A randomized pilot study of oncology massage to treat chemotherapy-induced peripheral neuropathy | Scientific Reports - Nature.com

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This single-blind (patients blinded), pilot study was designed to evaluate the optimum treatment schedule and initial efficacy of two treatment schedules of a standardized Swedish massage technique to treat chronic, lower extremity (LE) CIPN. The study was approved by the MD Anderson Cancer Center institutional review board (ClinicalTrials.gov Identifier: NCT02221700, registered 20/08/2014; IRB Protocol # 2014-0250). All research was performed in accordance with relevant guidelines/regulations including with the Declaration of Helsinki; informed consent was obtained from all participants.

Study participants were identified from oncology clinical centers through distribution of electronic and paper fliers, or via direct mail. Inclusion criteria were neuropathy attributed to oxaliplatin, paclitaxel, or docetaxel, with no prior history of attributable causes for CIPN; self-reported neuropathy score ≥ 3 on 0–10 scale and/or grade 2 or 3 neuropathy according to NCI CTC criteria; greater or equal to 6 months since last chemotherapy treatment; and age > 18. The self-reported neuropathy score is assessed as part of the standard of care in our integrative medicine center together with other symptoms that are part of the Edmonton Symptom Assessment Scale (ESAS); patients are asked to rate their neuropathy on a scale of 0–10, 10 being the worst, over the prior 24-h period. Participants must have been on a stable dose of medications for CIPN symptom management within 2 weeks of study enrollment, all drug classes allowed including duloxetine and pregabalin; stable dose was defined as: (1) no change in drug class; (2) increases or decreases that are less than or equal to 20% of the total dosage. Participants were taken off study if they changed medication (drug class) for pain control.

Exclusion criteria were: peripheral neuropathy pre-dating their chemotherapy; platelets < 50,000 or absolute neutrophil count < 500 within 6 months of enrollment; deep venous thrombosis (DVT) diagnosed within 12 months of enrollment or history of untreated LE DVT; bone metastases; active skin infection; lymphedema involving the treatment field; positive urine pregnancy test; or diagnosis of diabetes.

The recruitment goal was 90 participants. In enrolling 30 patients per treatment group, we expected a drop out of 20% with a final enrollment of 24 patients per treatment group. Once baseline measures were collected, participants were randomized to one of four massage groups in a 2:2:1:1 randomization ratio (Table 1). The alternate-site massage groups were created to control for symptom change over time and treatment effect (therapeutic presence) of the massage therapist. Measures in the control groups were collected at comparable time points as the other groups. Randomization was conducted using minimization based on age, sex, stage of disease, type of disease (breast or gastrointestinal), degree of neuropathy [as defined by baseline Pain Quality Assessment Scale (PQAS) total score], and time since diagnosis16.

Table 1 Study group assignments.
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Intervention​

Massage treatments were provided by one of three licensed oncology massage therapists, each with > 15 years experience. For the site-specific (LE) massage Group 1 and Group 2, massage practice followed a standardized protocol for CIPN. The total visit time was ≤ 30 min, including preparation, positioning, and 10–12.5 min of massage per leg. The setting had a controlled temperature with no background music. Patients were in the semi-Fowler position with knees bolstered. A hypoallergenic, unscented lotion was applied to both LE below the knees. The massage technique started distally in the toes, ending at the knee. Massage pressure was gradually increased, per patient tolerance, following oncology massage guidelines.

For the alternate-site massage control groups (Groups 3 and 4), massage practice involved the scalp/neck/shoulders and back above T4. For participants at risk for secondary lymphedema of the upper quadrant or other unique health conditions, positioning and massage was modified according to oncology massage safety standards. For treatment fidelity, a video and printed copy of the massage treatment protocol were available for review.

Assessments​

In addition to comparison of completion rates of 2X versus 3X a week as part of the primary aim, participant assessment included demographic information and a self-reported measure assessing neuropathic pain. We assessed pretreatment expectations and conducted exit interviews for all participants. To be evaluable, assessments must have taken place within a ± 7 days window of the scheduled time. Assessment measure responses were collected either electronically or by pen and paper and stored in a secure FileMaker Pro database. Data was collected at baseline, midpoint, and at 10 weeks after baseline (end-of-study).

For the purpose of this study, we focused on the 10-weeks follow-up to determine any lasting effects from the massage. Time from baseline to the 10-weeks end-of-treatment follow-up was consistent across massage treatment schedule groups to control for improvements that could take place simply due to the passage of time. This meant that there was a difference in time from end of last massage to 10-weeks follow-up depending on treatment schedule group (4 weeks from last massage for the 2X per week groups and 6 weeks for the 3X per week groups).

Pain Quality Assessment Scale (PQAS) was the primary outcome measure for the secondary aim. PQAS is a 20-item measure developed to quantify quality and intensity of neuropathic symptoms17. It was derived from the Neuropathic Pain Scale and includes symptom descriptors common to people experiencing neuropathic pain or other neuropathic sequelae. Subscales of the PQAS include: Paroxysmal Pain (PP; shooting, sharp, electric, hot, and radiating); Superficial Pain (SP; itchy, cold, numb, sensitive, and tingling); and Deep Pain (DP; aching, heavy, dull, cramping, and throbbing). Secondary analyses included examining the individual items and subscale scores where a 2-point change or greater was considered clinically significant18.

Expectation assessments were on a 5-point scale (not at all agree, a little agree, moderately agree, mostly agree, completely agree) and asked about expectation of massage effects on CIPN.

Statistical analysis​

Assuming a 20% drop out rate, the sample size used to assess the primary aim was 30 per arm. This sample size provides 80% power to detect a standardized difference of 0.736 SD units between the two treatment arms at a two-sided 5% significance level.

Data was summarized by descriptive statistics including mean and standard deviation, median and range for continuous variables and frequency and proportion for categorical variables. For the primary aim, the completion rate was defined as the average number of treatments completed of a possible 12 for patients in each treatment group. Optimum treatment schedule in terms of adherence was determined by using a Wilcoxon rank-sum test comparing number of massages completed between the two possible treatment schedules. For the secondary aim, we examined the effects of location (LE vs control), schedule (2X vs 3X/week) and their interaction on the PQAS subscales of PQAS-SP, PQAS-DP, and PQAS-PP at 10 weeks (end-of-study) using the Ordinary Least Squares (OLS) method for linear regression controlling for baseline levels. Multilevel linear modelling with random intercepts was used to assess location by schedule, location by time (visits 6, 12, and week 10), schedule by time interaction effects, and main effects on the PQAS subscales, controlling for the baseline outcome. Visits 6 and 12 correspond to weeks 3 and 6 for the 2X/week schedule groups, and weeks 2 and 4 for the 3X/week schedule groups, respectively. For individual PQAS items, we descriptively reported change score based on group assignment. Wilcoxon rank-sum test was applied to evaluate the association between each factor (location or schedule) with responses.

Ethics approval​

The study was approved by the MD Anderson Cancer Center institutional review board (ClinicalTrials.gov Identifier: NCT02221700; IRB Protocol # 2014-0250). No separate ethics approval was required.

Consent to participate​

Informed consent was obtained from all individual participants included in the study. The study was approved by the MD Anderson Cancer Center institutional review board (ClinicalTrials.gov Identifier: NCT02221700, registered 20/08/2014; IRB Protocol # 2014-0250). All research was performed in accordance with relevant guidelines/regulations including with the Declaration of Helsinki.