Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is an extremely common complication of many anti-cancer agents. CIPN-related symptoms are reported by more than two-thirds of patients within the first month of treatment, depending on the drugs being used and the criteria for diagnosis, and may persist long after the offending drug has been removed [1, 2]. Chemotherapy agents most frequently associated with CIPN include taxane drugs (e.g., paclitaxel); platinum-based drugs (e.g., oxaliplatin); vinka alkaloids (vincristine); and drugs used for the treatment of multiple myeloma (e.g., bortezomib, thalidomide) [3, 4]. CIPN is believed to result from cumulative damage to the peripheral nerves from inflammatory processes, with elevated levels of inflammatory markers, an altered cytokine profile, and reduced levels of nerve growth factors (NGFs) in peripheral nerves [5, 6]. Neurological symptoms associated with CIPN are primarily sensory, with numbness, tingling, or pain in the fingertips and toes, and a loss of certain sensations. Patients may report motor nerve impairment, with significant weakness in the limbs [2]. These patients invariably report a significantly impaired quality of life (QOL) and reduced functioning, with weakness and lack of sensation in the feet increasing the risk for falls [7].

Conventional pharmacological treatment of CIPN contrasts greatly from other forms of peripheral neuropathy. For example, the treatment of diabetic neuropathy emphasizes the need to optimize glucose control by increasing the dosage of medications. In contrast, conventional treatment of CIPN entails a decrease in the dose of medications, either through dose modification, discontinuation, or switching to a second-line drug [8, 9]. To date, no available pharmacological treatment has been shown to effectively prevent the onset of CIPN-related symptoms. In cases of painful CIPN, the serotonin and norepinephrine uptake inhibitor duloxetine (Cymbalta) may be of some benefit, though its use is limited by frequent and often severe adverse effects [10, 11].

CIM Modalities for CIPN

A large body of research has been published in the medical literature examining the effectiveness of complementary and integrative medicine (CIM) in the prevention and treatment of CIPN (Tables 1 and 2, respectively). These include manual therapies, such as acupuncture and touch therapies (e.g., reflexology); the use of dietary supplements, both herbal and non-herbal; and mind-body interventions, such as meditation and hypnosis. These modalities are often provided together during the integrative treatment session, making it difficult to assess the impact of each modality on its own. A qualitative study by Ben-Arye et al. examined the impact of a multimodal CIM program (acupuncture with manual, mind-body, or anthroposophic music therapies) among 69 female patients with breast and gynecological cancer undergoing taxane-based treatment regimens. A multidisciplinary narrative analysis found that patients who demonstrated a moderate improvement in CIPN-related symptoms experienced a short-term (24–48 h) reduction in paresthesia and numbness [12].

Table 1 Studies on CIM therapies for the prevention of CIPN-related symptoms
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Table 2 Studies on CIM therapies for the treatment of CIPN-related symptoms
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Acupuncture

During acupuncture treatment, extremely thin (≤ 0.40 mm) sterile stainless steel needles are superficially inserted at designated points along the skin. These points are selected in accordance with ancient Eastern paradigms of medical care, the prototypical of which is traditional Chinese medicine (TCM). Eastern medical practice (including countries such as Japan and Korea) combine acupuncture with other modalities such as herbal medicine, manual therapies (e.g., shiatsu and reflexology), movement modalities (e.g., Qi-Gong, Tai-Chi), and lifestyle-related changes in diet and physical activity. According to TCM, acupuncture stimulates and harmonizes the body’s energy (“Chi”), an effect which can be augmented by attaching electrodes from a 9-V battery (EA (electro-acupuncture)). The application of localized pressure on acupuncture points (acupressure) may also be of benefit, though this form of treatment is not considered to be as effective as needle insertion. Acupuncture has been included in the guidelines of organizations such as the Society for Integrative Oncology (SIO) and endorsed by the American Society for Clinical Oncology (ASCO) for indications such as chemotherapy-induced nausea and vomiting (grade B recommendation: “recommended - high certainty for a moderate benefit/moderate certainty for substantial benefit”), anxiety/stress reduction, depression/mood disturbance, cancer-related pain, hot flashes, and cancer-related fatigue, as well as for improving quality of life (grade C recommendation: “consider, based on the patient’s status - moderate certainty for a small benefit”) [13•, 14•].

