Lifestyle-Related Factors in the Self-Management of Chemotherapy-Induced Peripheral Neuropathy in Colorectal Cancer: A Systematic Review

Background. Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of chemotherapy treatment in colorectal cancer (CRC), negatively affecting the daily functioning and quality of life of CRC patients. Currently, there are no established treatments to prevent or reduce CIPN. The purpose of this systematic review was to identify lifestyle-related factors that can aid in preventing or reducing CIPN, as such factors may promote self-management options for CRC patients suffering from CIPN. Methods. A literature search was conducted through PubMed, Embase, and Google Scholar. Original research articles investigating oxaliplatin-related CIPN in CRC were eligible for inclusion. Results. In total, 22 articles were included, which suggested that dietary supplements, such as antioxidants and herbal extracts, as well as physical exercise and complementary therapies, such as acupuncture, may have beneficial effects on preventing or reducing CIPN symptoms. However, many of the reviewed articles presented various limitations, including small sample sizes and heterogeneity in study design and measurements of CIPN. Conclusions. No strong conclusions can be drawn regarding the role of lifestyle-related factors in the management of CIPN in CRC patients. Certain dietary supplements and physical exercise may be beneficial for the management of CIPN, but further research is warranted.


Introduction
Colorectal cancer (CRC) is a highly prevalent type of cancer and a common cancer-related cause of death worldwide [1]. In the past decades, an increase in survival and prevalence rates has resulted from the development of novel treatments and improved diagnostic methods, including early detection strategies through the implementation of population screening programmes. Consequently, more people nowadays survive longer after a CRC diagnosis and live with the physical and mental consequences of the disease and the adverse effects of its treatment [2][3][4].
CRC is treated through surgery in most cases, combined with (neo)adjuvant chemotherapy and/or radiotherapy depending on the cancer stage [5]. It is known that chemotherapy can cause severe adverse effects that can be highly detrimental to a patient both physiologically and psychologically, thus having a large impact on an individual's quality of life [6]. One common and severe adverse effect of chemotherapy is chemotherapy-induced peripheral neuropathy (CIPN), which usually consists of sensory axonopathies [6]. Although it can depend on the specific affected site of the peripheral nervous system, common signs and symptoms of CIPN usually include numbness and tingling of hands/feet, muscle weakness, lancinating/burning pain, cutaneous hyperesthesia, and loss of pain/temperature sensation [6]. CIPN may develop weeks to months after exposure to chemotherapeutic agents, can continue in spite of cessation of chemotherapy, and may be irreversible depending on the degree of neuron damage [6]. The chemotherapeutic agents 2 Evidence-Based Complementary and Alternative Medicine which most frequently cause CIPN are thalidomide, bortezomib, platinum derivatives, vinca alkaloids, and taxanes [7].
Platinum-based chemotherapy is the standard treatment for stage III-IV CRC, and it may also be recommended to high-risk stage II patients [5,8,9]. Oxaliplatin, a cytotoxic platinum compound which has been used in Europe since 1996, is one of the chemotherapeutic agents used in CRC [10]. Around 60% of CRC patients will receive oxaliplatin-based chemotherapy as part of their cancer treatment. Approximately 48% of patients receiving oxaliplatin-based chemotherapy will develop neuropathy symptoms during treatment, which may resolve after treatment or develop into chronic symptoms in 20-50% of these patients (a phenomenon known as "coasting") [11,12]. Another chemotherapeutic agent is cisplatin [13]. Platinum compounds form so-called platinum complexes which inhibit DNA replication, thus leading to apoptosis [7,14]. It is believed that acute oxaliplatin-related CIPN may be the result of rapid chelation of calcium by oxaliplatin-induced oxalate and that oxaliplatin is able to alter voltage-gated sodium channels, most likely through a pathway involving calcium ions [14]. Another mechanism that has been postulated to contribute to the development of CIPN is a decrease in cellular metabolism in dorsal root ganglion cells [14]. Possible risk factors associated with oxaliplatin-related CIPN include dosage, cumulative dose, treatment schedule, and the patient's muscle mass [14,15].
An increasing number of CRC survivors suffer from the negative and disabling consequences that CIPN has on their quality of life [3]. Currently, there are no effective treatment options for preventing CIPN or decreasing its symptoms. Neuroprotective agents such as thiols, neurotrophic factors, and anticonvulsants have been tested as possible preventive agents, but no conclusive results have been published [16]. For this reason, research is now also focusing on the potential of lifestyle factors for reducing or preventing CIPN [3]. These lifestyle factors refer to health-related behaviors, such as physical exercise, dietary habits, and intake of dietary supplements, as well as the use of natural products or complementary therapies which patients choose to engage in to selfmanage their CIPN symptoms, without necessary physician supervision. Previous research has suggested that lifestyle factors, such as an unhealthy diet and body composition, play an important role in CRC development and also affect the health-related quality of life of CRC survivors [1,17]. For this reason, it is of interest to investigate whether such lifestyle factors could also play a role in the development and consequences of CIPN in CRC survivors.
Although a recent systematic review by Brami et al. [18] reported evidence from randomized clinical trials (RCTs) on effects of natural products and complementary therapies on CIPN in general, the focus of the present systematic review was to evaluate available evidence from research on lifestylerelated factors and their effects specifically on oxaliplatinrelated CIPN in CRC. Therefore, the aim of this systematic literature review was to identify lifestyle factors that play a role in the development and occurrence of CIPN symptoms. Such factors could provide avenues for reducing the occurrence of CIPN in CRC patients as well as for promoting self-management options for CRC survivors suffering from chronic CIPN symptoms.

