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

Table 1

General summary of articles included in the review.

Reference & country	Sample characteristics	Study design	Lifestyle factor	Exposure	Treatment	Measure of peripheral neuropathy	Summary of results
Dietary Supplement
Afonseca et al., 2013 [19]; Brazil	34 patients (18 male, 16 female) diagnosed with gastric cancer (8) or CRC (26); Average age: 56.6 y/o	Phase II, prospective, randomized, placebo-controlled pilot study	Antioxidant: vitamin E	400 mg of vitamin E or placebo orally administered twice daily, starting 5 days prior to treatment (length not specified), plus 1 g (each) of calcium gluconate and magnesium sulfate IV for 30 mins prior and following oxaliplatin infusion	FLOX, FOLFOX, EOX, or XELOX	Assessed by the NCI-CTCAE v3.0	No significant decreases in the incidence of acute oxaliplatin-induced PN in the experimental group compared to the control.
Kottschade et al., 2011 [20]; United States	207 patients (155 female, 34 male) scheduled to undergo curative-intent chemotherapy, including CRC patients	Phase III randomized-placebo controlled clinical trial	Antioxidant: vitamin E	400 mg of vitamin E (dl-alpha-tocopherol) or placebo twice daily (orally administered) starting 4 days prior to chemotherapy until 1 month after chemotherapy	Patients received either taxane (109 patients), cisplatin (8), carboplatin (2), oxaliplatin (50), or combination (20) chemotherapy	CTCAE v3.0. North Central Cancer Treatment Group (NCCTG), a diary and questionnaires (at baseline, prior to each treatment and at 1 and 6 months succeeding chemotherapy completion)	No significant differences between the experimental and control group.
Salehi and Roayaei, 2015 [21]; Iran	65 patients (41 male, 24 female) with CRC; Mean age: 56 y (vitamin E group, ) and 59 y (control, )	Randomized controlled clinical trial	Antioxidant: vitamin E	400 mg/day of vitamin E, starting within 4 days of the beginning of chemotherapy	FOLFOX4 regimen	Symptom experience diary questionnaire, completed at baseline and after sixth course of chemotherapy	No significant difference in mean peripheral neuropathy score changes between vitamin E and an untreated control group.
Gedlicka et al., 2002 [22]; Austria	15 CRC patients (11 male, 4 female); Mean age: 65 y	Pilot trial	Antioxidant: alpha-lipoic acid	600 mg of IV ALA, administered once a week for 3–5 weeks, followed by 600 mg of oral ALA until recovery from neuropathic symptoms, for a maximum of 6 months	130 mg/m^2 oxaliplatin in combination with 3 mg/m^2 of raltitrexed every 3 weeks; Patients received a median of 6 chemotherapy courses and a mean oxaliplatin (cumulative) dose of 780 mg/m^2	Unspecified peripheral neuropathy grading scale	Symptoms improved in 8 patients. The average treatment with ALA was 2 months and the mean response time was 4 weeks.
Guo et al., 2014 [23]; United States	247 cancer patients (176 CRC), 129 male & 118 female.; Mean age: 56 y	Randomized, double-blind, placebo-controlled trial	Antioxidant: alpha-lipoic acid	600 mg oral ALA, 3x daily, or placebo for 24 weeks during chemotherapy (except during the period between 2 days before and 4 days after chemotherapy)	Nonplatinum exposure, cisplatin < 399 mg/m^2 or oxaliplatin < 750 mg/m^2; cisplatin > 400 mg/m^2 or oxaliplatin > 750 mg/m^2	FACT/GOG-Ntx sub-scale, version 4, at baseline, 24, 36, and 48 weeks of treatment	Oral ALA administration was ineffective at preventing CIPN.
Lin et al., 2006 [24]; China	14 stage III colon cancer patients (9 male, 5 female) with a minimum of 4 lymph node metastases; Mean age: 60 y	Randomized, placebo-controlled pilot study	Antioxidant: N-acetylcysteine	1200 mg of oral N-acetylcysteine or placebo administered 1.5 hrs prior to chemotherapy treatment	Biweekly 85 mg/m^2 oxaliplatin + weekly 5-FU (425 mg/m^2) bolus and 20 mg/m^2 LV dose	Assessed every 2 weeks with the National Cancer Institute, common toxicity criteria (NCI-CTC); Patients examined electrophysiologically after 4, 8, and 12 cycles of therapy	Significantly reduced experience of CIPN for patients in experimental group. No electrophysiological changes in the experimental group.
