3.1) 98.9 (3.1) .85 96.0 (2.9) .18 94.7 (3.3) .15 (P for group by time interaction .01) Intervention group 98.9 (2.3) 108.9 (2.2) <.001 103.3 (3.0) .06 102.4 (3.1) .16 Effect size 0.55 0.41 0.42 P value .90 .009 .08 .09 Symptom Distress Scale total score Control group 17.6 (0.9) 17.6 (0.9) .995 18.4 (0.9) .28 19.4 (0.9) .06 (P for group by time interaction .15) Intervention group 16.6 (0.7) 14.6 (0.6) .001 17.1 (0.9) .49 18.5 (0.9) .004 Effect size 0.54 0.24 0.16 P value .42 .009 .29 .49 Total Neuropathy Score Control group 7.6 (0.5) 7.6 (0.6) .92 — — (P for group by time interaction .01) Intervention group 8.1 (0.5) 6.2 (0.5) <.001 Effect size 0.42 P value .43 .10 NCI-CTCAE-sensory (moderate/severe) Control group N = 27 (63%) N = 26 (62%) .91 — — (P for group by time interaction 0.046) Intervention group N = 29 (66%) N = 16 (37%) .001 P value .76 .02 NCI-CTCAE motor (moderate/severe) Control group N = 30 (70%) N = 28 (67%) .62 — — (P for group by time interaction .07) Intervention group N = 33 (75%) N = 21 (50%) .003 P value .59 .11 Abbreviations: FACT/GOG-Ntx, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity; NCI-CTCAE, National Cancer Institute–Common Toxicity Criteria for Adverse Events. Marginal mean (standard error) estimated with ANCOVA and GEE. Comparison with baseline. Control versus intervention group comparison. 8 Integrative Cancer Therapies Figure 2. Worst pain intensity score changes over time. Figure 3. FACT-G Neurotoxicity scale (total score) changes over time. FACT-G total score (P < .01), and the total score for the some significant effects in the ANCOVA model became FACT/GOG-Ntx scale (P < .01; see Figure 3). The neuro- insignificant in the GEE model. toxicity subscale score, the FACT/GOG-Ntx TOI score, and The NCS showed values largely within the normal FACT/GOG-Ntx total score remained significantly better in ranges or borderline ones for all parameters at baseline the acupuncture arm at the 14-week assessment, and at 20 (Table 3). At 8 weeks, there was no significant difference weeks, physical well-being and FACT/GOG-Ntx TOI score from baseline. continued to remain better in the acupuncture arm (Table 2 We examined if there was a correlation between out- and Figure 4). Overall symptom distress was also lower in comes and expectations, faith in the treatment, and faith in the acupuncture arm at the end of the intervention (P < .01). complementary therapies. There were no significant correla- Sensitivity analysis showed that the results were sus- tions in any of the outcome variables and these beliefs, tained when LVCF was used. The effect size estimation except in the case of symptom distress score at 14 weeks, from ANCOVA and GEE were also similar, although the which was correlated with faith in complementary therapies GEE had larger standard error (due to its complexity) hence (r = 0.31, P < .05) and also had an inverse correlation with Molassiotis et al 9 Table 3. Median Values of Nerve Conduction Studies for Combined Right and Left Foot at Week 8 Between Control and Experimental Groups. Control Intervention Variable (n = 8) (n = 9) P Sum of both foots in peroneal, motor (extensor digitorum brevis)—distal latency (ms) 6.6 7.1 .83 Sum of both foots in peroneal, motor (extensor digitorum brevis)—amplitude (µV)—first recording 13.8 16.1 .68 Sum of both foots in peroneal, motor (extensor digitorum brevis)—amplitude (µV)—second recording 12.6 14.7 .63 Sum of both foots in peroneal, motor (extensor digitorum brevis)—velocity (m/s) 90.5 93.0 .75 Sum of both foots in tibial, motor (abductor hallucis brevis)—distal latency (ms) 8.6 9.2 .82 Sum of both foots in tibial, motor (abductor hallucis brevis)—amplitude (µV)—first recording 27.2 33.3 .30 Sum of both foots in tibial, motor (abductor hallucis brevis)—amplitude (µV)—second recording 20.2 26.2 .06 Sum of both foots in tibial, motor (abductor hallucis brevis)—velocity (m/s) 89.5 93.0 .33 Sum of both foots in sural, sensory (behind malleolus)—distal latency(ms) 4.2 4.4 .25 Sum of both foots in sural, sensory (behind malleolus)—amplitude (µV) 14.0 13.0 .71 Sum of both foots in sural, sensory (behind malleolus)—velocity (m/s) 100.0 87.0 .27 Adjusted for baseline scores. P = .04 when only the values for the right foot were assessed. Figure 4. FACT/COG-Ntx Trial Outcome Index changes over time. expectations (r = −0.32, P < .05). Furthermore, no adverse exciting as there are limited treatment options available for effects were reported after checking the therapists’ records. managing CIPN. Clinical assessment that combines touch perceptions and deep nerve impairment