The Effect of Foot Reflexology on Chemotherapy-Induced Nausea and Vomiting in Patients With Digestive or Lung Cancer: Randomized Controlled Trial

Background Cancer is a chronic disease with an incidence of 24.5 million and 9.6 million deaths worldwide in 2017. Lung and colorectal cancer are the most common cancers for both sexes and, according to national and international recommendations, platinum-based chemotherapy is the reference adjuvant treatment. This chemotherapy can be moderately to highly emetogenic. Despite antiemetic therapy, chemotherapy-induced nausea and vomiting (CINV) may persist. Moreover, cancer patients are increasingly interested in alternative and complementary medicines and have expressed the desire that nonpharmacological treatments be used in hospitals. Among alternative and complementary medicines, foot reflexology significantly decreases the severity of CINV in patients with breast cancer. Objective The primary aim of this study was to assess the benefits of foot reflexology as a complement therapy to conventional treatments regarding the severity of acute CINV in patients with digestive or lung cancer. The secondary objectives assessed were the frequency and severity of delayed CINV, quality of life, anxiety, and self-esteem. Methods This study was conducted between April 2018 and April 2020 in the Hospices Civils de Lyon, France. This was an open-label randomized controlled trial. Participants were randomized into two groups: the intervention group (ie, conventional care with foot reflexology; n=40) and the control group (ie, conventional care without foot reflexology; n=40). Foot reflexology sessions (30 minutes each) were performed on outpatients or inpatients. Eligible participants were patients with lung or digestive cancer with an indication for platinum-based chemotherapy. Results The severity of acute nausea and vomiting was assessed with a visual analog scale during the second cycle of chemotherapy. A significant increase of at least 2 points was observed for the control group (7/34, 21%; P=.001). Across all cycles, the foot reflexology group showed a trend toward less frequent delayed nausea (P=.28), a significantly less frequent consumption of antiemetic drugs (P=.04), and no significant difference for vomiting (P=.99); there was a trend toward a perception of stronger severity for delayed nausea in the control group (P=.39). Regarding quality of life and anxiety, there was no significant difference between the intervention group and the control group (P=.32 and P=.53, respectively). Conclusions This study’s results indicate that foot reflexology provides significantly better management of acute nausea severity and decreased consumption of antiemetic drugs in patients with lung or digestive cancer. In order to fulfill patients’ desires to use nonpharmacological treatments and complementary and alternative medicines in hospitals, foot reflexology could be provided as a complementary intervention to conventional antiemetic drugs. Foot reflexology did not result in adverse effects. To assess the benefits of foot reflexology in routine practice, a larger study with several health care centers would be needed with a cluster randomized controlled trial. Trial Registration ClinicalTrials.gov NCT03508180; https://clinicaltrials.gov/ct2/show/NCT03508180 International Registered Report Identifier (IRRID) RR2-10.2196/17232

2017 CONSORT checklist of information to include when reporting a randomized trial assessing nonpharmacologic treatments (NPTs)*. Modifications of the extension appear in italics and blue.
Section/Topic Item Checklist item no.
CONSORT item Extension for NPT trials Title and abstract 1a Identification as a randomized trial in the title The effect of foot reflexology on chemotherapy-induced nausea and vomiting in digestive or lung cancer patients: a randomized controlled trial

Introduction
Section/Topic Item Checklist item no.
CONSORT item Extension for NPT trials Background and objectives 2a Scientific background and explanation of rationale Cancer patients are increasingly interested in complementary and alternative medicines (CAMs) [1] . According to the systematic review reported by Keen et al. the main reasons why patients use CAMs is to treat their cancer, to treat side effects of treatment, and to improve quality of life [2] . Patients with chronic disease, including cancer, express the desire that nonpharmacological treatments and CAMs be used in hospitals [3] . At the time of writing, the most frequently provided CAMs in private and public oncology centres in European countries are mind-body techniques, acupuncture, homeopathy, energy therapies, health promotion, traditional herbal medicine, as well as manipulation and body-based practices (kinesiology, osteopathy, physiotherapy, and reflexology) [4] . Foot reflexology is a holistic approach that is reported to decrease significantly the severity of anxiety in patients with metastatic cancer [5] and improves the perceived pain and anxiety [6] . Moreover, a significant decrease in the severity of chemotherapy-induced nausea and vomiting (CINV) has been observed in breast cancer patients receiving chemotherapy [7] . So foot reflexology seems very interesting because among the side effects induced by chemotherapy, CINV is the most feared by patients [8] ; it decreases overall quality of life [9,10] and induces metabolic complications [8] . In addition CINV can lead to dose reduction, postponement of treatment and even discontinuation [11] which can decrease the effectiveness of treatment [12] . To anticipate or relieve CINV, the recommendation is to prescribe antiemetic drugs [8] , but some patients report that they are not sufficiently effective [13] . According to national and international recommendations, adjuvant treatment for lung and digestive cancers, which are among the most frequent in the world [14] , is chemotherapy most of which are moderately to highly emitting [15][16][17][18][19] . The hypothesis is that foot reflexology delivered at each course of chemotherapy decreases the severity of CINV and anxiety and improves quality of life. 2b

Specific objectives or hypotheses
The aim of the present study is therefore to assess foot reflexology as a CAM to decrease the side effects induced by chemotherapy, specifically CINV by platinum-based chemotherapy, in patients with lung or digestive cancer.

