Acupuncture in adults with Chemotherapy-Induced Peripheral Neuropathy: a systematic review

ABSTRACT Objective: to analyze and synthesize knowledge about the effect of acupuncture on chemotherapy-induced peripheral neuropathy symptoms in adults with cancer. Method: the method used was a Systematic Review. Potential articles were identified by searching in the PubMed of National Library of Medicine, Cumulative Index to Nursing and Allied Health Literature, Embase, Cochrane Central and Scopus. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses strategy, 607 articles were identified. After removing the duplicates, all titles and abstracts were reviewed, and seven articles were selected for full review. After the full review, five studies were selected for inclusion. Results: of the five articles included, four were cohort studies and one was a quasi-experimental study. All articles showed that acupuncture was associated with an improvement in the peripheral neuropathy, but the type of protocol, use of medications, time of treatment, and different outcome measures made it difficult to compare the studies. Conclusion: the use of acupuncture appears to be associated with an improvement in the symptoms of chemotherapy-induced peripheral neuropathy and has no side effects. In order to improve the evidence about benefits associated with acupuncture, more experimental studies using both subjective and objective measures are needed.


Introduction
Chemotherapy is one of the most important treatments for cancer, but it has many adverse effects that adversely impact the patient's quality of life. One adverse effect of chemotherapy is chemotherapyinduced peripheral neuropathy (CIPN) (1) .
CIPN is a serious problem because it leads to difficulties in adherence to chemotherapy treatment, which may have an impact on both the patient's daily life and the long-term outcome of the treatment. The drugs that can cause CIPN include Cisplatin, Oxaliplatin, Paclitaxel, Thalidomide, and Bortezomib (1) . Patients who receive Cisplatin, for example, may experience loss of all sensory modalities, ataxia and gait imbalance, early reduction/loss of deep reflexes, paresthesia (burning sensation, tingling), numbness (loss of sensation), among others. These symptoms may continue for months after the end of treatment (1) .
The intensity and degree of severity of the symptoms depends on the drug, dose, treatment time, and other co-morbid conditions, such as Diabetes, prior exposure to neurotoxic agents, and alcohol exposure (2) . CIPN is diagnosed by a health care provider, usually based on the patient's self-report, but a growing number of objective measures are becoming available. Objective measures include nerve conduction studies (NCS), neurological examinations, and cytokine assessments. A few studies on pharmacological treatments for CIPN, such as vitamin E, glutathione, and lipoic acid, have been conducted, but their quality is poor and the results are not consistent, owing largely to reliance on self-reported outcomes (1) . The primary approach to the management of CIPN is dose delays and dose reductions; thus, it is very important to diagnose CIPN as early as possible, so that the chemotherapy dose can be adjusted (2) .
There has been a growing interest in acupuncture, a common complementary therapy, as a new intervention for CIPN. Acupuncture is an ancient practice that originated within the Traditional Chinese Medicine (TCM) in which needles are inserted into the patient's skin at various points in the body (3) . Acupuncture results in a sensation known as De-Qi, which is considered fundamental to its effect, but the actual receptors and nerve fibers involved are unknown (4) . The meaning of Qi, which is subjective and dependent on the context and coordinates in which it is experienced, is considered to be the patient's "energy" or "the arrival of vital energy" (5) . The mechanisms of action of acupuncture are still not fully understood, but the most commonly held hypotheses are that acupuncture leads to increased blood flow in the capillaries at the needle insertion sites, releases local opioid peptides, reduces inflammation, and stimulates specific areas of the brain (6) .
Researchers have studied the impact of acupuncture on many disorders such as musculoskeletal diseases (7) , chronic lower back pain (8) , nausea in pregnancy (9) and headache (10) .
Researchers have also shown that acupuncture is effective for the treatment of many cancer symptoms caused by chemotherapy or radiotherapy, such as nausea (11) , vomiting (11) , cancer pain (12) , hot flashes (13) , and fatigue (14) . Furthermore, recent studies (15)(16) with other modalities such as laser acupuncture and

Method
The method used was a Systematic Review of the literature (SR). A SR is a strategy that aims to identify, evaluate and synthesize relevant studies on a given topic, gathering evidence that responds to a specific clinical problem. Systematic reviews are used to establish evidence-based clinical practice (17) . The present review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) strategy (18) , with the following inclusion and exclusion criteria:  The search resulted in a total of 607 articles (Table 1). After the removal of duplicates, all titles and abstracts were reviewed and 7 articles were selected for reading of the full text. Two further articles were removed after the full review because they did not meet inclusion criteria ( Figure 1).