at week 8 (primary outcome assess- Discussion ment) by blinded assessors clearly shows significant This is the first fully powered trial using acupuncture to improvements. This is further supported by the clinician- treat CIPN, showing, both through patient-reported out- rated CTCAE where significant sensory changes were also comes and clinical neurological assessment, that it signifi- detected. For the CTCAE motor item, statistically signifi- cantly improved CIPN in the acupuncture group compared cant differences were not shown, although the numeric dif- with the standard care wait-list control group. The current ference in favor of the acupuncture group was 22%; when findings alongside available small-scale pilot/feasibility tri- we assessed individual limb score changes, the left hand 8-14 als or uncontrolled trials and case series confirm the ben- motor impairment was also improved in the acupuncture eficial effect of acupuncture in treating CIPN. This is group (P < .05). This may also indicate that acupuncture 10 Integrative Cancer Therapies may be more effective in dealing with sensory impairment is expensive as well as uncomfortable and time-consum- than motor. ing for the patients, hence we allowed this part of the Pain intensity and pain interference with daily life were study to be on a voluntary basis. significantly better in the acupuncture arm, despite the There is debate in the literature if the results of acu- small number of patients who experienced (mostly mild) puncture are due to placebo effects and the need for a pain in the overall sample, suggesting a strong effect. The sham group in acupuncture trials. The current study change in intensity in the acupuncture group was 38% from answers an effectiveness research question using a prag- baseline, whereas in the control group, pain intensity matic trial design. The decision not to use a sham-control slightly increased. The impact of the improvement was methods in this study was not taken lightly and considered notable, as most patient-reported outcomes in the study, a number of aspects, including the difficulty in masking including overall quality of life, neurotoxicity-related acupuncture in very “acupuncture-experienced” people symptoms (ie. tingling/numbness in the hands/feet), physi- like the Chinese and the ethics of using shams and having cal well-being, and functional well-being, were enhanced to attend for treatment for 8 weeks while still continuing to in the acupuncture group. The change in pain interference experience discomfort. Also, a crucial question is whether (1 point in the acupuncture group) is also consistent with various sham methods can elicit a therapeutic effect and minimal clinically important differences (MCIDs) reported criticisms of shams in acupuncture trials have been previ- 26 27,28 in past studies of 0.5 to 1 point in a group of patients with ously discussed by ourselves and other researchers. bone metastasis showing improvement (although MCIDs In the revised CONSORT standards for reporting acu- for those deteriorating were 1.4-2.3 points). However, puncture trials, it is also highlighted that sham needling another study on bone metastasis patients showed that techniques may evoke neurophysiological and other MCID for pain interference is 2 to 3.5 points in those with responses, an area for which we have lack of knowledge, complete/partial response or 0.5 to 2.2 points in those with leading to compromises in the interpretation of results. indeterminate response, and in our study the change was 1 Until this debate is resolved, we should not deny patients point only. Quality of life indicators, such as neurotoxic- from the opportunity of symptom improvement using acu- ity subscales, neurotoxicity TOI, physical well-being, and puncture, if they prefer or have access to use it. In the cur- functional well-being, also showed highly statistically sig- rent trial, we decreased placebo effects by minimizing nificant improvements in the acupuncture group. Published interactions and communication between the therapist and MCIDs for the FACT physical well-being and functional the patients, using a wait-list control arm, assessing the well-being are around 2 to 3 points of change, and our role of patient expectations from treatment and using both data showed change of 3 and 1.8, respectively, at the end of objective and subjective outcome measures. intervention, although there are no established MCID val- Study limitations may include the small sample size ues for neurotoxicity subscale scores. It is interesting to see (although this was a fully