Much of this research has examined the physiological effects of acupuncture, in both animal and human models. The emphasis has been on the peripheral and central mechanisms of acupuncture analgesia, which are initiated upon insertion of the acupuncture needle into the epidermal layer of the skin. Needle “wrapping” occurs, with the induction of a micro-inflammatory process with increased blood flow and cellular remodeling, and a reduction in the mechanical stress state in regional mechanoreceptors [15]. Local acupuncture analgesia is believed to be the result of a number of processes, including the activation of Aβ-, Aδ- and C-afferent fibers [16]; increased noradrenaline and dopamine release [17]; release of adenosine via fibroblast signaling; and increased mast cell degranulation and histamine release [18, 19]. Centrally mediated analgesia is believed to reflect a somato-autonomic reflex and release of central neurotransmitters [20], which include endorphin, serotonin, substance P, and enkephalin [15, 21, 22]; and the activation of descending inhibitory pathways [23, 24]. The central effects of acupuncture have been studied using functional-MRI and PET-CT scans, which show altered activity and connectivity in higher brain structures involved in pain modulation, including the insula and limbic areas, as well as somatosensory areas such as S1 and S2 [25, 26].

Clinical research on the ability of acupuncture to prevent the onset of CIPN has been inconsistent. In a study by Greenlee et al., 63 female patients with stage I–III breast cancer were randomized to either “true” or “sham” EA treatments prior to and during treatment with taxane agents. No difference was found between the two groups in the incidence of CIPN symptoms, and patients in the EA treatment group had a slower recovery [27]. However, a phase IIA single-arm study by Bao et al. showed that of 27 female patients with stage I–III breast cancer receiving neoadjuvant/adjuvant weekly paclitaxel treatments, 26 did not show signs of CIPN during the treatment period [28].

While there are a number of clinical studies examining the effectiveness of acupuncture in the treatment of existing CIPN-related symptoms, the majority of these contain a small sample size and heterogenous groups of patients. Level 1 evidence research (randomized controlled studies) includes a study by Rostock et al., which compared acupuncture/electro-acupuncture with hydroelectric baths and high-dose vitamin B supplementation in a heterogeneous population of oncology and hemato-oncology patients [29]. While this study did not find any beneficial effects with the acupuncture treatments, a second study by Han et al. showed that the addition of acupuncture to methylcobalamin produced an additive effect in multiple myeloma patients treated with the neurotoxic agent bortezomib [30].

The majority of research to date has been of level 2 evidence (pragmatic), either without a control group or observational. Studies of acupuncture/EA in multiple myeloma patients with bortezomib-induced neuropathy showing a subjective beneficial effect include those by Bao et al. [31], Garcia et al. [32], and Zhi et al. [33]. In patients with neuropathy caused by taxane and other chemotherapy agents, acupuncture/EA was shown to be of benefit by Donald et al. [34], Wong et al. [35], Zhang et al. [36], and Lu et al. [37]; for the neurotoxic drug bortezomib by Bao et al. (n = 26) and Garcia et al. (n = 19) [31, 32]; and for a mixed group of oncology and hemato-oncology patients by Donald et al. (n = 18) [34]. Objective assessment of CIPN using nerve conduction velocity (NCV) was found to improve following acupuncture treatment by Schroeder et al. and by Han et al. [30, 38], though in other studies this was not the case [32]. In all of the clinical studies, acupuncture was found to be a safe treatment option, with no significant adverse events reported.

Touch Therapies

Touch therapies are a group of CIM modalities in which the therapist either applies direct pressure to areas or points on the patient’s skin (e.g., acupressure, therapeutic massage, reflexology), or else places their hands over the skin without touching it (e.g., Reiki, therapeutic touch) [39]. The application of pressure to acupuncture points (acupressure) can induce similar physiological effects to those of acupuncture, though with a less intense response than needle insertion. Treatments such as acupressure have been shown to have a clinical response for indications which respond to acupuncture, such as chemotherapy-induced nausea and vomiting [40]. It should be noted that despite the seemingly innocent nature of touch therapies, therapists need to avoid applying pressure to vulnerable areas of the body, such as open wounds and bruises, venous blood clots, sites with tumor involvement, areas near drains or other medical devices, and areas of post-radiation skin sensitivity [41].

