Efficacy and safety of auricular acupressure for chemotherapy-induced peripheral neuropathy among patients with breast cancer: a study protocol for a randomized controlled trial

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is generally defined as damage to the peripheral nerves caused by toxicity of chemotherapeutic agents such as platinum-based antineoplastic agents, vinca alkaloids, epothilones, taxanes, proteasome inhibitors and immunomodulatory drugs (1,2). CIPN is characterized mainly by changes in sensory function that may be accompanied by deficits in motor and autonomic function such as numbness, tingling sensation, altered sensation, allodynia, weakness, and dysesthesias (3). These neuropathic symptoms can affect functional abilities in daily living and lead to difficulties in continuing chemotherapy which may be associated with a negative effect on overall survival (4,5). According to the National Comprehensive Cancer Network Task Force Report, taxanes as part of first-line therapy for early-stage and metastatic breast cancer were associated with a high incidence of CIPN in 57–83% of patients treated with paclitaxel and 11–64% of individuals receiving docetaxel (6). Although its prevalence has decreased over time, at least 28% of patients continue to experience neuropathic symptoms at 6 months or more after completing chemotherapy (3,7,8).

The lack of ideal neuroprotective or therapeutic agents for CIPN is emphasized as a key unmet need among cancer patients and healthcare professionals (9). For example, duloxetine is the only symptomatic treatment for CIPN recommended by the American Society of Clinical Oncology based on sufficient evidence; however, its therapeutic effect is modest (10). Various non-pharmacological management modalities have been developed as better alternatives in complementary and integrative medicine (11). A recently published systematic review and meta-analysis showed that acupuncture, therapeutic massage, foot bath, and exercise have been used most frequently to reduce neuropathic symptoms and improve the health-related quality of life (12). Among these interventions, acupuncture therapy is a well-accepted therapeutic modality used to relieve cancer- and treatment-related symptoms as well as other peripheral neuropathic symptoms, possibly due to the lack of known serious side effects, effective combinations with other treatments, and alterative way to help patients who cannot receive pharmacological treatments (13,14). However, the needle insertion method of acupuncture is also known to be a barrier that cannot completely be free from safety-related issues such as infectious adverse events following acupuncture (15).

Auricular acupressure (AA), which was derived from auricular acupuncture used in traditional Chinese medicine, is a noninvasive method of applying physical pressure to acupuncture points. It has been used as a low-risk complementary treatment to relieve symptoms for which needle insertion acupuncture has already proven to yield clinical benefits (16). Previous studies support the clinical applicability of AA in the effective management of medical conditions such as menstrual migraines (17), chronic low back pain (18), acute postoperative pain (19), insomnia and daytime dysfunction (20-23), and overweight (24). A recently published interventional study that assessed changes in CIPN symptoms among 13 cancer patients showed that AA yielded beneficial effects in CIPN management (with a 38–48% reduction in symptom intensity compared to pre-treatment) and maintained a similar degree of long-term effects until after 1 month (25).

The potential mechanism of AA is based on Paul Nogier’s findings of an inverted fetus on the auricle representing a somatotopic map of the human body onto the ear, reported in 1956. According to his concept, each specific point of the entire auricular surface corresponds to specific organs and regions of the body (26). Although two studies have examined changes in brain activity corresponding to auricular acupuncture points by using neuroimaging techniques such as functional magnetic resonance imaging, there is scientific evidence to supports a somatotopic connection between auricular points and body structures (27,28). A recently published functional magnetic resonance imaging study also revealed that auricular point pressure can directly stimulate auricular areas innervated by both the trigeminal and vagus nerves and, consequently, could lead to alterations in brain connectivity and functional modification of the central pain processing pathway of the brain (29). From this point of view, AA can have beneficial effects on CIPN symptom management through stimulating both the auriculo-vagal afferent pathway, hence reducing pain perception in the brain, and the efferent vagus nerve by stimulating the cholinergic anti-inflammatory pathway, thereby controlling the extent of the inflammatory response (1,30-32). Taken together, it has been suggested that AA may be a useful, non-pharmacological, and noninvasive approach that yields beneficial effects regarding symptom management in individuals with CIPN.