Kono et al., 2011 [25]; Japan	90 patients (52 male, 38 female) with metastatic CRC.; Average ages: 62 (Group A), 61.5 (Group B), 63 (Group C), 64 (Group D)	Retrospective analysis of intervention study	Herbal extract (traditional medicine): Goshajinkigan (GJG or TJ-107)	7.5 mg/day of GJG administered orally before or in between meals in 2-3 doses during therapy; 1 g of IV Ca and Mg (each) prior to and after therapy (Groups B & C)	FOLFOX4 or FOLFOX6 regimens	Evaluations based on the Neurotoxicity Criteria of Debiopharm; Assessment of PN in relation to oxaliplatin (total dose) was based on Kaplan-Meier analyses	CIPN grade 1, 2 or worse occurred less regularly in Group A (chemotherapy + GJG), however the results were not significant. CIPN of grade 3 did not occur in any of the groups receiving GJG (Groups A and C).; GJG reduced toxicity in patients receiving oxaliplatin chemotherapy.
Kono et al., 2013 [26]; Japan	89 patients (48 male, 41 female) with histologically confirmed CRC; Mean ages of 67 y (experimental group) and 61 y (control)	Phase II, randomized, double-blind, placebo-controlled study	Herbal extract (traditional medicine): Goshajinkigan (GJG or TJ-107)	GJG powder (2.5 g) or placebo administered orally 3 times/day prior to meal starting on first day of oxaliplatin infusion for 26 weeks	FOLFOX4 or mFOLFOX6 regimens	Assessed at baseline and every two weeks until 8th cycle, succeeded by assessment every 4 weeks until week 26, according to NCI-CTCAE v3.0	Incidence of grade 2 or 3 oxaliplatin-induced PN was significantly lower in experimental groups compared to controls. GJG may serve to delay PN.
Nishioka et al., 2011 [27]; Japan	45 patients (22 male, 23 female) with advanced of recurrent CRC; Mean age: 67 y (experimental group) and 65 y (control)	Randomized, placebo-controlled study	Herbal extract (traditional medicine): Goshajinkigan (GJG or TJ-107)	7.5 mg/day of GJG or placebo administered orally before or in between meals in 2-3 doses during therapy	FOLFOX6	Patients assessed at baseline and prior to each treatment. CIPN evaluations were based upon the Neurotoxicity Criteria of Debiopharm (DEB-NTC)	Incidence of grade III CIPN was significantly lower in GJG group but there were no significant differences in grade I or II CIPN. The percentage of PN of grade II and III was lower in the experimental group compared to the control.
Oki et al., 2015 [28]; Japan	182 patients (99 male, 83 female) with resected stage III colon cancer.; Mean age: 62 y (experimental group, ) and 60 y (control, )	Randomized, placebo-controlled study	Herbal extract (traditional medicine): Goshajinkigan (GJG)	7.5 mg/day of GJG or placebo administered orally before or in between meals in 2-3 doses during therapy	FOLFOX6	Primary neuropathy assessed by NCI-CTCAE v3.0 (DEB-NTC was used for comparison) and by standardized questions regarding symptoms of neurotoxicity to classify grade (1–4)	Incidence of grade 2 or greater peripheral neuropathy was 50.6% in GJG group and 31.2% in control group. Time to onset of grade ≥ 2 sensory neuropathy was significantly less in GJG group (hazard ratio: 1.9, ).
Yoshida et al., 2013 [29]; Japan	29 CRC patients (17 male, 12 female); Mean age: 60.4 y	Retrospective analysis of intervention study	Herbal extract (traditional medicine): Goshajinkigan (GJG or TJ-107)	GJG powder (2.5 g) administered orally 3 times/day before or between meals	mFOLFOX6 or XELOX regimens	PN measured at the end of chemotherapy according to the CTCAE v.4	Significant difference between groups in regard to the deleterious effects of PN, with patients in the experimental group suffering from less deleterious PN. Furthermore, the incidence of grade III PN was lower in the experimental group compared to the control.
