Full title: “Using Acupuncture to Treat Chemotherapy-Induced Peripheral Neuropathy”
ABSTRACT
Chemotherapy-induced peripheral neuropathy (CIPN) affects 30%-70% of chemotherapy patients, some describing it as the most troubling side effect. Symptoms include numbness, tingling and burning pain in the hands and feet. This is a qualitative systematic review identifying acupuncture clinical trials treating CIPN. Human research with a control group from any geographic location written in the English language were included. Searches were done on PubMed, Cochrane Reviews, and article reference lists. Of the six studies included, half found a benefit to acupuncture, while the rest found no benefit or even increased pain. Key results suggest avoiding electroacupuncture during chemotherapy. Improvements were found in studies using auricular acupuncture, and objective nerve conduction velocity measurements. Small sample sizes and mixed results warrant further research before making definitive treatment recommendations. Standardized point selection and measurement scales would help to compare groups. Western medicine has few effective treatments, making acupuncture an attractive alternative.
INTRODUCTION
Background on Cancer from a Western Medical Perspective
“Cancer is a group of diseases characterized by the growth and spread of abnormal cells. If the spread is not controlled, it can result in death.”1 The cause of many cancers is unknown. However, many types of cancer can be caused by lifestyle choices such as smoking tobacco or being overweight. 1 On the other hand, some cancers are caused by genetic mutations, hormones and immune conditions.1
In the U.S., an estimated 1.68 million new cancer cases were expected to be diagnosed in 2016. 1 In the U.S., approximately 41 out of 100 men and 38 out of 100 women will develop cancer during their lifetime. 2 In the U.S., nearly 14.5 million people were living beyond a cancer diagnosis in 2014, and this number is expected to rise to almost 19 million by 2024. 2
The economic impact of this disease is also staggering. In 2014, U.S. total cancer expenses totaled $87.8 billion according to the Medical Expenditure Panel Survey (MEPS). 3
Background on Chemotherapy and Chemotherapy-Induced Peripheral Neuropathy
Some studies report an incidence as high as 70% of patients experience CIPN, but others report 30% to 40%. 4 CIPN negatively affects a patient’s quality of life. CIPN was reported by one-third of patients as their most troubling cancer-related side-effect.”4 It may also require chemotherapy dose reduction or cessation resulting in a higher morbidity and mortality. 5 CIPN may persist or even intensify long after chemotherapy treatments are completed. 6 CIPN adds an average of $17,344 in healthcare costs per patient per year compared to those without these symptoms. 7
The peripheral nervous system is most susceptible to the damaging effects of cytotoxic and biologic agents used to treat cancer. “The chemotherapy agents most commonly causing neuropathy are taxane (paclitaxel, docetaxel), vinca alkaloids (vincristine), platinum compounds (cisplatin, carboplatin), proteasome inhibitors (bortezomib), and antiangiogenic compounds (thalidomide).”4 The most common symptoms of CIPN include painful paresthesia in the hands and feet, allodynia, numbness, and cold hypersensitivity. 4
Western medicine poorly understands the pathophysiology of CIPN, and as a result, treatments to prevent it are inadequate. 5 CIPN neurotoxicity involves DNA damage, mitochondrial toxicity, oxidative stress, and ion channel remodeling which can lead to apoptosis (cell death) in the peripheral nervous system neurons. 8 Once CIPN is established, Western treatment options are also limited. 5 As a result, there is an urgent need for complementary and alternative medicine. 9
Background on Cancer from a Traditional Chinese Medicine Perspective
During the 16th to the 11th century B.C., inscriptions on bones and tortoise shells mentioned the word liu or tumor. 10 According to the Zhen Zi Tong10 and Shuo Wen Jie Zi dictionaries, 10 the word zhong (swelling) was a type of abscess, where liu meant “to flow.” When combined, zhong liu meant swollen tumor or neoplasm. 10 In a book called the Zhou Li compiled in the Qin dynasty (221-207 B.C.), doctors treated a malignant swollen sore without ulceration10 – very similar to tumors of the breast, head or neck that we see now. The theory is a tumor develops when there is tissue proliferation due to qi and blood accumulation. 10
Cancer can occur due to several factors such as invasion of external pathogens, inappropriate diet, emotions, and a combination of phlegm with qi and blood stagnation. 10 Also, “deficiency and depletion of the zang fu organs is an inevitable outcome of various pathological factors and at the same time is a prerequisite for the development of cancer.”10
Background on Peripheral Neuropathy from a Traditional Chinese Medicine Perspective
As chemotherapy was not practiced in ancient China, the only way to find TCM treatments for CIPN is to look at the condition’s symptoms. Examples include relating it to wei zheng or wilting condition; ma mu as the experience of numbness and tingling; and bu ren describing insensitivity or lack of feeling. 11
METHOD
The purpose of this study is to determine whether acupuncture is an effective treatment for CIPN. This is a qualitative systematic review including human clinical trials with a control group written in English. Because there is less research available for acupuncture, there will be no limit to study inclusion based on publishing date. In contrast, research regarding CIPN mechanisms and incidence will be limited to reports published after 2013 because after 5 years, systematic reviews become out of date due to new evidence of therapeutic effectiveness. 12 Outcomes identify how acupuncture affects CIPN pain, numbness and tingling by measuring pain, quality of life, and nerve conduction velocities. Research trial articles will be searched by the primary author on PubMed and the Cochrane Reviews database using the following search terms: acupuncture, Traditional Chinese Medicine, TCM, alternative medicine, neuropathy, CIPN (chemotherapy-induced peripheral neuropathy), and chemotherapy.