To the best of our knowledge, only three consecutive studies, conducted by the same research group, have evaluated the effects of AA on CIPN management using a one-group pretest-posttest design (25,29,33). More evidence obtained from randomized controlled trials (RCTs) is needed to translate these findings into clinical practice. The present study aims to assess the feasibility of AA in the management of CIPN and to evaluate changes in CIPN symptoms and patients’ livelihoods while undergoing taxanes-based treatment for non-metastatic cancer of the breast. We present the protocol in accordance with the SPIRIT reporting checklist (available at http://dx.doi.org/10.21037/apm-20-1469).

Methods

Study design and setting

The present study is a randomized, double-blind, sham-controlled trial. The experiment will be conducted at a single large-volume territory hospital, the largest hospital in the central region of South Korea. Trained researchers will screen female patients who are newly diagnosed with taxane-induced peripheral neuropathy after receiving chemotherapy for breast cancer. Eligible participants will be stratified by the current status of administration of pharmacological agents (gabapentinoids and duloxetine) in the treatment of CIPN and randomly allocated in a 1:1 ratio to the experimental AA group or the sham AA group. All participants will undergo AA for three weeks and follow-up at 4 weeks (Figure 1). The protocol of the present study has been reviewed and approved by the Institutional Review Board of Human Research of the Chungnam National University (approval No. 201906-SB-088-01). Informed consent developed in accordance with the Declaration of Helsinki will be obtained from all individual participants before starting any data collection in this study. The protocol fulfills the populated Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist (Figure 2) and the checklist for items in Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) (additional Table S1). This study has been registered at the Clinical Research Information Service (cris.nih.go.kr; KCT0004930).

Figure 1 Flowchart of the patient selection process.

Figure 2 Locations of specific acupressure points. A, shenmen; B, liver; C, spleen; D, finger; E, toe; F, tooth; G, tongue; H, jaw; I, internal ear.

Study participants

A total of 120 patients will be recruited at the Cancer Center of the Chungnam National University Hospital. All patients who underwent chemotherapy within a year for breast cancer will be selected as potentially eligible subjects through screening by the researcher. After screening, we will invite patients for enrollment according to the inclusion and exclusion criteria listed in Table 1.

Table 1 Patients’ eligibility criteria
Full table

Sample size estimation

The sample size was calculated based on the primary outcome. According to a single study that evaluated AA as intervention for CIPN, an overall change of 3.0 points in mean scores between pre- and post-intervention assessment was observed, with a significant decrease in the worst pain score, which was referred to in the study (25). However, the aforementioned study was conducted by using a one-group pretest-posttest design and no other studies could yield data to compute standardized variations connecting two means obtained from two groups. Accordingly, the sample size was calculated considering the highest number of participants required in pilot studies and the general formulas for superiority design in RCTs (34). To identify changes in scores between pre- and post-intervention periods in the present study, the null and the alternative hypotheses are H0: d_P-d_B =0 and Ha: d_P-d_B >0, respectively (d_B: baseline-score, d_P: post-score, and δ: clinical admissible margin of superiority). Based on the study hypotheses, 24 patients per group would be needed to attain a power of 80% for detecting a variation between groups with a two-sided level of significance less than 0.05 (see below). Considering a possible dropout rate of 0.2, a total of 120 patients (30 patients in each group) are needed.

$$n=2\times {\left[\frac{Z_1\frac{\alpha }{2}+Z_1-\beta }{\delta }\right]}^2\times s^2$$[1]

$$n=2\times {\left[\frac{1.96+0.845}{3}\right]}^2\times {3.64}^2$$[2]

n=23.17

Randomization and blinding

A randomization code list was generated by Sealed Envelope Ltd. and assessed on June 7, 2019, by a person who is not involved in the present study. Participants will be stratified based on the current status of administration of pharmacological agents to prevent confounding effects which can influence the outcome variables. They will then be assigned randomly to two arms in allocation sequence in a 1:1 ratio: medication AA group (experimental group 1), non-medication AA group (experimental group 2), medication-sham AA group (control group 1), and non-medication-sham AA group (control group 2), with 4 groups in all. Each group will contain an equal number of participants. To prevent researcher bias from confounding the results, each member of the study team will be blinded to the randomization code, allocation, and equivalent treatment except for one who will perform the intervention.