Included Eligibility
Additional records identified through other sources (n = 0) Records after removal of duplicates (n = 381) Records screened (n = 40)

Records excluded (n = 33)
Full-text articles evaluated for eligibility (n = 7) Full-text articles excluded with reasons (n = 2) Studies included in the qualitative synthesis (n = 5)

Identification
*PRISMA -Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Figure 1 -Flowchart, according to PRISMA*, to select the studies found (18) The characteristics of the studies to be analyzed were: title, authors, year of publication, design, evidence level, population and sample size, measure for CIPN, treatment and results, and comments from the authors about specific characteristics of the study.
The studies were evaluated according to the level of evidence required for the question of the systematic review. As the question investigated in this review was the effects of a treatment, the following levels of evidence were considered: Level I: systematic reviews; Level II: individual randomized controlled trials; and Level III: quasi-experimental studies, and cohort studies (20) .
The critical evaluation of the studies was done by two independent reviewers, according to the

Studies from the Joanna Briggs Institute Critical
Appraisal Tools (21) . These instruments were chosen because they allow the methodological evaluation of the studies and of the scientific evidence found in the proposed systematic review.

Results
The Figures 2 and 3     Briggs Institute Critical Appraisal Tools (21) The quasi-experimental study included in this review met all of the criteria outlined by the Joanna Briggs Institute for studies of this design, and thus it is of good quality. One cohort study (23) did not meet the Joanna Briggs Institute Checklist for cohort studies, indicating significant methodological weaknesses.
The weaknesses included use of questionnaires that have not been tested for validity and reliability, and failure to identify and control confounding factors in the analysis. In another cohort study (26) , the authors identified possible confounding factors but did not use strategies to control them. The other cohort studies were well done.
The articles included in the review are summarized in Figure 4. All authors found that acupuncture had a positive effect on CIPN symptoms in at least some participants, with no adverse events. However, there were also some individuals who did not report a Measure for CIPN* Neurological examination and nerve conduction studies. Nerve conduction studies data were collected before treatment and after 6 months of treatment by examination of the sural and tibial nerves. In the nerve conduction studies, a change of velocity in the sural nerve of 2m/s slower or faster was considered significant and a change in the amplitude of the sensory nerve action potential of more than 2uV was a seen as a significant impairment or improvement in the sural nerve.

Treatment
Used of traditional Chinese acupuncture. Treatment: 10-week treatment with the ST34, five extra points EX-LE12 and four additional points at EX-LE8 (Ba Feng). The needles were inserted bilaterally.

Results
Acupuncture group: all had hypoesthesia in stocking distribution. After 6 months, five patients had improvement in the conduction velocity of the sural nerve and one did not have change.
Control group: all reported hypoesthesia in stocking contribution. After six months, three patients showed no change in the conduction velocity of the sural nerve, one had improvement and one had increased neuropathic pain. No adverse effects were reported.

Comments
The sample size was small. The same acupuncture protocol was used to treat all patients in the experimental group. Patients had many types of cancer. Patients of the acupuncture group completed chemotherapy 2-21 months before acupuncture, but those of the control group completed chemotherapy 1-14 months before acupuncture.

Evaluation of acupuncture in the management of chemotherapy-induced peripheral neuropathy Donald, Tobin and Stringer 2011 (23)
Design Cohort

Evidence level III
Population + sample size Eighteen patients (eight men and ten women, with mean age of 51.83 years) in England. Seventeen patients completed the study but one died. Fourteen patients were referred for acupuncture to complement their conventional treatment for CIPN* (drugs not identified).
Measure for CIPN* Self-report

Treatment
Use of traditional Chinese acupuncture. Acupoints were selected based on patient presentation at each session and the needles remained in place for 30-45 minutes. One patient received acupuncture twice a week for 3 weeks while 16 received weekly treatments for 6 weeks. The points used and the numbers receiving treatment at each point in brackets were: SP6 (18), ST36 (18), LV3 (14), LI4 (13), BL60 (12) and Ba Feng/Ba Xie (10).

Results
Fourteen patients reported that acupuncture improved their CIPN* and three reported no change. Six reported one additional benefit such as improved sleeping and relaxation, and reduced stress, seven reported more than one additional benefit and four had no additional benefits. No adverse effects were reported.

Comments
Patients had different types of cancer and used different chemotherapy drugs. No control group. Eight patients had other comorbidities such as Type 2 diabetes mellitus, which may have affected outcomes. A different protocol was used for each patient.

Title and author of the article
A Pilot Study of acupuncture in treating bortezomib-induced peripheral neuropathy in patients with multiple myeloma Bao, et al. 2014 (24) Design Cohort

Evidence level III
Population + sample size Twenty-seven patients with multiple myeloma (mean age of 63) treated in United States of America with bortezomib and with persistent CIPN* (grade 2 or more) -criteria NCI-CTC 4.0 † .