Excluded research consists of case studies, protocols without results, articles, surveys, and unpublished data, as well as research on TENS (transcutaneous nerve stimulation), vitamins, supplements, and herbs. Acupuncture trials with bee venom injections will be excluded, as using hypodermic needles are outside the California acupuncture scope of practice. 13 Research studies on neuropathy due to diabetes, autoimmune disorders, genetic disorders, human immunodeficiency virus (HIV), or trauma will be excluded as they have a different pathogenesis from CIPN.
RESULTS
Background on CIPN Severity Measurements
Comparing studies is difficult, since there does not seem to be a consistent standard scale to measure the stage and severity of CIPN. Generally, three different ways were used to determine improvement: pain, quality of life, and nerve conduction velocities.
First, there were several scales used to measure pain within these studies. The most common was the VAS (visual analogue scale), 14 measuring a patient’s subjective experience of pain utilizing a questionnaire about pain intensity. These studies generally used a numerical scale from 0 to 100 with a lower number indicating less pain, and a higher number indicating more intense pain. In this review, the NRS (numerical rating scale) measures pain similarly to the VAS, but with a scale of 0 to 10. The neuropathic pain scale (NPS) is also a subjective patient questionnaire consisting of 10 items designed to specifically address neuropathic pain such as reaction to light touch, timing, intensity, and quality of the pain. 15-16 Another subjective patient questionnaire designed to evaluate cancer pain, is the Brief Pain Inventory – Short Form (BSFSF), in which pain is rated on a scale of 0 to 10. It consists of nine questions assessing pain severity and its impact on daily functions. 17 Although originally designed to evaluate diabetic neuropathy, the TNS (Total Neuropathy Score) is now also used to evaluate CIPN pain. 18-19 In addition to the patient’s subjective report, this scale also includes objective measures such as pin prick, vibration threshold and nerve conduction studies. The TNSc is a version of the TNS scale designed to measure only the clinical signs and symptoms of CIPN. 18-19
There were several scales used to measure changes in quality of life. The FACT-GOG-Ntx (Functional As – sessment of Cancer Therapy/Gynecologic Oncology Group/Neurotoxicity questionnaire) was used most often. A predecessor questionnaire was the FACT-G (Functional Assess – ment of Cancer Therapy – General), developed to identify a cancer survivor’s quality of life. This scale is a subjective patient questionnaire with 28 items identifying the state of illness and physical capabilities, as well as the patient’s social and emotional state. 20 Building on this previous scale, the FACT/ GOG-Ntx 19,21 was developed for women diagnosed with gynecologic malignancies who were treated with neurotoxic drugs such as taxanes and platinum. These patients complained of CIPN, making this more specific scale appropriate for the included research studies. Another variation of this questionnaire is the FACT-Taxane with additional items specific to taxane such as arthralgias, myalgias, and skin dis – coloration. 19
The U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute 22 devised yet another way to measure treatment side effects. Originally called the Common Toxicity Criteria (CTC), it is now known as the Common Terminology Criteria of Adverse Events (CTCAE). The National Cancer Institute defines an adverse event (AE) as any side effect due to the medical treatment rather than the disease. This scale measures the AE as a grade 1 to 5, where grade 1 is considered mild, and grade 5 results in death.