Clinical research has shown that touch therapies may have a beneficial effect in preventing the onset of CIPN-related symptoms. In an assessor-blinded, prospective, randomized controlled clinical trial, Izgu et al. examined the effectiveness of classical massage in preventing the onset of CIPN in 40 female patients with breast cancer who were receiving adjuvant paclitaxel treatment. When compared with usual care, the incidence of peripheral neuropathic pain was significantly lower in the massage-treated group, and sensory action potential amplitude of the median nerve significantly higher, with tibial nerve latency significantly shorter than in controls [42].

Touch therapies may also help relieve existing CIPN-related symptoms, especially when combined with other CIM modalities. In a randomized controlled trial of 60 patients with grade II-IV CIPN-related symptoms, Kurt and Can found that reflexology improved sensory function, though it was not associated with a reduction in peripheral neuropathy severity [43]. In a retrospective study, Ben-Horin et al. examined the medical records of 30 consecutive breast cancer patients who received both chemotherapy and treatment for CIPN according to an Acupuncture and Reflexology Treatment for Neuropathy (ART-N) protocol, rating symptom severity at baseline, during, and after treatment. The ART-N protocol was shown to be both feasible and beneficial in reducing the severity of CIPN-related symptoms in these patients [44].

Mind-Body Therapies

Mind-body therapies include a wide range of treatments which are used to promote relaxation. These include modalities such as progressive muscle relaxation (PMR), guided imagery, autogenic training, biofeedback, self-hypnosis, and deep breathing exercises [45]. Mind-body therapies are included in the SIO and ASCO guidelines for the treatment of symptoms in patients with breast cancer, with a grade A or B recommendation for anxiety/stress reduction; depression/mood disturbance; and quality of life [13•, 14•].

While it remains to be shown whether mind-body therapies can prevent the onset of CIPN, an observational study by Galantino et al. of 10 patients with varied solid tumors found a beneficial effect for existing symptoms with somatic yoga and meditation. An improvement was also seen in the patients’ flexibility and balance, with a reduction in the risk for falling [46]. Finally, Prinsloo et al. examined the effect of electroencephalogram neurofeedback (NFB) among 62 oncology patients with CIPN, comparing NFB to a waitlist control, observing a reduction in pain which was significantly greater than with controls [47].

Dietary Supplements

Many of the dietary supplements being used by patients with cancer are believed to be effective in relieving diabetic neuropathy, though the evidence for this indication is still as yet unclear. An extensive and in-depth examination of all dietary supplements being used by non-conventional practitioners is beyond the scope of this review. We have thus focused on the most extensively researched supplements, each with a reported neuroprotective effect suggesting their reported effectiveness in the prevention and treatment of CIPN.

Non-herbal Dietary Supplements

Vitamin E

Vitamin E (alpha-tocopherol) is a popular supplement with anti-oxidant activity, which is found in a wide variety of plant oils, nuts, and green leafy vegetables. Vitamin E deficiency can affect the central and peripheral nervous systems, with symptoms of peripheral neuropathy. It is for this reason that many believe that vitamin E supplementation can prevent the onset of CIPN, as well as reduce existing CIPN-related symptoms.

In two consecutive clinical trials, Argyriou et al. examined the effectiveness of vitamin E supplements in the prevention of CIPN. In the first study, 32 patients undergoing 6 courses of paclitaxel-based chemotherapy were randomly assigned to receive chemotherapy with or without vitamin E supplementation. The incidence of CIPN was shown to be significantly lower in the vitamin E–treated group (p = 0.03) [48]. In their second trial, 30 patients scheduled to receive six courses of cumulative cisplatin-based regimens were randomly allocated to chemotherapy with/without vitamin E supplementation. Here too, the incidence of neurotoxicity was significantly lower in the vitamin E–treated group (p = 0.026) [49]. However, in a much larger phase-III, randomized, double-blind, placebo-controlled trial, Kottschade et al. examined the effect of vitamin E supplementation in 297 patients undergoing treatment with neurotoxic chemotherapy, primarily taxanes. The vitamin E–treated group showed no reduction in the incidence of CIPN, including the time to onset of neuropathic symptoms, or modifications in chemotherapy doses related to these symptoms [50].

It should be noted that the use of vitamin E supplements by oncology patients is problematic, to say the least. In a prospective multicenter randomized blinded controlled trial of 35,533 men, long-term use of vitamin E and selenium supplementation was associated with an increased risk of developing prostate cancer (hazard ratio, 1.17; p = 0.008) [51•]. Thus, the potential benefits of vitamin E supplementation, should they be shown to be of significance in future research, need to take into consideration the increased risk for promoting cancer development.