Methods
For the purpose of this review, a systematic search of the literature was conducted through PubMed, Embase, and Google Scholar. The initial literature search, limited to the time period between 1994 and 2015, was performed on December 8, 2015, by the use of the following search strategy: ((colon OR rectum OR colorectal) AND (cancer OR neoplasm) AND (neuropathy OR peripheral neuropathy) AND (chemotherapy OR platin) AND (lifestyle OR behavior * OR management OR supplement * OR vitamin * OR mineral * OR alternative therapy OR complementary therapy OR BMI OR exercise OR physical activity)).

Article Selection.
A total of 1,077 records were identified in the initial search ( Figure 1). Only original research articles describing the prevention and/or management of oxaliplatinrelated CIPN in colon, rectum, or CRC patients were eligible for inclusion. All types of study designs were eligible, except for case reports because of the low level of evidence provided by these studies. For studies containing mixed cancer populations that included CRC, the results of CIPN among CRC patients had to be reported separately from the results of CIPN among patients with other tumors to be eligible for inclusion. Furthermore, articles were required to describe lifestyle-related or alternative/complementary management options for CIPN. For this reason, studies describing prescription medication were not eligible. Studies in which dietary supplements were administered intravenously were also ineligible, and so were animal or cell studies. Finally, studies were only included if the publication was an original research article (e.g., no systematic reviews, book chapters, dissertations, poster abstracts, editorials, and letters to the editor) and if the study had been published in a peer-reviewed journal in English. On the basis of these criteria, 17 full-text articles deriving from the initial search were evaluated for eligibility. An additional 25 articles were identified through citation tracking and screened for eligibility ( Figure 1).