The final quality of life criteria developed by the European Organization for Research and Treatment of Cancer is the Quality of Life Questionnaire (EORTC-QLQ-C30). This model measures the patient’s functionality – physical, role, cognitive, emotional and social. It also measures symptoms such as fatigue, pain, nausea, and vomiting. Finally, it has a scale to evaluate the patient’s overall health and quality of life. 23 It too, has supplements to make it more specific to the disease being measured, such as the QLQ-CIPN2024 adding questions specific to CIPN. Similarly, the QLQ-OV28, designed for women diagnosed with ovarian cancer, adds scales regarding the patient’s body image, sexuality, attitude to the disease or treatment, as well as other chemotherapy-related side effects like peripheral neuropathy, hormonal complaints, and digestive issues. 25-26
The third type of CIPN evaluation related to nerve conduction velocities (NCV) to identify any abnormalities in mixed, motor or sensory nerves by electrically stimulating nerves with small safe pulses over the limbs and then measuring the results. 27 W ithin the category of NCV, two types of nerve velocities are measured – motor nerve conduction velocity (MCV) and sensory nerve conduction velocity (SCV) as a way to gauge CIPN severity.
REVIEW OF THE RESEARCH
After screening titles and/or abstracts, 14 articles were excluded for the following reasons: the focus was on an intervention other than acupuncture, the neuropathy was not related to chemotherapy, the acupuncture treatment plan included injecting pharmaceutical derivatives into acupuncture points, the patients were not human, the study was not written in English, there were duplicated studies, the study did not have a control group, or they were not relevant. After detailed evaluation, 6 studies were included in the review for treating CIPN with acupuncture. For an alphabetical summary of the clinical studies see Table 2.
Overall, there were few studies to review, treating a fairly small number of patients during a relatively short period of time. This makes it difficult to generalize results to the overall CIPN patient population. Also, peripheral nerves take a long time to grow after injury, growing only 2 mm to 4 mm per day. 28 Therefore, a longer treatment window may be necessary to realize results. For overall results of acupuncture treating CIPN, some studies found no difference between the control and acupuncture, some found the pain increased, while others noted a decrease in pain and improved nerve conduction velocities. Of note, two studies using electroacupuncture (EA) during chemotherapy infusions found the treatment increased CIPN pain, suggesting EA may not be beneficial during chemotherapy. Out of the six studies included, two took place while patients were still receiving chemotherapy, while the remaining four took place after patients were completely finished with chemotherapy.
Alemi et al. (2003)
A study by Alemi, Rubin, Pichard-Leandri, Fermand-Brule, Dubreuil-Lemaire and Hill 29 evaluated auricular acupuncture compared to sham auricular acupuncture, as well as a control group receiving ear seeds. The goal for having two separate control groups was to identify whether inserting needles at invalid acupuncture points was a valid control. This study randomly assigned 90 patients into three groups. For the acupuncture groups, stainless steel needles were implanted into the ear, and the patients were instructed to record when the needles fell off. They received a treatment once a month for three months. An electronic voltmeter was used to find ear points eliciting an electric response. The two control groups received treatments at placebo points – one group receiving needles, the other receiving ear seeds. Overall, this study adhered closely to STRICTA guidelines, with the exception of identifying the acupuncturist qualifications. This last item may not be as relevant, since the points were determined by electrical response. After 60 days, 79 patients completed the trial, with the acupuncture group demonstrated improvements with a decrease in VAS pain scores. Contrary to expectations, the two placebo groups had no effect as a result of their treatments.
Greenlee, et al. (2016)
The study by Greenlee and colleagues 30 researched whether acupuncture could prevent CIPN in breast cancer patients undergoing taxane chemotherapy. This study included 63 women who received 12 weekly treatments and were randomly assigned to two groups – either electroacupuncture or sham electroacupuncture as the control. The electroacupuncture group received 2 Hz treatments based on a Traditional Chinese Medicine (TCM) diagnosis of qi and blood deficiency and stagnation. The sham acupuncture group received treatment using Park Sham collaps – ible needles which touched but did not penetrate the skin. 31 While the design of the study closely matches STRICTA guidelines, the short amount of time patients received treatment may hamper positive results. The outcome measures included the BSF-SF, FACT/GOG-Ntx, FACT-Taxane, and NPS scales. According to the BSF-SF evaluations, at 16 weeks, the sham acupuncture group pain scales reverted to their baseline level, while the electroacupuncture group’s pain was actually getting worse, suggesting that patients should not receive EA while getting chemotherapy treatment for taxane. The other scales showed no measurable difference between the two groups.