Treatment
Use of traditional Chinese acupuncture. Ten acupuncture sessions (twice a week for 2 weeks, once a week for 4 weeks, and biweekly for 4 weeks). Points: bilateral ear points (shen men, point zero and 2 additional points where electrodermal signal was detected), bilateral body points LI4, TE5, LI11, ST40 and Ba Feng in upper and lower extremities. The needles remained in the skin for 20 minutes. Patients continued using the prescribed medications for CIPN* but the drugs used were not identified.

Results
Nerve conduction studies: (n =15) five showed at least 10% increase in motor nerve amplitude, eight showed no significant changes and two showed at least 10% decrease. No significant correlations between symptoms and nerve conduction results. Cytokine studies: no correlation with other measures or grade. Significant reduction in FACT/GOG-NTx ‡ score (p < .0001) and Neuropathic Pain Scale score (p < .0001). Eighteen of 26 (69%) patients had at least 30% reduction in Neuropathic Pain Scale score.
No adverse effects reported.

Comments
Only 14 weeks of treatment. All patients received the same protocol. Median time after discontinuation of bortezomib was 19 months.

Title and author of the article
Evaluation of group acupuncture for cancer-related symptoms: a retrospective analysis Tofthagen, et al. 2015 (25) Design Cohort

Evidence level III
Population + sample size Forty-two patients participated in the study. Mean age was 66.1 and the majority of patients were women. Breast cancer was the main diagnosis. Thirty-five had Chemotherapy-Induced Peripheral Neuropathy.
The study was done in the United States of America.
Measure for CIPN* The patients were questioned about their symptoms using a 0-10 symptom severity scale.

Treatment
Use of traditional Chinese acupuncture. The points used were determined by the areas of body where neuropathy was reported.

Results
The participants reported a reduction in CIPN* and other symptoms after four acupuncture sessions. No adverse effects reported.

Comments
It was unclear how many treatments were applied or what the frequency of the treatments was.
The outcome was only measured through self-report. Different acupoints for each patient were used.

Title and author of the article
The feasibility of an acupuncture protocol in the treatment of chemotherapy induced peripheral neuropathya pilot study Russo 2017 (26) Design Cohort

Evidence level III
Population + sample size Eleven patients (three men and eight women) with CIPN* grade II or greater, based on the World Health Organization criteria.
The mean age was 65.9 years.
The study was done in the United States of America.
Measure for CIPN* Neuropathic Pain Scale, QLQ-C30 § and QLQ-CIPN20 QOL scales || . Each patient completed the questionnaires before the first session, at the fourth acupuncture session, and at the final acupuncture session.

Title and author of the article
The feasibility of an acupuncture protocol in the treatment of chemotherapy induced peripheral neuropathya pilot study Russo 2017 (26) Treatment Traditional Chinese acupuncture was not used (no further information was given). Protocol: the Hua Tuo Jia Li, UB 32, Ba Xie, Ba Feng, LI 10, LI 11 to LI5, GB 34. Needles remained in the skin for 20 minutes. Acupuncture sessions occurred once a week for 10 weeks. The same protocol was applied to all subjects. The patients were taking various supplements and medications, but there was no pattern in the medications taken.

Results
Significant improvement in neuropathic pain, CIPN* symptoms, and sensory condition. The sample was small and many statistical analyses were conducted on the same sample, with no Bonferroni correction.
No adverse effects reported.

Comments
Included both patients with acute and chronic CIPN*.
The cancer diagnoses of participants were not stated. Data were collected only at the end of the study, and no results of each individual treatment were available. Authors were unsure whether the tools used accurately measured symptom experience. agents across the studies included in this review may explain some of the variability in the findings (28) . The authors of one study (28)  were used in several studies (23)(24)(25)(26) , there were no studies using exactly the same acupoints.
The authors of one study (24) discussed the possible mechanisms of action of acupuncture, but its findings did not support any of these mechanisms. In general terms, analgesia in the context of acupuncture occurs through the activation of a pain control system, which is a complex system involving the stimulation of neurons from different regions of the brain. These neurons send a signal of inhibition of pain to the spinal cord.
In this system, there are neurotransmitters such as serotonin, encephalin and endorphin that are also released to aid in the analgesic effect of acupuncture (29) .
This may explain why nerve conduction studies had no significant correlation with pain improvement, as these studies merely analyzed the speed and amplitude of action potentials, but did not analyze the substances involved in the process. According to the International