The primary aim of the study was to investigate the efficacy of a 10-week course of acupuncture in the management of patients’ most troublesome symptoms relating to CIPN measured by a self-reported outcome scale. Secondary aims included use of clinicians’ functional assessments of neuropathy (graded in accordance with CTCAEv4.03) to evaluate effectiveness of acupuncture, in addition to patient reported pain related scores and quality of life assessments.
The study was set over two sites, which form part of a large tertiary cancer centre in North West of England.
Patients with breast cancer and multiple myeloma were initially eligible for randomisation if their neuropathy was of grade II or above (CTCAE v4.03). To increase recruitment the protocol was amended to widen patient eligibility to include gastrointestinal and gynaecological cancer diagnoses. The rationale for using patients from these four cancer disease groups was to allow for comparison of effect across pathologies/different drug regimens, without making the trial design too complex. Additional key inclusion criteria included a platelet count of ≥ 30 x 109/L, a neutrophil count of ≥ 0.5 x 109/L and a MYMOP2 score of their most troubling CIPN symptom of ≥ 3. The blood counts stipulated for entry to the study are lower than would be recommended in standard clinical practice. Study processes monitored the safety of these amended parameters, although this was not a documented aim of the trial.
This study (Trial No. NCT02275403) was designed as a parallel group, open label, randomised phase II clinical trial. Acupuncture was added to standard care for CIPN, in patients randomised to the intervention (Acupuncture) arm. Patients received medication to manage symptoms of CIPN in accordance with local trust policy in addition to 10 weekly sessions of acupuncture from a trained acupuncturist. Patients randomised to the control Arm (Control) received only medication to manage symptoms of CIPN in accordance with local trust policy.
Eligible patients were randomised in a 1:1 ratio to either Acupuncture or Control. A stratified permuted block (size 6-10) allocation scheme was implemented by the study statistician using a bespoke computer system which had username/password control and a full audit trail. Researchers telephoned a central number whereupon trained CTU staff recorded the participant’s details in the system and the allocated trial ID and arm were only revealed after commitment of these details ensuring “allocation concealment” from both researchers and CTU staff. The system also sent an automatic confirmatory e-mail to site. The following two factors were controlled for in the algorithm:
- Cancer diagnosis (Breast Cancer vs. multiple myeloma vs. gastrointestinal cancer vs. gynaecological cancer)
- Treatment intention (one of the below):
- Patient was currently on chemotherapy or any other cancer treatment (to end during the 10-week study or beyond)
- Patient was on chemotherapy, but this had been suspended due to neuropathy or continued but the neurotoxic agent omitted (but could restart in the 10-week study period)
- Patient was due to start their next line of chemotherapy during the 10-week study period
- Patient had finished treatment for their cancer and no further treatment is planned to start within the 10-week study period
Recruitment for the study began in April 2015 and ended in November 2018. Participants remained on the study for 10 weeks, with those allocated to Acupuncture attending the hospital for acupuncture every week. In addition, they were followed up one week after the final acupuncture session to document any adverse events. Patients in Control were only required to attend for the compulsory assessment visits at baseline, 6 and 10 weeks. Whilst not a documented aim of the study, participants were assessed at week 6 and 10 to provide some explorative data on whether a 10-week course of acupuncture is required to provide a significant level of benefit or whether 6 weeks might be sufficient (Appendix 2).
Intervention - Acupuncture
The needles used in this study were for single use, size 32 gauge (0.25mm) and 15-30mm in length. The points were punctured perpendicularly to a depth of approximately 1.0cm (0.5 inch), dependent on the patients’ size, sensitivity, state of health and the particular point. The intervention was documented based on the STRICTA recommendations for reporting acupuncture trials by [[i]]. Patients received a standardised 40-minute, weekly acupuncture session. Eight core points were needled bilaterally (LV3, SP6, ST36, EXLE (x4) and BL60) for lower limb CIPN, as utilised by Abuaisha et al, Zhang et al and Schroeder et al [[ii], [iii], [iv]]. Five bilateral core points (EXUE (BAXI) (x4) and LI4) were needled for upper limb CIPN as previously employed by Bao et al [[v]] and Rajan [[vi]] who used Ll4 as the distal and analgesic point. If a patient was experiencing both lower and upper limb CIPN, all points were needled giving a maximum of 26 core points. There was flexibility in cases of lymphoedema for example, for the selection of alternative points to maintain an equal dose of treatment. Acupuncturists had flexibility to add and record points for related symptoms, reflecting naturalistic current acupuncture practice within this NHS setting (see Table I).
Conversation between therapist and patient was limited to facilitation of treatment only. Although appropriate care was shown to the patient, any conversation about the effects of acupuncture was kept to the minimum and in response to questions the patients raised.