Yuan et al., 2006 [30]; China	31 patients (21 male, 10 female), 23 CRC and 8 gastric cancer.; Mean age: 58 y	Randomized, controlled, crossover trial	Herbal extract (traditional medicine): Jiawei Hiangqi Guizhi Wuwu Decoction (JHGWD)	One dose of JHGWD twice decocted in water (to 100 ml), then mixed (200 ml), and divided into two portions taken twice daily, starting at the beginning of chemotherapy until the 21st day of treatment (21-day cycles)	2 cycles of chemotherapy: Day 1; 130 mg/m^2 oxaliplatin (diluted in 500 ml of 5% glucose solution) IV solution; Days 1–5; 200 mg of IV LV and 500 g 5-FU	PN measured according to the World Health Organization Toxicity Criteria	Significantly stronger and longer neurotoxicity symptoms occurred in the control group compared to the experimental group (87.1% compared to 64.5%).
Liu et al., 2013 [31]; China	120 CRC patients (83 male, 37 female); Mean age: 52.5 y	Randomized, double-blind, placebo-controlled trial	Herbal extract (traditional medicine): guilongtongluofang	One dose of the extract once decocted in water to 100 mL and then to 200 mL Dose was then divided into two portions taken twice daily Administered 3 days prior to the start of each course of chemotherapy and continued for 10 consecutive days	6 cycles of FOLFOX4	Neuropathy assessed every 2 (completed) cycles using the NCI-CTC	CIPN significantly lower in the trial group after 2 and 6 cycles (significant difference in the onset of CIPN across groups). Furthermore, the cumulative incidence of grade I and sensory neuropathy was significantly lower in the trial group
Ikeguchi et al., 2011 [32]; Japan	20 patients (13 male, 7 female) presenting with advanced, unresectable CRC, or recurrent CRC.; Mean ages of 71.3 y (experimental) and 69.6 y (control)	Randomized, controlled trial	Herbal extract: fucoidan	150 ml/day of fucoidan solution (4.05 g fucoidan) for 6 months during chemotherapy	FOLFOX6 or FOLFIRI regimens	PN measured according to the World Health Organization Toxicity Criteria	No significant difference in incidence of peripheral neuropathy between fucoidan and untreated control group
Wang et al., 2007 [33]; Taiwan	86 patients (56 male and 30 female), with metastatic CRC	Randomized, controlled trial	Amino acid: glutamine	15 g of levo-glutamine administered orally twice daily for 7 consecutive days every 2 weeks beginning at the start of chemotherapy	85 mg/m^2 oxaliplatin on days 1 and 15, accompanied by 20 mg/m^2 of FA over 10–20 mins, succeeded by a 500 mg/m^2 5-FU bolus on days 1, 8, and 15 every 28 days	Patients assessed electrophysiologically at baseline and again after 2, 4, and 6 cycles of chemotherapy according to the (NCI-CTC)	Experimental group showed a lower percentage of grade I and II CIPN after two cycles, as well as a significantly lower incidence of grade III and IV CIPN after 4 cycles.
Physical activity
Mols et al., 2015 [3]; The Netherlands	1643 CRC cancer survivors (935 male, 708 female); Mean age: 66.7 y/o (chemotherapy group), 70.5 y/o (no chemotherapy group); Average years since diagnosis: 5.6 (chemotherapy group), 6.1 (no chemotherapy group)	Cross-sectional study	Exercise	Average time (hrs/weeks) spent walking, biking, housekeeping, gardening, and in sports	Details not available	EORTC QLQ-CIPN20	Chemotherapy resulted in a significantly larger number of patients reporting CIPN symptoms (despite physical activity). Patients meeting the recommended Dutch physical activity guideline of 150 mins/week of moderate to vigorous exercise reported significantly less CIPN.
Tofthagen et al., 2014 [34]; United States	4 (2 male, 2 female) CRC patients, having completed oxaliplatin-based chemotherapy 6 months prior to recruitment; Age: 80 y/o (participant 1), 66 y/o (participant 2), and 61 y/o (participant 3), age of fourth participant unspecified	Pilot, single-group intervention study	Exercise: strength and balance training	Biweekly, 60-minute sessions for 12 weeks; Session composed of 20 mins of strength training, 20 mins of balance training, 10 mins of stretching, and 10 mins of functional balance training	Oxaliplatin-based chemotherapy (exact treatment not specified)	CIPNAT and modified version of the Total Neuropathy Score Assessment occurred at baseline and at 4, 8, and 12 weeks	Peripheral neuropathy symptoms were significantly improved over time, according to the TNS. The mean scores for balance and strength also showed improvement over time.