Lifestyle Factors.
Results are presented in Table 1. The lifestyle factors identified through the literature search were grouped into four categories: (I) dietary supplements, (II) physical activity, (III) alternative (complementary) therapies, and (IV) multiple/other strategies.
(I) Dietary Supplements. The most researched natural remedy for CIPN was Goshajinkigan (GJG or TJ-107), a traditional Japanese herbal extract ("Kampo formula"). Four included studies evaluated the effects of oral administration of GJG and concluded that administering a minimum of 2.5 grams of GJG during chemotherapy significantly reduced the toxic effects of oxaliplatin, reducing the incidence of CIPN and its intensity [25][26][27]29]. More specifically, Kono et al. [25] found that the incidence of CIPN symptoms at higher doses of oxaliplatin was lower in the groups receiving GJG. At the same time, patients receiving GJG tolerated higher cumulative doses of oxaliplatin [25]. A study by Nishioka et al. [27] found a significant reduction of grade III CIPN for patients receiving GJG. Finally, Yoshida et al. [29] observed a significant difference in the development of CIPN between GJG and control patients, with less than 10% of GJG patients presenting CIPN symptoms. In contrast, however, a recent randomized placebo-controlled trial by Oki et al. [28] showed

10
Evidence-Based Complementary and Alternative Medicine that GJG supplementation (7.5 mg/d) during FOLFOX6 chemotherapy in patients with resected stage III colon cancer led to a significantly earlier time to onset of sensory neuropathy (grade 2 or greater) compared to a placebo group. A further traditional herbal extract that appeared to have a positive effect on CIPN was the Jianwei Hiangqi Guizhi Wuwu Decoction (JHGWD), a traditional Chinese medicine composed of botanical materials [30]. Administration of JHGWD during oxaliplatin chemotherapy significantly reduced the intensity of CIPN symptoms, as well as their duration [30]. Furthermore, the symptoms presented by control patients were more severe in nature and of longer duration [30]. Another traditional Chinese medicinal remedy studied was guilongtongluofang, an aqueous extract of dried herbs. In their study, Liu et al. [31] found that 200 mL of guilongtongluofang taken twice daily significantly lowered the percentages of grade I and II CIPN after 2 and 6 cycles of chemotherapy. The risk of grade I CIPN was significantly lower in the treatment group, and the onset of CIPN symptoms was significantly later in the treatment group than in the control group (9.4 weeks versus 6.5 weeks, resp.) [31]. Furthermore, a randomized controlled study of fucoidan, a sulfated polysaccharide extracted from brown seaweed, showed that the incidence of peripheral neuropathy in patients with advanced CRC was not significantly different between a fucoidan-treated group and an untreated control group [32].
Three studies investigated the effect of vitamin E (400 mg) on CIPN and found no significant differences between oral administration of vitamin E and placebo [19,20] or an untreated control group [21]. Contradicting results were found in relation to the effects of the antioxidant alpha-lipoid acid (ALA). In a study by Gedlicka et al. [22], 7 patients suffering from grade II CIPN and 1 patient presenting grade III CIPN showed improvement of at least one grade. In contrast, Guo et al. [23] found no significant differences between ALA and placebo. Another antioxidant, -acetylcysteine, was shown to have beneficial effects in patients undergoing oxaliplatin chemotherapy by reducing the incidence of CIPN, as well as by reducing neurophysiological changes during the course of treatment [24].
Finally, supplementation of the amino acid glutamine in patients undergoing oxaliplatin chemotherapy for metastatic CRC resulted in reduction of grade I and II CIPN following two cycles of therapy and reduction of grade III and IV CIPN after four and six cycles [33]. Patients also reported less CIPNrelated interference of their daily activities (7.1% interference for patients receiving glutamine versus 40.9% interference for control patients) [33].
(II) Physical Activity. Evidence supporting a role of physical activity in alleviating CIPN symptoms was scarce; only two studies were identified. According to a cross-sectional study by Mols et al. [3], CRC survivors who reported to meet the recommended Dutch physical activity guideline of 150 minutes of moderate-to-vigorous physical activity per week also reported less CIPN symptoms. Furthermore, a small single-arm trial on the effectiveness of strength and balance training for CRC patients, who had finished their chemotherapy treatment, showed improved balance and lower extremity strength after four weeks of biweekly 60-minute training sessions, as well as improved neuropathic symptoms [34].
(III) Alternative (Complementary) Therapies. Some evidence was found for the use of complementary therapies to manage neuropathic symptoms, such as acupuncture. A small pilot study by Ogawa et al. [36] reported improved neuropathic symptoms after 4-6 sessions of contact needle therapy (traditional acupuncture). Another small study observed that acupuncture improved nerve conduction velocity in mixed cancer patients, including CRC, with CIPN [37]. Similarly, a case series of 10 patients receiving traditional Chinese acupuncture showed significant amelioration of CIPN symptoms, as well as lowered incidence of CIPN and reduction of symptom mitigation [38]. A further study tested the effects of Scrambler therapy in patients with CIPN, a method of cutaneous nerve stimulation that aims to relieve pain by providing "nonpain" information to block the action of pain stimuli [35]. Statistically significant improvements were observed in pain perception, motor and sensory scales, and interference with life scores [35].
(IV) Multiple/Other Strategies. A single cross-sectional study was identified which described multiple self-management strategies applied by stage III-IV CRC patients in order to minimize neuropathic symptoms [11]. A variety of strategies were mentioned by participants, including use of dietary supplements (e.g., B vitamins, ALA, and glutamine), over-thecounter medications (e.g., nonsteroidal anti-inflammatory drugs), and nonpharmacological strategies such as avoiding cold/keeping warm, massaging/rubbing affected areas, and various types of physical activity or exercise (e.g., walking, biking, or yoga) [11]. However, since only qualitative data analyses were performed in this study, no significant relief effects of the reported self-management strategies could be shown.