Participants randomised to Control were able to access the site’s existing acupuncture service provision after the 10 week study period was over.
All outcome data was collected at baseline, 6 and 10 weeks. The primary outcome measure chosen for the study was the Patient Reported Outcome Measure (PROM): "Measure Yourself Medical Outcome Profile" (MYMOP2), see appendix 1 [[vii]]. With this validated scale, patients identified and graded their own worst symptom, thus data capture was flexible enough to address the complexity of CIPN. MYMOP2 is scored on an integer 0-6 scale with higher scores denoting greater issues. The eligibility criteria for the study required a ‘Most Troublesome’ CIPN symptom score of ≥ 3 at baseline, with the primary end-point being a subjective ≥2 point improvement (success). The necessary sample size required to appropriately power the study for a hypothesised improvement in success proportions from 30% to 55%, was calculated at 100 patients with a plan to randomise 120 to allow for attrition (90% power; relaxed 10% one-sided alpha).
MYMOP2 data was triangulated with assessment of functionality, which was completed by a clinician at the set time points. The clinicians used standardised questions and visual assessments of function, in accordance with CTCAE v4.03. The key secondary endpoint was functional improvement set at reduction of CIPN to grade ≤ I (CTCAE v4.03). Additionally, a broader measurement of change in symptom burden and quality of life was assessed through completion of the EORTC QLQ-C30 and associated CIPN20 module.
Patients were also asked to complete weekly diaries throughout the study period to capture daily pain scores and CIPN medication usage. These supplementary measures allowed for evaluation of the following secondary endpoints:
- Change in quality of life and symptom burden (EORTC QLQ-C30 + CIPN20 module)
- Alteration in pain related scores
Both of the randomisation stratification factors were collapsed to binary factors in the analysis as some levels had low frequencies. Approximately 50% of patients in both arms had a diagnosis of breast cancer, (see Table 1 below) therefore a decision was made to stratify diagnosis as Breast cancer (yes/no). Equally approximately 40% of participants had completed treatment on study entry therefore adjustment was made for treatment complete status (no/yes) (see Table 1 below). All analyses were carried out on an intention to treat basis i.e. as randomised.
Primary Outcome (Week 10)
The analysis of the primary outcome was undertaken with a logistic regression, the focus being on the trial arm effect after adjustment for diagnosis, treatment status and the baseline MYMOP2 score. In addition, a worst-best case sensitivity analysis was conducted in which any missing outcomes in ‘Acupuncture’ were imputed as "failures" and those in ‘Control’ as "successes".
Secondary outcomes (week 10)
Physician assessed CTCAE CIPN grade ≤ 1: analogous analyses to those for the primary outcome were conducted for this binary outcome variable i.e. logistic regression with adjustment for diagnosis, treatment status and baseline grade. Again a worst-best case sensitivity analysis was conducted in which missing outcomes in ‘Acupuncture’ were imputed as "failures" and those in ‘Control’ as "successes".
EORTC QLQ-CIPN20: During the data collection period of the study, we sought and received advice from the EORTC that previously proposed subscales for this PROM (sensory, motor and autonomic), had been found unreliable and their current recommendation is to use an overall score based on the first 18 of the 20 items in the questionnaire. This maps to a 0-100 scale with lower scores being better. An analysis of covariance (ANCOVA) model was used with adjustment for baseline score, diagnosis and treatment status.
EORTC QLQ-C30 Summary Score: The Summary Score was calculated from the mean of 13 of the 15 QLQ-C30 scales (the Global Quality of Life scale and the Financial Impact scale were not included). Prior to calculating the mean, symptom scales are reversed to obtain a uniform direction of all scales. The summary score was only calculated if all of the required 13 scale scores were available (using scale scores based on the completed items, provided that at least 50% of the items in that scale have been completed). This results in a 0-100 scale in which higher scores represents better overall quality of life. An analysis of covariance (ANCOVA) model was used with adjustment for baseline score, diagnosis and treatment status.
Patient reported pain scores: Participants were asked to complete diaries in which they recorded their worst pain daily on an integer 0-10 scale with landmarks (0= “no pain at all”, 10= “the most intense pain I can imagine”). Within patient weekly mean scores were calculated and the week 1 means were taken as baseline as there was no true baseline i.e. no pre-randomisation diary. An analysis of covariance (ANCOVA) model was used with adjustment for baseline score, diagnosis and treatment status.
Longitudinal models: Outcome data were also recorded at week 6 and longitudinal models with both week 6 and week 10 outcomes were fitted in further exploratory analyses. These models again adjusted for baseline value, diagnosis and treatment status. In addition, they included the week effect and the full interaction of week with each of the other model terms. With this approach we were able to assess differences in the trial arm effect between weeks 6 and 10.