Glutamine

Glutamine (and its negatively charged form, glutamate) is the most prevalent non-essential amino acid in the blood. Preliminary animal studies suggest that the supplement may prevent neurotoxicity caused by agents such as vincristine, paclitaxel, or cisplatin [52]. In a pilot study by Wang et al., 86 patients with metastatic colorectal cancer scheduled for treatment with the neurotoxic drug oxaliplatin were randomized to usual care with or without the addition of an oral glutamine supplement. After 2 cycles, the incidence of CIPN was significantly lower in the glutamine-treated group, with lower rates of grade 3/4 neuropathy after four and six cycles [53]. However, a multicenter, randomized, double-blind placebo-controlled trial by Loven et al. examined the effect of glutamate on the development of CIPN among 43 patients with ovarian cancer undergoing six cycles of paclitaxel and carboplatin. There were no significant between-group differences in symptom frequency, though patients receiving the glutamate supplement presented with lower symptom scores than those in the placebo group [54].

Glutamine may be effective in alleviating existing CIPN-related symptoms. In a non-randomized, controlled clinical trial of 46 patients treated with high-dose paclitaxel prior to stem cell transplantation, Stubblefield et al. showed that glutamine supplementation reduced CIPN-related symptoms which included weakness, loss of vibration sense, and toe numbness, when compared with controls [55].

Acetyl-l-carnitine

Acetyl-l-carnitine (ALCAR) can be found in muscle and liver tissue and in foods such as meats, poultry, fish, and dairy products. ALCAR is believed to have a neuroprotective effect which is mediated by histone acetylation and neuronal nerve growth factor, as well as the regulation of acetyl-CoA and acetylation of tubulin. ALCAR has shown a neuroprotective effect in diabetic-related neuropathy [56, 57] and should theoretically be of benefit for CIPN. However, in a double-blind randomized clinical trial, Hershman et al. compared the efficacy of oral ALCAR with a placebo preparation in 409 female patients undergoing a taxane-based chemotherapy regimen. At week 12, subjective (FACT-NTX) scores were worse in the ALCAR-treated group (0.9 points lower), a finding which persisted and even increased at week 24 (1.8 points lower), with decreased functional status [58•]. It is for this reason that the SIO and ASCO recommend against the use of ALCAR for the prevention or treatment of CIPN [13•, 14•].

Alpha-Lipoic Acid

ALPA (alpha-lipoic acid) has significant antioxidant activity and has been shown in vitro to induce apoptosis (cell death) in a series of cancer cell lines [59, 60]. A number of clinical trials have shown a neuroprotective effect of ALPA in patients with diabetic-related neuropathy [61, 62]. However, in a randomized clinical trial by Guo et al., 70 patients undergoing platinum-based chemotherapy were randomly allocated to ALPA supplement or placebo preparation. No between-group statistical differences were found between the ALPA and placebo treatment arms with respect to the incidence of CIPN-related symptoms [63].

Omega-3 Fatty Acids

The polyunsaturated omega-3 fatty acids are an integral part of the phospholipid membrane of cells in the central and peripheral nervous systems. These include α-linolenic acid (ALA), which can be found in plant oils, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both found in fish oils. The National Institutes of Health Office of Dietary Supplements recommends omega-3 supplementation for those with inadequate intake; this is in light of the evidence supporting the positive effects of omega-3 in reducing cardiovascular disease and improving infant health and neurodevelopment, as well as many other potential benefits [64]. In a randomized, double-blind, placebo-controlled trial, Ghoreishi et al. evaluated 57 female patients with breast cancer receiving paclitaxel. Patients were randomized to omega-3 fatty acid or placebo capsule preparations, with a significant between-group difference observed in the incidence of CIPN, showing a 70% lower risk in the omega-3 fatty acid group [65].

Herbal Medicine

Goshajinkigan

Traditional Japanese herbal (Kampo) medicine is an ancient practice influenced by TCM. Kampo medicine often combines a number of ingredients, each with its role in the treatment of disease, as well as synergy with the other herbal components. The Kampo formula Goshajinkigan is comprised of 10 herbal components and is used to treat diseases of the peripheral sensory nervous system.

