Effects of Integrative Approaches for the Management of Chemotherapy-Induced Peripheral Neuropathy in Colorectal Cancer Patients: A Systematic Review of Randomized Controlled Trials and Quasi-Experimental Studies.

Introduction
Colorectal cancer (CRC) is ranked as the third most prevalent cancer globally.1 According to the National Comprehensive Cancer Network (NCCN) guidelines, American Society of Clinical Oncology (ASCO) recommendations, and multiple large longitudinal studies, neoadjuvant or adjuvant oxaliplatin-based chemotherapy is recommended for patients with CRC, except stage I and low-risk disease, to reduce the mortality rate.2–7 Despite the benefits of oxaliplatin, it contributes to chemotherapy-induced peripheral neuropathy (CIPN) owing to the inflammation or degeneration of the peripheral nerves.8,9 Over 80% of patients with CRC experience acute CIPN symptoms, including cold-induced peripheral paraesthesia and muscle spasms during oxaliplatin-based chemotherapy.10,11 More than 50% of patients experience chronic CIPN symptoms such as tingling, numbness, and pain six months after chemotherapy cessation and nearly 25–84% experience continuous symptoms after three years.10,12,13
While not life-threatening, CIPN significantly affects daily activities and quality of life (QoL).9,14,15 Acute CIPN affects treatment efficacy, indicated by 22% requiring prolonged infusion, 15–34% needing dose reductions, and 6–21.4% leading to cessation of treatment, thus increasing the risk of chronic CIPN.16,17 Furthermore, chronic CIPN contributes to poorer psychosocial well-being and physical function. It is associated with increased fatigue, anxiety, depression, and reduced social engagement, adversely affecting work, community involvement, and recreational activities.8,18–20 A meta-synthesis indicates that CRC survivors perceive life as more challenging due to CIPN-induced changes, with increased fatigue and dissatisfaction with life changes reported.9,21 In addition, it exacerbates functional disabilities, increases postural instability and cautious walking patterns, reduces hand function, and contributes to a 30% increase in fall incidence.12,22–24
Effective management of symptoms, including CIPN, is essential for high-quality care in cancer survivorship and in the emerging survivorship-focused care models.25 ASCO guidelines and existing systematic reviews only recommended duloxetine as the pharmacological treatment for painful CIPN.26–29 However, the intolerance of side effects such as dizziness, giddiness, nausea, somnolence, restlessness, fatigue, and insomnia limits its use, with a dropout rate of approximately 25%.30 Pregabalin may be effective in improving neuropathic pain in cancer patients receiving oxaliplatin.31 However, a Phase III double-blinded RCT revealed that pregabalin did not improve chronic neuropathic pain in patients with CRC.32 Additionally, the side effects of pregabalin can include dizziness, weight gain, and oedema, which may also affect patient adherence to the medication.
Given the limitations of pharmacological treatments for CIPN owing to side effects and variable efficacy, it is necessary to explore integrative approaches, which are the non-pharmacological interventions encompassing complementary therapies and lifestyle interventions alongside with the conventional medicine to promote better health outcomes of symptom management and QoL in cancer patients receiving or received treatment,33–35 for managing CIPN in patients with CRC. Complementary therapies and lifestyle modification were proven to be effective in symptom management and improving QoL in cancer patients, in which those interventions were used alongside the conventional treatment,36–39 particularly for the management and prevention of CIPN.40,41 Recent systematic reviews have demonstrated that physical activities,28,42–44use of herbs,40,45 massage,46 acupuncture,28,43,47,48 neurofeedback,28 and behavioural and cognitive-behavioural therapies28 significantly improve symptoms of CIPN. However, these reviews included patients with various cancer types, such as breast, gynaecological, and gastrointestinal cancers, and most participants received taxane-based chemotherapy. Indeed, the presentations of oxaliplatin-induced peripheral neuropathy (OIPN) and taxane-induced peripheral neuropathy (TIPN) differ, despite being categorised as CIPN. Patients experience acute OIPN during the entire treatment period, whereas TIPN usually occurs in the first three days of each chemotherapy cycle. Chronic OIPN worsens after the completion of treatment for up to three months after treatment, and 25% of patients may perceive persistent OIPN for up to five years or more.12 In contrast, TIPN usually improves after the cessation of treatment.49,50 Furthermore, the tingling, numbness, and pain over the lower extremities may last for more than one year in patients experiencing OIPN, contributing to the increased risk of balance problems.50 Therefore, the needs of patients with CRC experiencing OIPN are unique. In addition, the existing reviews included studies examining interventions for the prevention of CIPN instead of focusing on the management of CIPN. Derken et al conducted a systematic review of the potential lifestyle modifications for preventing and managing OIPN in patients with CRC; however, the inclusion of single-arm studies and studies on the preventive measures of OIPN did not provide conclusive findings regarding the effective management of OIPN in patients with CRC.41 Therefore, the findings of the current review may not specifically address the effective management of OIPN in patients with CRC receiving oxaliplatin-based chemotherapy. Therefore, this systematic review aimed to (1) assess the effects of various integrative approaches on CIPN in patients with CRC; (2) examine the intervention effects on QoL, pain, and gait balance, and (3) investigate any adverse effects associated with these interventions.

