Electroacupuncture use for treatment of taxane-induced peripheral neuropathy in patients with breast cancer: protocol for a pilot, randomised, blinded, sham-controlled trial (EA for CIPN)

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent dose-limiting side effect of neurotoxic chemotherapeutic agents including taxanes, platinum-based agents and vinca alkaloids. CIPN commonly produces sensory disturbances including paresthesia and dysesthesia in hands and feet, with a ‘glove-and-stocking’ distribution, less commonly affecting motor dysfunction in the areas of balance and gait.1 2 The most common symptoms of sensory neuropathy include numbness and tingling, which occur more often than ‘shooting/burning’ neuropathic pain.3 4 CIPN reduces treatment tolerability and is a common cause of dose modification, leading to reduction or premature cessation of chemotherapy treatment.5 In addition, CIPN can also produce long-term functional deficits and reduced quality of life.6 Although some patients experience improvement of CIPN symptoms once chemotherapy is completed,7 8 approximately 30% of patients experience persistent CIPN ≥6 months postchemotherapy resulting in long-term disability.8 In particular, a common survivorship issue identified in breast cancer patients receiving curative intent (neo)adjuvant chemotherapy is long-term mild to severe sensory neuropathy that can be present for more than 5 years following the completion of chemotherapy.9


The current proposed potential mechanisms associated with taxane-related CIPN include altered excitability of peripheral neurons10 and immune system modulation/neuroinflammation,11 as well as microtubule damage, axonal mitochondrial abnormalities and direct axonal toxicity at distal terminals.2 11 Although there have been increasing research efforts to profile CIPN, there remains a gap in knowledge around optimal management.12 The current standard of care relies on dose reduction or cessation, which are inadequate at addressing CIPN and increase the risk of mortality.7

With a lack of effective treatment options, there has been an increasing focus on non-pharmacological strategies. Electroacupuncture (EA) is a traditional Chinese medicine therapy used within integrative oncology as a non-pharmacological treatment option for oncology patients.13 EA has a demonstrated safety profile,14–16 with no potential for drug interaction with chemotherapy and limited risk for treatment side effects in oncology patients.17 18 The intervention involves insertion of acupuncture needles at specific points, with electrical impulses administered at a specific frequency and intensity via the needles.19

The specific mechanism for EA is largely unknown; however, there is an increasing use in cancer care to manage various cancer pain syndromes, including CIPN, aromatase inhibitor-related arthralgia20 and more generalised pain.21 There are a range of documented effects on nerve function, and in animal models, EA has been shown to activate a range of nerve fibre types, including those involved in skin and muscle innervation.22 Furthermore, as well as its potential antihyperalgesic effect, EA has been shown to mediate an anti-inflammatory action through the hypothalamus–pituitary–adrenal axis,13 potentially exerting direct effects23 on the nearby nerves and surrounding neural tissues.24

There have been a number of clinical studies and systematic reviews of the efficacy of acupuncture in people with CIPN.14 25–29 Most studies assessed the efficacy of EA or acupuncture for CIPN in a postchemotherapy setting16 30–34 where patients have well-established and persistent CIPN, usually 3 months or more after completion of chemotherapy. Notably, in the pilot randomised controlled trial (RCT) of women with CIPN postadjuvant taxane therapy for breast cancer, a significant reduction in CIPN sensory symptoms was seen after 8 weeks of EA.30 Similar results were seen in a larger pragmatic trial conducted by Molassiotis et al where the assessor-blinded RCT showed a significant reduction of pain intensity and pain interference scores on the Brief Pain Inventory at the end of intervention and a significant improvement (p<0.05) of Total Neuropathy Score-Clinical Version.35

More recently, there have been a subset of studies looking at acupuncture use during chemotherapy to treat established CIPN.15 36 In the single-arm phase IIA study, Bao et al investigated the use of acupuncture at onset of CIPN in women with breast cancer.15 Findings of the study showed that 26 out of the 27 patients completed 12 cycles of paclitaxel treatment without developing grade III CIPN on the NCI-CTCAE clinical grading scale. These preliminary findings suggest that EA or acupuncture may be beneficial as an early intervention to improve the prognosis of CIPN. A similar outcome was seen in a larger RCT with 168 patients undergoing taxane therapy for breast or gynaecological cancers.36 The trial showed significant improvement of sensory-based symptoms after 6 weeks of two-times-per-week acupuncture. However, the study did not provide treatment blinding with a sham group; instead, it incorporated a comparison arm that combined acupuncture with other touch and mind-body therapies.

Only one study investigated EA used during chemotherapy for its potential neuroprotective effects in paclitaxel-treated patients.19 In the study by Greenlee et al, the use of EA did not show a protective effect to prevent CIPN and the EA group demonstrated worsening of pain symptoms compared with the sham group. However, while the study was a sham-controlled RCT, the findings of the study were restricted by a small sample size. Other studies have been limited by retrospective study design and lack of a control group37 38 to show efficacy in prevention of CIPN.

Overall, there is consensus that more robust clinical trials are needed to investigate the efficacy of acupuncture in this setting. There are also substantial differences between studies in terms of inclusion and exclusion criteria, CIPN assessment tools, endpoints and duration of study. The current study aims to trial EA as an early intervention for the onset of CIPN during chemotherapy. The current pilot study addresses a key research concern in cancer care and survivorship as supported by numerous local and global collaborative efforts.2 7 39 The current proposed study is aimed at addressing this gap by conducting an RCT pilot study of EA to assess its feasibility and acceptability in a comprehensive cancer care setting. A key feature of the study design is weekly screening for CIPN during chemotherapy, to allow early detection and timely EA intervention of CIPN while symptoms are low grade, with the aim to prevent worsening of symptoms.8 Identification of an effective intervention to treat CIPN during paclitaxel chemotherapy would significantly reduce patient treatment burden and promote quality of life in patients exposed to neurotoxic chemotherapies.

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