In a randomized clinical trial, Nishioka et al. examined the effectiveness of Goshajinkigan in the prevention of CIPN among 45 patients with colorectal cancer undergoing a treatment regimen consisting of fluorouracil (5-FU) and oxaliplatin (FOLFOX protocol). After 10 cycles of chemotherapy, the incidence of grade 3 peripheral neuropathy was 0% in the treatment group compared with 12% in placebo-treated controls. The incidence of CIPN then increased to only 33% after 20 courses of treatment in the Goshajinkigan-treated group; this compared to 75% in controls [66]. In a subsequent multicenter collaborative study, Kaku found a beneficial effect for Goshajinkigan in the prevention of CIPN among 27 patients receiving carboplatin/paclitaxel treatment for ovarian or endometrial cancer, with a significantly lower incidence of symptoms among the patients in the herbal treatment group when compared with the placebo treatment group [67]. However, in a subsequent randomized, double-blind placebo-controlled trial by Oki et al., an interim analysis on the effectiveness of Goshajinkigan in preventing oxaliplatin-induced peripheral neuropathy among patients with colorectal cancer was terminated after 142 of the planned 310 patients were recruited, when it was discovered that there was no significant difference between the herbal and placebo treatment groups in the incidence of CIPN [68].

Safety-Related Issues

Many patients feel that because they are “natural,” CIM therapies must be both effective and safe [69]. However, a number of modalities have been associated with adverse effects (e.g., touch therapies in patients with multiple myeloma or thrombocytopenia) and may exacerbate CIPN-related symptoms (e.g., ALCAR) or increase the risk for cancer (vitamin E). CIM interventions should be provided under medical supervision, such as that provided in an integrative oncology (IO) service. Many of the leading cancer centers have IO programs, which are supervised by integrative physicians who are conventional physicians with training and extensive experience in the use of CIM for the treatment of cancer and cancer treatment–related symptoms. The integrative physician can provide guidance to patients and their healthcare providers on the effective and safe use of CIM, especially when it is being provided in conjunction with conventional oncology treatments.

Discussion

The symptoms associated with CIPN are extremely prevalent and cause significant suffering and impaired quality of life and function. The prevention and treatment of CIPN present a significant challenge to healthcare providers treating this patient population, with conventional treatment options focused primarily on dose modifications and stopping or changing the treatment regimen. Other approaches should be explored, including from the field of CIM, especially those modalities shown to be of potential benefit without significant adverse effects or negative interactions with conventional treatment. A number of these modalities have been researched extensively, and though most of this research has been pragmatic, there is enough evidence to guide researchers to those modalities which have been shown to be safe and with consistently positive findings for this condition. It is important to avoid investment of time and resources in researching therapies which have consistently been shown to be ineffective, or which have potentially negative effects on symptoms or disease progression. Priority can and should be given to CIM modalities which have been included in the guidelines of organizations such as the SIO and ASCO for CIPN or other symptoms, such as acupuncture, touch, and mind-body interventions [13•, 14•].

The findings of the clinical research on the ability of CIM therapies to prevent or alleviate CIPN-related symptoms are limited in both the size of their samples and the limitations of their methodologies. While it would be more desirable to prove efficacy of these treatments using an explanatory research format (i.e., randomized controlled trial), the pragmatic approach (uncontrolled, observational) is much more reflective of the “real life” setting of integrative medicine, with its non-conventional paradigms and multidisciplinary approach to the care of the patient with cancer. Finally, many CIM modalities generate a large array of specific and non-specific effects (e.g., the use of touch, breathing, and meditating gestures in addition to needle insertion) that challenge the concept of the isolated control treatment with which a “true” modality can be compared. An example of this is the use of sham/placebo needles in acupuncture studies, which induce physiological effects similar (if not as intense) to “true” acupuncture treatment and are thus not true “placebo” treatments [70].

Conclusion

Further research is needed to better understand the impact of CIM on the prevention and treatment of CIPN. From the findings presented in this review, it would seem appropriate to pursue modalities such as acupuncture, touch therapies, and mind-body medicine. Dietary supplements which may have the potential to be of benefit include glutamine/glutamate, omega-3, and the Kampo remedy Goshajinkigan. Alpha-lipoic acid (ALPA) does not seem to have any beneficial effect; the benefits of vitamin E supplementation are at present not clear, and there is evidence that the vitamin may promote the development of prostate cancer; and ALCAR may increase the risk for CIPN. It is important that any CIM treatments provided to patients with cancer take place in an integrative setting and under the guidance of an integrative physician specializing in this field. In this way, patients and their healthcare professionals can make an informed decision regarding the use of effective and safe CIM modalities, for CIPN and other symptoms.