Trial design 3a
Description of trial design (such as parallel, factorial) including allocation ratio Open label randomised clinical trial (RCT) in which the patients are randomised to two groups at a ratio of 1:1; The interventions for each group with sufficient details to allow replication, including how and when they were actually administered The patients randomised to the interventional group will benefit from a foot reflexology session (30 minutes) at each chemotherapy course for four courses. Foot reflexology will be administered by two qualified reflexologists (they have been trained in the French school École des Techniques en Réflexologie). All patients will continue to receive standard antiemetic treatments.
According to Lee's meta-analysis the optimal comparator is a control-group with conventional care without foot reflexology or massage therapy [20] .

Precise details of both the experimental treatment and comparator
5a Foot reflexology is CAM based on the principle of acupressure that helps the body to restore homeostasis. It is a holistic approach which allows one to apprehend the body as a whole. Each part of the body is represented by a zone or reflex point on the foot. The reflexologist stimulates each reflex zone using specific thumb and finger techniques on the patient's feet.
Depending on the objective to be achieved, the zones on the feet are stimulated using different types of pressure. During a session focused on the treatment of CINV, the reflexologist mainly stimulates the reflex points related to the digestive system, as well as the lymphatic and kidney zones to help the body eliminate toxins. The reflexology chart used in the present clinical study is based on the one proposed by Eunice Ingham [21] . The reflex zones of the whole body are equally found on the hands; the reflexologist shows the patient the appropriate zones during the first reflexology session so that he/she can stimulate these reflex points between Description of the different components of the interventions and, when applicable, description of the procedure for tailoring the interventions to individual participants. sessions.

5b
Protocol of intervention was standardized by reflexologists. During a session focused on the treatment of CINV, the reflexologist mainly stimulates the reflex points related to the digestive system, as well as the lymphatic and kidney zones to help the body eliminate toxins. The reflexology chart used in the present clinical study is based on the one proposed by Eunice Ingham [21] Details of whether and how the interventions were standardized. .

5c.
Details of whether and how adherence of care providers to the protocol was assessed or enhanced NA 5d Adherence of participants to reflexology is assessed with a follow-up logbook completed between each course of treatment

Details of whether and how adherence of participants to interventions was assessed or enhanced
Section/Topic Item Checklist item no.
CONSORT item Extension for NPT trials Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed Primary outcome Nausea/vomiting The primary endpoint is the relative change in the severity of nausea and vomiting, as assessed by a VAS (subjective assessment of the severity of nausea: 0-mm no symptom 100mm paroxysm of nausea or vomiting). For patients in the interventional group, this is measured when the patient is arrives at the outpatient clinic and after the foot reflexology session during the second course of chemotherapy. For patients in the control group, this is measured when the patient arrives at the outpatient clinic and after the second course of chemotherapy.
The assessment is carried out by a nurse or clinical research assistant.

Secondary outcomes Nausea/vomiting
The benefits of foot reflexology on CINV will also be assessed using the proportion of between chemotherapy courses during which the patient took at least one antiemetic drug and by the frequency of CINV.

Quality of life:
The benefits of foot reflexology on quality of life will be assessed by the relative change in the overall European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire -Core 30 items EORTC QLQ C30 [22] score between the end of study visit and the first administration of chemotherapy.

Anxiety:
The benefits of foot reflexology on anxiety will be assessed by the relative change in the overall hospital and anxiety depression scale (HADS) [23] score between the end of study visit and the first administration of chemotherapy.

Body image:
The benefits of foot reflexology at the level of body image will be assessed at the end of study visit using the body image questionnaire (BIQ) [24] which measures body image at a given time; the analysis of the BIQ takes into account the self-esteem assessed at inclusion using the Rosenberg scale [25] .
6b Any changes to trial outcomes after the trial commenced, with reasons Sample size 7a How sample size was determined In the study reported by Billhult et al., the mean improvement for CINV (measured using a visual analogue scale, VAS) in the placebo group was 49.5%, and 73.5% in the foot reflexology group (with a common standard deviation of 32.2%) [26] . Assuming these same hypotheses, for a two-sided alpha risk of 5%, it is necessary to include 40 patients per group to demonstrate a statistically significant difference between the two groups with a power of 90%. According to Lee's meta-analysis the optimal comparator is a control-group with conventional care without foot reflexology or massage therapy (22). To limit bias, conventional care is similar for all patients with standard antiemetic drugs.

If blinding was not possible, description of any attempts to limit bias
Section/Topic Item Checklist item no.