Alternative (complementary) therapy
Coyne et al., 2013 [35]; United States	39 patients (16 male, 23 female) presenting CIPN (included CRC patients); Mean age: 56.5 y	Single-arm trial	Scrambler therapy	45-minute daily treatment for 10 consecutive days Stimulus increased to the max. bearable intensity	Patients received different chemotherapy regimens (including oxaliplatin, cisplatin, and carboplatin)	Pain Numeric Rating Scale and QLC-CIPN-20	Significant improvement of neuropathy found for patients suffering from low, average, and intense pain.
Ogawa et al., 2013 [36]; Japan	6 patients (3 male, 3 female) with CRC (5) or breast cancer (1); Mean age: 64.3 y	Single-group intervention study	Contact needle therapy (traditional acupuncture)	4–6 treatments (sessions, length of each not specified) in 3 months	All patients received oxaliplatin regimens expect for patient II, who received docetaxel and paclitaxel	Evaluated according to the CTCAE v.3 and by the FACT/GOG-Ntx	All patients showed improvement of PN symptoms.
Schroeder et al., 2012 [37]; Germany	6 patients (3 male, 3 female) presenting with colon cancer, lymphoma, and breast or bronchial cancer + 5 control patients (4 male, 1 female); Mean age: 64 y	Nonrandomized controlled pilot study	Acupuncture	Standard traditional Chinese medicine acupuncture guidelines were followed; 10, 20-minute sessions (treatments) over 3 months	Varied per patient/cancer: Colon: oxaliplatin, cisplatin; Breast: docetaxel/doxorubicin/; cyclophosphamide; Bronchial: cisplatin; Lymphoma: rituximab/fludarabin/; cyclophosphamide	Nerve conduction velocity (NCV) measured (with a Neuropack-Sigma) at baseline and once again at a 6-month follow-up	Nerve conduction velocity significantly improved in 5 of the 6 experimental patients, compared to one patient in the control group.
Valentine-Davis and Altshuler, 2015 [38]; United States	10 patients (5 male, 5 female) presenting with different stages of colon cancer; Mean age: 53 y	Retrospective case series	Acupuncture	Acupoints selected individually prior to each session During each session, stainless steel surgical-grade 1/2 to 1′′ (long) needles Needle retention time varied from 10 to 45 minutes (average of 20 mins); No electrostimulation performed	Different per patient; Some participants had already completed their courses of chemotherapy while others were still in treatment; Nevertheless, all participants underwent oxaliplatin-based chemotherapy	Measured according to the CTCAE v.4.0	All 10 participants showed improvement in CIPN symptoms (in regard to prevention and mitigation of symptoms). Acupuncture plans focused on increasing blood flow to distal points produced the best improvement.
Multiple/other
Tofthagen et al., 2013 [11]; United States	111 stage III-IV CRC; Age: >18 y/o	Mixed methods, descriptive, cross-sectional study	Multiple, varied per participant, including supplements (B vitamins, oral calcium and magnesium, omega-3 fatty acids, etc.), NSAIDs (acetaminophen, ibuprofen), acupuncture, massage, light therapy, exercise, and keeping warm/avoiding the cold	Details of exposure to lifestyle factors not available	Oxaliplatin-based chemotherapy (1–8 years prior to study, the average being 3 years)	Questionnaires, CIPNAT	Self-management strategies for alleviating peripheral neuropathy symptoms reported by participants included taking supplements/medications, avoiding cold/keeping warm, and various types of physical activity/exercise (e.g., walking, biking, and yoga).

IV: intravenous; LV: leucovorin; CRC: colorectal cancer; FOLFOX: folinic acid, fluorouracil, oxaliplatin; XELOX: oxaliplatin, capecitabine; Bev: bevacizumab; DOC: docetaxel, fluorouracil, cyclophosphamide, epirubicin; PAC: paclitaxel, cyclophosphamide, doxorubicin; PN: peripheral neuropathy; SOX: oxaliplatin, S-1; FOLFIRI: folinic acid, fluorouracil, irinotecan; NSAIDs: nonsteroidal anti-inflammatory drugs.