Intervention

All participants will undergo AA on the unilateral ear for three weeks. At each visit, the following procedures will be performed: (I) check the ear to identify the target points based on the protocol; (II) sterilize the entire external ear with 75% isopropyl alcohol; and (III) attach Vaccaria seeds (with diameters of approximately 0.2 cm) covered using waterproof adhesive tape (with dimensions of approximately 0.7 cm × 0.7 cm) in the target auricular points. The Vaccaria seed is a natural botanical seed that does not have any medical benefits or harmful effects on health. The person who will perform these procedures will instruct the participants to apply steady pressure on the taped seed attached to the ear points until maximal tolerable discomfort is sensed. Each procedure will take about 2 minutes with pressing on each target auricular point for at least one second in each trial and a two-minute pause between two auricular pressings. All participants will be instructed to repeat the pressings themselves thrice daily for five consecutive days and then to remove the taped seeds from the ear on the morning of the sixth day. Two consecutive days will be excluded to prevent the well-known side effect of treatment (contact dermatitis) that can be induced by the long-term use of adhesive tapes. New seeds will be replaced according to a weekly schedule including the day of visit, five days of application, and two days off. The participants will be advised to call the researcher immediately when the seeds or tapes are detached from the ear. Regardless of the groups, each trial participant will record each performance and event during the intervention period in a diary.

Experimental groups

Participants in two AA groups (experimental groups 1 and 2) will undergo AA treatment at every visit once a week for three weeks. The auricular points selected for this study include those of the shenmen, liver, spleen, toe, and finger. The shenmen, liver, and spleen points will be used in common for all experimental groups and one of either the toe or finger points will be used depending on the region at which pain is felt by the participant. The rationales for selecting these points are based on literature reviews and the clinical recommendations of three of the Korean AA educators. Specifically, the shenmen has explicitly been described as a master point and has been used to manage symptoms such as sleep disturbance and pain (25,35). The liver point stores and promotes “Qi” circulation and the spleen point regulates blood supply and flow. Thus, both the liver and spleen points contribute to the improvement metabolism which reduces the neurotoxic effects of chemotherapeutic agents. The toe and finger points are the direct reflex points of symptomatic body parts according to the physical reflex theory and will be used to relieve physical symptoms after chemotherapy (Figure 2).

Control groups

Participants in two sham AA groups (control groups 1 and 2) will undergo AA treatment on sham points of the ear. Four sham points will be used, including those of the tooth, tongue, jaw, and internal ear. These auricular points are clearly remote from the treatment points and are unrelated to neuropathic symptoms (36) (Figure 2).

Recruitment and data collection

Potential participants will be invited by a skilled researcher to ensure that standard procedures and guidelines for data collection are observed. Simultaneously, advertisements will be also posted in the research site to improve the rate of recruitment. Details of the study will be provided to those who are interested in this clinical trial. Individuals who meet the inclusion and are willing to participate will be finally enrolled after providing written informed consent. As shown in Table 2, participants will enter the intervention within a week after completing the baseline assessment. Additional assessment will be performed once a week during the intervention period. A follow-up assessment will be performed on the day of completion of the AA intervention and 4 weeks later.

Table 2 Study timeline according to the SPIRIT checklist
Full table

Outcome measures

The outcome measures are presented in Table 2.

Numeric rating scale (NRS)

The NRS will be used to estimate the overall intensity of CIPN symptoms. This measure is one of the most widely used clinical tools and known for its easy applicability. Participants will respond by rating the intensity of symptoms on an 11-point scale ranging from 0 (no symptoms) to 10 (worst possible symptoms). The validity of the NRS has been confirmed in studies of patients with cancer (37,38).