powered trial), the use of CTCAE that symptom distress from multiple symptoms also as one of the objective measures that has been criticized as improved, suggesting that acupuncture for CIPN can a scale that can misdiagnose CIPN, the lack of sham- or impact on a wider range of symptoms, perhaps as a result attention-control methods, and use of multiple secondary of some acupoints used not being specific only to CIPN. outcomes at multiple time-points. Also, it is not clear if the Improvements were sustained for longer term albeit not in duration of effect can extend beyond 20 weeks, as we have all outcomes assessed, but primarily in physical and func- not used “booster sessions,” a common practice in acupunc- tional well-being and neurotoxicity-related symptoms. It ture treatments. However, our previous research in relation may be prudent to provide patients with additional less fre- to cancer-related fatigue showed that such booster sessions quent “boosting” sessions to maintain the initial effect, a may not enhance or extend the acupuncture effect. Pain, common practice among therapists, although this may need as an outcome for CIPN trials, may also not be the most testing in the future. appropriate primary endpoint as highlighted in the litera- The NCS was not a useful test in this study, as most ture, as the CIPN experience is wider than pain and patients had no evidence of neurophysiological impair- involves many other sensations that are more commonly ment, with values in the nerves assessed being often present in CIPN. Indeed, in our trial pain was not the most within normal ranges. Perhaps CIPN affects more small frequently reported experience, with less than half the nerve fibers (ie, A-delta fibers or C fibers), whereas NCS patients experiencing mild-to-moderate pain. Also, the neu- is able to measure primarily large nerve fibers with rou- rotoxicity-related (secondary) outcomes were the ones to tine electrodiagnostic tests being mostly normal in show consistently and more long-term improvements after patients with small fiber neuropathies. The role of NCS the intervention. and other neurophysiological tests in the diagnosis of Acupuncture can be a treatment option for patients expe- CIPN needs further investigation. The small number of riencing CIPN, although access to such a service and costs patients undergoing NCS is a limitation; however, the test for private treatments may affect the uptake of acupuncture Molassiotis et al 11 from patients. Specific attention should be paid to the adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32:1941-1967. “dose” and duration of treatment and the specific acupoints 8. Bao T, Goloubeva O, Pelser C, et al. A pilot study of acu- used. Further trials in a wide range of participants should be puncture in treating bortezomib-induced peripheral neuropa- carried out to confirm the results of the present study. thy in patients with multiple myeloma. Integr Cancer Ther. 2014;13:396-404. Acknowledgments 9. Garcia MK, Cohen L, Guo Y, et al. Electroacupuncture for We thank Dr Radha Raghupathy, Dr Annette Poon, and Dr Ashley thalidomide/bortezomib-induced peripheral neuropathy in CY Wong from Clinical Oncology, Prince of Wales Hospital, multiple myeloma: a feasibility study. J Hematol Oncol. Hong Kong; Dr Yu Chung Li, Dr Anthony Kwun To Leung, and 2014;7:41. doi:10.1186/1756-8722-7-41 Dr Kam Hung Wong from Clinical Oncology, Queen Elisabeth 10. Wong R, Major P, Sagar S. Phase 2 study of acupuncture-like Hospital, Hong Kong; and Dr Janice Ho, Dr Jerry Yeung, Ms transcutaneous nerve stimulation for chemotherapy-induced Echo Lau, and Mr Hon-fat Wong, Integrative Health Clinic, peripheral neuropathy. Integr Cancer Ther. 2016;15: School of Nursing, The Hong Kong Polytechnic University, for 153-164. their contributions to the study. 11. Greenlee H, Crew KD, Capodice J, et al. Randomized sham-controlled pilot trial of weekly electro-acupuncture Declaration of Conflicting Interests for the prevention of taxane-induced peripheral neuropathy in women with early stage breast cancer. Breast Cancer Res The author(s) declared no potential conflicts of interest with respect Treat. 2016;156:453-464. to the research, authorship, and/or publication of this article. 12. Schroeder S, Meyer-Hamme G, Epplée S. Acupuncture for chemotherapy-induced peripheral neuropathy (CIPN): a pilot Funding study using neurography. Acupunct Med. 2012;30:4-7. 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Integrative Cancer TherapiesPubmed Central

Published: Mar 25, 2019

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