Discussion
Currently, there are no established treatments for CIPN. This systematic literature review aimed to identify lifestylerelated factors that could potentially empower CRC patients to decrease the risk of developing CIPN and/or reduce CIPN symptoms, thereby reducing the impact of CIPN on their daily functioning and quality of life. Although 22 eligible studies were identified that described a number of lifestyle-related factors, no conclusive evidence was provided regarding any particular factor. Nevertheless, the findings of this review may offer clues for potentially relevant lifestyle factors that could be further explored in future studies.
There is some weak evidence pointing to beneficial effects of herbal extracts or supplements for managing or preventing CIPN in CRC. In general, most evidence points to traditional medicines, such as GJG, as possible management options for CIPN symptoms [25][26][27]29]. This evidence is further supported by animal studies suggesting that GJG may prevent cold hyperalgesia and mechanical allodynia without adversely affecting the antitumor effect of oxaliplatin on tumor cells [39]. However, one study also showed negative effects of GJG on neuropathy [28] and the majority of studies reviewed were limited by design, such as having small sample sizes, and results were difficult to compare because of the use of different methods to measure CIPN. Therefore, the results of these studies should be interpreted with caution. Regarding the discrepancy across articles with regard to the method of measuring CIPN, it is important to note that toxicity scales can vary in the way they score symptoms. A change from "grade II to grade I" CIPN defined according to one scale may not be directly comparable to another study in which a change in CIPN is defined based on a different scale. For this reason, varying CIPN measurement methods may therefore explain why contradictory results have been observed in different studies on the same variable. This could, for instance, have been the case for the contradicting results regarding the effect of ALA on CIPN [22,23]. Furthermore, although questionnaires and self-reports are the preferred measure of CIPN [16], they can be highly susceptible to social desirability bias and be influenced by the ability of participants to accurately recall and estimate the level of past pain symptoms.
Besides the variation in measurement methods, there was a large variation in sample sizes of the reviewed studies. The largest study included 1,644 CRC survivors [3], while 7 out of the 22 articles reviewed reported findings of studies with less than 20 participants [22,24,32,34,[36][37][38]. As it is hardly possible to generalize the results obtained in studies with such small sample sizes, future studies in larger samples of CRC patients are needed. Furthermore, 7 articles reported results of studies in mixed cancer samples [19,20,23,30,[35][36][37]. Although these mixed cancer populations were included in this review since they also contained CRC patients, it is possible that the results of these studies reflected effects of the lifestyle factor of interest on CIPN in patients with cancers other than CRC. The reviewed articles also presented a large variety in study designs. Only 11 out of the 22 articles described results of randomized controlled trials, which would be the preferred design for evaluating effects of lifestyle factors on CIPN.