Total neuropathy score (TNS)

The TNS is a physician-based evaluation method used to assess CIPN symptoms. The TNS will be scored on a range of 0-40 (each on a scale of 0-4) by a physician through interview and several tests including sensory, motor, autonomic symptoms, pin sensibility, vibration sensibility, strength, tendon reflexes, vibration threshold, thermal threshold, sural amplitude, and peroneal amplitude (39). We will use 9 items (except for sural amplitude) because there is no electrodiagnostic machine at the center of the hospital. The psychometric properties of the scale were determined in previous studies of patients with neuropathy caused by chemotherapy (40,41).

European Organization for Research and Treatment of Cancer Quality of Life (EORTC-QLQ) Chemotherapy-Induced Peripheral Neuropathy 20 (CIPN 20)

The EORTC-QLQ-CIPN20 will be used to assess the symptoms of CIPN and functional limitations related to these symptoms. This measure comprises sensory, motor, and autonomic domains. Participants will be asked to assess the severity of symptoms and interference with functioning by using a 4-point Likert scale ranging from 1 (not at all) to 4 (very much). Increasing scores indicate worse CIPN states (42). The original measure includes 20 items, 19 of which will be used in the present study because one item applies to male respondents. This measure is a valid and reliable tool for evaluating CIPN symptoms and functional limitations (43,44).

Functional Assessment of Cancer Therapy-General (FACT-G)

The FACT-G will be used to assess health-related quality of life. This measure includes four subscales on wellbeing: the physical (7 items), social/family (7 items), emotional (6 items), and functional (7 items) domains. Each item is rated on a 5-point Likert scale ranging from 0 (not at all) to 4 (very much) (45). The FACT-G has been used worldwide and is confirmed to be a reliable and valid instrument (46,47).

Data management and monitoring

Data obtained from participants will be encoded using a unique identifier and recorded. The data will then be stored in both an electronic database and a locked cabinet. Only permitted researchers can access and manage the data. Checks for logic will be performed to identify missing data and inconsistencies. The whole process of this trial will be conducted under the supervision of monitors that include researchers, ethics committee, and data supervisors.

Safety and withdrawals

Patients will be interviewed for intervention and assessment at each meeting for intervention and assessment, as well as over telephone calls and regular text messaging between visits. We will enquire about adverse events, including their occurrence and severity related to this trial. If any adverse event (skin damage, infection, and allergic reaction in the ear with AA treatment) occurs, the research team of this trial will provide the corresponding treatment to the participant. The principal investigator will immediately report any adverse events to the ethics committee in the authors’ institution. A safety analysis will be performed to assess the incidence of adverse events and the number of patients who experience adverse events in each group. Participants will be free to withdraw from the trial at any time and for any reason. Withdrawals will be documented, and an active follow-up will be conducted to monitor the occurrence of any adverse events throughout the study period.

Data analysis

Statistical analyses will be carried out by a statistician who is blinded to the random allocation using SPSS version 24 (IBM Corporation, Armonk, NY, USA). To improve sensitivity of outcomes, all data will be analyzed through two approaches using a 5% significance level. An intention-to-treat analysis that includes all participants who receive the intervention at least once will be performed and missing data will be handled using the last-observation-carried-forward method. Since the trial was designed to confirm the effectiveness of AA, an additional per-protocol analysis was performed, which includes only participants who complete the entire trial, and excludes participants who violate the protocol. Baseline outcomes in the experimental and control groups will be compared using an independent t-test or Wilcoxon rank sum test depending on the distribution of the data. Analysis of covariance will be used to assess the mean differences while controlling for a current status of administration of pharmacological agents. Changes in mean scores from the baseline to follow-up assessment in each group will be computed to assess the effect of the intervention. To examine the interaction between groups and time, repeated-measures analysis of variance will be performed. Clinically relevant covariates will be included in these analyses.