Han et al. (2017)
A study conducted by Han and colleagues 32 examined the use of acupuncture and methylcobalamin to treat bortezomib-induced peripheral neuropathy (BIPN). This study did not include injections into acupuncture points so it was included in the review. This research studied 104 multiple myeloma patients who had completed chemotherapy. Over 84 days, patients received a total of 10 acupuncture treatments. The cycle began with treatments daily for three days, then every other day for 10 days, then this treatment cycle repeated after 28 days for three cycles. In conjunction with the acupuncture treatment, patients received 500 μg methylcobalamin injections every other day for 20 days, followed by two months of oral methylcobalamin three times a day. The control group received the same methylcobalamin regimen without acupuncture. Methylcobalamin, an active form of Vitamin B12, is thought to improve nerve conduction and promote regeneration of injured nerves. 33 The report closely adhered to STRICTA guidelines, but needed to discuss the TCM diagnosis, type of needles used, and whether the needles were stimulated after insertion. After treatment, the acupuncture plus methylcobalamin group experienced significant improvements in pain realizing an 85.7% reduction in VAS pain scores compared a pain reduction of 77.6% in the control group. Finally, the report appears to contradict itself on the MCV values – saying there was no change in the acupuncture group, then later reporting there was a significant change.
Lu et al. (2012)
The next pilot study by Lu and colleagues 34 examined how acupuncture affects quality of life for women with ovarian cancer. The trial treated a total of 21 patients at two cancer centers who were receiving chemotherapy at the time. Patients received a total of 10 acupuncture treatments two to three times a week over a total of 21 days. The active acupuncture group was treated with needles at a depth of 10 mm on recognized acupuncture points, as well as 25 Hz EA on at least two points on the patient’s legs. In contrast, the control group received needles that did not correspond to acupuncture points, and were needled to a depth less than 0.2mm. This study closely followed STRICTA guidelines, except it did not mention the acupuncturist qualifications. The outcomes were measured using EORTC-QLQ-C30 and EORTC-QLQ-OV28. The patient’s neuropathy was measured 30 minutes after treatment, so any tingling, or numbness increase felt at that time could have been part of the treatment rather than a true increase in neuropathy. Also, in Japanese acupuncture, the treatment depths are very shallow, so there is a chance the control group received some benefit from the treatment. In addition, the short treatment length could have influenced the results. At the end of the study, there were no significant CIPN differences between the sham and acupuncture groups.
Rostock et al. (2013)
Rostock, Jaroslawski, Guethlin, Ludtke, Schröder, and Bartsch35 conducted a four-arm randomized trial evaluating EA’s effectiveness to treat CIPN. In Germany, where it was conducted, hydroelectric baths and vitamin B supplements are used to treat neuropathy. The study randomly assigned 60 patients who had completed chemotherapy into four treatment groups: EA, hydroelectric baths, vitamin B complex, and placebo. Patients in the EA group received a total of seven to nine total treatments over a three-week period. The hydroelectric bath group dipped either their arms or legs, depending on which limbs had CIPN, up past the elbow or knee joint respectively for 15 minutes with a current of 50 Hz in the water. In the vitamin B protocol, patients ingested three high dosage capsules, containing 100 mg of thiamine nitrate and 100 mg of pyridoxine hydrochloride, each day for three weeks. The placebo group followed the same regimen, but ingested capsules containing lactose. There were some limitations to this study. From a STRICTA perspective, it was missing the TCM rationale for treatment, needles used, and the needle depth. The outcome was measured using the NRS pain scale, and the NCI-CTC scale but found no significant difference between the treatment groups. The authors noted the patient’s pain scores for all groups were low at the beginning of the study, leaving little room for improvement. Patients also received other treatments such as sport therapy, physiotherapy and massage at the same time which could be part of the reason placebo groups did so well. The placebo group may have also fared better because 88% started the study with paresthesia – compared to 100% of the EA group. Although not mentioned in the study, the electric current in the hydroelectric bath could have a similar effect to EA.
Schroeder et al. (2012)
Schroeder, Meyer-Hamme, and Epplée 36 published a pilot study investigating whether acupuncture could improve NCV for CIPN patients. This study included a total of 11 patients, with a self-selected control group who refused acupuncture. Patients in the acupuncture group received a total of 10 treatments over the course of three months. The research closely adhered to STRICTA guidelines, except omitting the brand of needle used. In addition, the groups were not randomly assigned, but instead self-selecting. Outcomes were measured by NCV, with the acupuncture group demonstrating improvement after follow-up at six months post-treatment, suggesting that acupuncture has a positive effect on CIPN. The length of time for follow-up is a strength of this study compared to the others in this review, given the time it takes for nerves to regenerate.
DISCUSSION
After reviewing the six included studies, it is difficult to make broad generalizations about the outcomes. Three studies showed improvement after acupuncture (Alimi et al., 29 Han et al., 32 and Schroeder et al. 36), while three showed either no difference from the control group, or increased pain (Greenlee et al., 30 Lu et al., 34 and Rostock et al. 35). Generalizing the results is also hampered by the small sample sizes in each of these studies. Another challenging part of evaluating these studies overall is that the patient population is heterogeneous – some were treated during chemotherapy, while others only after chemotherapy was completed. Future research should also consider studies over a longer period of time due to the time it takes nerves to regenerate.