Though the evidence for a role of lifestyle-related factors in preventing and managing CIPN was weak in general, the results of this review may provide relevant leads for future research. Some areas of further research have already been mentioned, and a few others can be pointed out; especially some of the self-management methods described by patients themselves may warrant further investigation [11]. Factors of interest could be, for example, the use of NSAIDs or B vitamins to alleviate chronic CIPN symptoms. Other studies on CIPN, which did not meet the inclusion criteria for the present review, mentioned meditation, yoga, and Reiki [40], as well as gingko biloba and acetyl-L-carnitine supplementation [41,42], as possibly relevant lifestyle-related factors. Furthermore, although the studies reviewed did not find any relationship between vitamin E and CIPN in CRC patients treated with oxaliplatin, studies testing the efficacy of this micronutrient to reduce CIPN in cisplatin (a platinum compound similar to oxaliplatin) therapy have shown beneficial effects [43][44][45]. The relationship between vitamin E and CIPN should thus be studied further. In addition, the study by Lin et al. [24] offers a potentially promising treatment option warranting further investigation, as N-acetylcysteine naturally increases blood levels of glutathione, which is another antioxidant that has also been shown to possess neuroprotective qualities when administered intravenously during oxaliplatin therapy [46,47]. Moreover, the evidence that glutamine could help manage CIPN has been further supported by animal studies and intravenous administration of the amino acid [48,49]. Finally, it might be interesting to investigate the role of calcium and magnesium supplementation, as suggested by the findings of a case report [50] and also because some evidence exists regarding the role of calcium and magnesium infusions on platinum-related CIPN [51][52][53][54].
Somewhat unexpectedly, evidence regarding the role of physical activity on CIPN was found to be limited in CRC survivors. There is evidence that physical activity reduces CIPN in breast cancer patients, ovarian cancer patients, and patients with diabetic peripheral neuropathy [55][56][57][58][59]. For this reason, further studies in CRC survivors are highly needed to examine the effects of physical activity on CIPN, especially since physical activity can have beneficial effects on many health-related outcomes in CRC survivors. Moreover, although the evidence concerning CRC is limited, evidence suggests that acupuncture can reduce the symptoms of non-CRC CIPN, diabetic peripheral neuropathy, and neuropathic symptoms experienced by HIV-positive patients [60][61][62][63]. It could therefore be relevant to further investigate acupuncture treatments, as such traditional medicine might offer patients a drug-free coping mechanism for neuropathic pain. Lastly, animal studies have provided insight into other factors/ supplements which could be worth studying in CRC patients, such as curcumin, flavonoids, reduced poly-amine diets, and vitamin C, all of which have been found to decrease CIPN in mice models [64][65][66][67][68].

Conclusion
The results of this systematic review indicate that evidence regarding lifestyle-related factors and their potential for the prevention and management of CIPN is very limited. The studies identified in this review might suggest a possible role for supplements such as herbal extracts, physical activity, and alternative therapies such as acupuncture in the selfmanagement of CIPN. Further research with stronger study designs, larger samples, and uniform measures of CIPN is pivotal to confirm such claims.
Taken together, the studies reviewed are inconclusive regarding a possible role for lifestyle-related factors in the management of CIPN in CRC. Nevertheless, this systematic review can provide potential guidance for future studies concerning the role of lifestyle factors in the development and management of CIPN in CRC.

Disclosure
All authors have approved of the contents of the manuscript.

Conflicts of Interest
The authors report no conflicts of interest.