Discussion

Chemotherapy-induced neuropathic symptoms are commonly reported by patients who have received chemotherapeutic regimens, including taxanes such as paclitaxel (Taxol) and docetaxel (Taxotere) (48). Since taxane was introduced in the 1990s, it has been used as a representative drug in combination with anthracyclines and alkylating agents to treat breast cancer, and has led to an improvement in the survival rate (49). To date, the mechanism underlying CIPN has not yet been elucidated fully. Possible mechanisms underlying the function of taxane include blocking of axonal transport by the microtubule, which is important for neuronal survival and function (50,51). A previously published review identified taxane as a risk factor for CIP and reported differences in incidence rates and severity depending on whether taxane was used or not (52). We also verified whether the cumulative dose of taxane, a physiologic factor, directly affected the occurrence of CIPN symptoms among Korean breast cancer survivors using a structural equation model (53). Based on these findings, the present study will focus on a group of patients treated with taxane-based chemotherapy that should be investigated for the risk of developing CIPN.

In the present study, we will schedule treatment sessions on a weekly basis, including 2 days off between weeks for 3 weeks. There are two reasons for this treatment schedule. First, the safety is an important issue in an interventional study. We found that the probability of adverse events may increase if the AA is performed for longer than 1 week. Hence, the 2-day pause between weekly treatments will enable recovery from auricular stimulations caused by the pressure and prevent the risk of skin damage, infection, and any allergic reactions caused using attached tapes and materials (36). This treatment schedule will be an effective way of improving safety. Second, an appropriate intervention period is considered regarding feasibility. In previous studies, acupuncture interventions were performed over various periods (ranging from 4 to 12 weeks) in managing CIPN symptoms (25,54-57). To the best of our knowledge, only one study applied a 4-week AA intervention to cancer patients with CIPN symptoms (25). Yeh et al. suggested that a 3-week plan for AA therapy may be more feasible due to the schedule of chemotherapy (58). Thus, the inclusion criteria of the present study do not identify the end of chemotherapy but only consider whether chemotherapy is performed during the intervention period. Although the total number of treatment cycles varies depending on the regimen prescribed, chemotherapy with docetaxel is generally administered once every 3 weeks (59,60). Considering of the treatment schedule applied in clinical settings, a 3-week AA intervention was determined. A recently published study of the trend in auriculotherapy application in the last 10 years in Korea also supports the fact that our intervention has no considerable barriers in applicability regarding the entire period and weekly schedule of AA intervention (61).

In the present study, we will invite patients who receive pharmacological agents to reduce CIPN symptoms, as well as their counterparts who do not take any medications. Controlling for the current administration of pharmacological agents may contribute to the clear elucidation of the effect of intervention on CIPN; however, ethical concerns may exist. Our approach can help researchers improve the rate of participation and adherence and conduct the natural setting trial in clinical practices (62).

Various studies have confirmed the role of AA in managing symptoms related to cancer and treatment, as well as CIPN (25,58,63,64). However, there are research gaps regarding study design, sample size, presence of control groups, and controlling confounding variables (65). To develop a well-designed trial, we considered the following aspects: (I) applying a random allocation method to prevent selection of bias, the Hawthorne effect, and the placebo effect, (II) including a sham control group to minimize the placebo effect, and (III) assessing the study outcomes by using both clinician-administered and self-reported measures. Our study would likely add knowledge required to fill the gaps in research. This protocol offers a standardized process to guide current and future studies and accumulates pieces of evidence regarding clinical experiences in applying non-pharmacological interventions. Since the present study seeks to investigate the effectiveness and safety of AA, the findings are expected to provide convincing evidence in these regards for breast cancer patients with CIPN. Moreover, the results will provide healthcare professionals with lessons for managing CIPN symptoms.

Acknowledgments

Funding: MK was supported by the National Research Foundation of Korea grant funded by the Korea government (grant number: 2017RA2B4004328) and the Brain Korea 21 Plus project of the National Research Foundation of Korea Grant. This funding source will not have any role including design, execution analyses, interpretation of the data, and decision of this study.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at http://dx.doi.org/10.21037/apm-20-1469

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm-20-1469). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The present study was reviewed and approved by the ethics committee of the Chungnam National University (approval No. 201906-SB-088-01). Informed consent developed in accordance with the Declaration of Helsinki will be obtained from all individual participants before starting any data collection in this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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