CONSORT item Extension for NPT trials
Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes A detailed statistical analysis plan was written and validated before the data were unblinded. Because of the low number of patients with nausea, we had to reconsider the statistical methods that were initially planned in the protocol to analyze the primary outcome. Instead of modelling the primary outcome, we compared the proportion of patients with at least 2 or more increased unit on the VAS between the two groups using Fisher's exact test. Statistical analyses of treatment effects were performed in the intention-to-treat (ITT) population, which included all randomized patients with available information. Baseline clinical parameters were described using mean and standard deviation (SD), or median and interquartile ranges [IQR] for normally and non-normally distributed continuous variables, respectively, and with frequency and percentages for categorical variables. Unless otherwise specified, categorical variables were compared between treatment groups using Fisher's exact test, and continuous variables with the nonparametric Wilcoxon rank-sum test, with a two-sided P value of less than 0.05 being considered as statistically significant. All statistical analyses were performed using the SAS® Software version 9.4 in a Windows environment (SAS institute, Cary, NC, US).
When applicable, details of whether and how the clustering by care providers or centers was addressed 12b

Methods for additional analyses, such as subgroup analyses and adjusted analyses
For the primary endpoint, a secondary analysis will be performed per protocol, including patients with the endpoint assessment, and for whom the strategy allocated during randomisation was fully implemented (patients allocated to the foot reflexology group but not having received their four sessions of foot reflexology will be excluded from the analysis).

Results: Enrollment currently ongoing
Participant flow (a diagram is strongly recommended SEE last page) 13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analyzed for the primary outcome For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) Most participants in the foot reflexology (82.4%) and control groups (94.1%) had no nausea at the start of the second chemotherapy cycle. There was significantly more frequently an increase of at least 2 points among the control group (20.6%, P=0.011; Table 3). Control (n=34) P VAS1 >0, n (%) 6 (17.5) 2 (5.9) VAS2 >0, n (%) 4 (11.8) 8 (23.5) VAS increase ≥2, n (%) 0 (0.0) 7 (20.6) 0.0011

Abbreviations: VAS, visual analogic scale
Twenty-two (52.5%) of the foot reflexology group and 29 (72.5%) of the control group completed their daily diaries after at least one cycle. Whatever the group, we observed that incidence of delayed nausea was lower than delayed vomiting (Table 4). Across all cycles, there was a trend towards less frequent delayed nausea in the foot reflexology group (P=0.28), a significantly less frequent consumption of antiemetic drugs (P=0.037), and no significant difference for vomiting (P=0.99); there was a trend towards a perception of stronger severity for delayed nausea in the control group (P=0.39). Among the 21/22 patients in the foot reflexology group who completed daily diaries and answered the question, 6 (28.6%) practiced self-massage and all considered it to be effective to decrease delayed nausea.
There was no significant difference in terms of quality of life (P=0.32) or anxiety (P=0.53) between the interventional and the control groups.
At the baseline, self-esteem is low irrespective of the group (mean of score<31); the mean of score RSES was 23.6 (SD 2.7) for control group (n=35) and 25.3 (SD 2.7) for foot reflexology group (n=35; P<0.004). At the end of study, the mean of score BIQ was 51.1 (SD 20.4) for control group (n=22) and 41.1 (SD 17.8) for foot reflexology group (n=16; P=0.15). 17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory NA Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) Adverse events were experienced by 12 participants (7 foot reflexology group, FR and 5 control group, C): dyspnea (FR), tinnitus (FR), sepsis (C), neutropenia (C), renal failure (FR and C), leg-vein thrombosis (FR), radiation esophagitis (FR and C), and pulmonary embolism (C). None of the adverse events were attributed to foot reflexology by the physicians. Second, the number of subjects necessary to assess the primary endpoint is not reached because few patients had acute nausea at cycle 2; however, the benefits of reflexology are demonstrated as the results are significant. Moreover, few patients completed the BIQ that are not cancer-specific and may not have been adapted to such patients; semi-structured interviews seem more appropriate to assess these outcomes. Lastly, some patients did not complete their daily diary. To best assess delayed nausea, we should consider calling the patient within 5 days of hospital discharge after each cycle.
In addition, take into account the choice of the comparator, lack of or partial blinding, and unequal expertise of care providers or centers in each group Generalizability 21 Generalizability (external validity, applicability) of the trial findings The main objective of the present study was to assess the benefits of foot reflexology in acute CINV. More than half of the participants were men with metastatic lung cancer with an average age of 63 years who received moderately emetogenic chemotherapy. Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence In conclusion, according to the results of this study foot reflexology decreased significantly acute nausea with a significant less consumption of antiemetic drug between each cycle in lung and digestive cancer patients. We also observed a lower occurrence of delayed nausea in the reflexology group. Therefore, foot reflexology seems to be a promising and innovative complement to conventional antiemetic drugs.
To assess the performance of this intervention in routine practice, a larger study with several health care centres would be relevant with a cluster RCT.

Other information
Registration 23