Each study used a different point prescription, and only one study, by Greenlee et al., 30 mentioned a TCM diagnosis or rationale for why the points chosen. While a diagnosis of qi and blood stagnation along with some deficiency might be straightforward in these cases, the organ affected by cancer may change the treatment protocol. This makes it difficult to determine an optimal point prescription to treat CIPN.
In addition, each study used a different scale to measure the outcome, making it difficult to do direct outcome comparisons, especially since the scales are largely subjective. The most promising studies had an objective way to choose the acupuncture points, such as Alimi et al. 29 using the electronic voltmeter to select auricular points, or Schroeder et al. 36 and Han et al. 32 choosing NCV as an objective outcome measurement. It would be interesting to do a meta-analysis of the NCV studies.
For the studies utilizing EA, none described their reasoning for the Hz setting or the treatment length of time. For instance, Greenlee et al. 30 used 2 Hz for 30 minutes, Lu et al. 34 used 20-25 Hz for 30 minutes, and Rostock et al. 35 used 50 Hz for 15 minutes. Research shows that enkephalin, endorphin, and endomorphin are released with EA of 2 Hz, while dynorphin is released with a frequency of 100 Hz. 37 These four peptides are an essential way that EA mediates pain in the central nervous system. 37 By combining the 2 Hz and 100 Hz frequencies, all four neuropeptides are released in order to provide the greatest short-term therapeutic effect to reduce pain. 37 Silva, Silva, and Prado suggest 100 Hz EA may be helpful in preventing pain, while 2 Hz does not. 38 Therefore, future studies of EA may want to investigate 100 Hz EA to prevent CIPN, while alternating 2 Hz and 100 Hz EA for existing CIPN. In addition, sessions should strive to be at least 20 minutes, because the “analgesic effect of acupuncture has a slow onset, and reaches a peak after 20 minutes.”39 Also, any future studies should take care to administer a quality of life or pain questionnaire prior to each individual EA treatment, since the vibration and treatment itself could temporarily increase pain and affect results. Keeping in mind the limitations of the available research, the data suggests avoiding EA while the patient is currently receiving chemotherapy treatment, since two studies (Greenlee et al., 30 and Lu et al. 34) mentioned it potentially increased pain. It would also be interesting to research the appropriate estim frequency for nerve regeneration.
Based on three of the studies, there is evidence that acupuncture can help improve CIPN pain. Theoretically, the study by Alimi et al. 29 had positive results because treatments lasted longer since stainless steel needles were retained in the ear, in addition to customized treatments for each patient. One other interesting result, the two studies (Han et al., 32 and Schroeder et al. 36) us – ing objective measurements of NCV both demonstrated improvements as a result of the acupuncture intervention. Nerve conduction studies are the standard to measure CIPN by typically showing a decreased amplitude in sensory nerve action potentials. 4 However, Stubblefield and colleagues argue that nerve conduction studies correlate poorly with subjective patient reports and produce inconsistent findings, but they do note that patients tend to underreport their symptoms. 19 In contrast, the other studies used largely subjective measurements to determine outcomes that may affect the ability to definitively determine results. Cavaletti et al., 40 and Brewer et al., 41 in separate research papers, noted patient-derived questionnaires and physician-based grading scales suffer from subjectivity and inconsistency.
Because there is little Western medicine can offer for pain relief or prevention of CIPN, and there has been some evidence acupuncture can benefit these patients, there is a case to consider acupuncture for this condition. In addition, acupuncture done by trained practitioners is generally a safe procedure, and the number of adverse events relating to it is below that of common medical treatments. 42-43
CONCLUSION
These studies demonstrated mixed results, highlighting a great need for additional research to determine whether acupuncture has a benefit in treating CIPN. Based on these few studies, acupuncture may provide a benefit in improving NCV, and auricular acupuncture appears to be beneficial. However, it appears EA should be avoided while the patient is currently undergoing chemotherapy. New research should include large, multi-site trials with a defined protocol. From a Western medicine perspective, more research needs to be done to identify the cause of peripheral neuropathy and work towards a global measurement scale so outcomes from research trials can be more easily compared with more definitive conclusions. Finally, because Western medicine lacks effective treatments, the low risk of acupuncture treatments, and some evidence pointing to its ability to improve nerve conduction velocity, acupuncture should be considered as a complementary treatment for patients experiencing CIPN.
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