Methods
This review adhered to the reporting guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement in 2020.51 The review protocol was prospectively registered in PROSPERO under the registered ID: CRD42025644115.

Search Sources and Strategies
Electronic databases, including Web of Science, Cochrane Library, PubMed, MEDLINE, CINAHL, APA PsyINFO, AMED, and CNKI, were systematically searched from inception to 18th January 2025 to identify eligible studies. Additionally, the literature search included citation searching and incorporation of grey literature. Reference lists from relevant systematic reviews28,40–42,44,46–48 were also examined to identify potentially relevant studies. According to the National Centre for Complementary and Integrative Health and Society for Integrative Oncology, the common integrative approaches include the use of special diets, dietary supplements, herbs and probiotics, massage, spinal manipulation, manual therapies, heat or cold therapies, psychological interventions, mindfulness, spiritual practices, psychotherapy, mediation, relaxation therapies, art, dance, acupuncture and exercise.33,35 Therefore, those keywords and relevant terms were used in the literature search. According to guidelines in the Cochrane Handbook, search terms were based on the “PICO” framework: population, intervention, control and outcomes.52
Table 1 lists all search terms that were used in all databases. The detailed search strategies and results for all databases are reported in Supplementary Table 1.

Eligibility Criteria
The selection of articles was based on the following inclusion and exclusion criteria:

Population
Participants who had CRC at any stage, were diagnosed with CIPN/ OIPN, and had received or were currently receiving oxaliplatin were included. The inclusion criteria were also extended to studies that did not specify the level of OIPN before intervention, while the non-pharmacological interventions commenced post-initiation of the first oxaliplatin cycle. Approximately 90% of patients with CRC exhibit at least one symptom of acute OIPN following their initial cycle of oxaliplatin-based chemotherapy.17,53 That means patients with CRC experience OIPN at baseline before the intervention. Studies encompassing various cancer types were included only if patients with CRC constituted at least 50% of the sample or a subgroup analysis for these patients with CRC was reported. Studies were excluded if participants had pre-existing non-chemotherapy-induced peripheral neurological impairments, including conditions such as sciatica, diabetes, peripheral vascular disease, alcohol-induced neuropathy, drug-induced neuropathy, and other neurological disorders.

Intervention
All studies with integrative approaches, including complementary interventions or lifestyle modifications, delivered via different modalities, were selected, while studies investigating integrative interventions with the pharmacological management of OIPN were excluded.

Comparison
The comparison groups consisted of either usual care, such as educational leaflets or basic education on OIPN management; no intervention; waitlists; or active alternative interventions.

Outcomes
The primary outcome of this review was the presence of CIPN/ OIPN. Eligible studies should assess CIPN/ OIPN as a primary or secondary outcome, evaluating either general or specific aspects such as sensory or motor neuropathy levels, peripheral sensitivities, functional impacts, and symptoms. Secondary outcomes included pain, balance or gait issues, QoL, and adverse events.

Study Design
Two-arm experimental studies, such as randomized controlled trials and quasi-experimental studies were included in this review. Studies included in this review were required to be published in English or Chinese, and peer-reviewed. Exclusion criteria encompassed observational studies, qualitative studies, studies reporting secondary data analyses, theses, conference abstracts, study protocols, book chapters, case studies, or studies involving non-human subjects.

Data Extraction
Data extraction was conducted independently by two reviewers (KYL and YYC) using a standardised form to gather comprehensive information, including authors, publication year, study design, participants’ demographics (age, gender), cancer types and stages, baseline CIPN severity, sample size, setting, intervention details, outcomes, and results. Disagreements regarding data extraction were resolved by consulting with a third reviewer (LJL).

Methodological Quality Appraisal
Two reviewers (KYL and YYC) independently assessed the methodological quality of the included studies using the Effective Public Health Practice Project (EPHPP) tool,54 which evaluated six domains: selection bias, study design, confounders, blinding, data collection methods, and withdrawals/dropouts. Each domain was rated as “strong”, “moderate”, or “weak”. A study was deemed “strong” if no domains were rated as “weak”, “moderate” if one domain was “weak”, and “weak” if two or more domains were “weak”. Disagreements regarding the quality assessment were settled by consulting a third reviewer (LJL).

Data Synthesis
Owing to the heterogeneity of the interventions in this systematic review, narrative synthesis was conducted instead of a meta-analysis. Efficacy indicators, specifically the between-group effect size (Cohen’s d) for all continuous outcomes at postintervention and follow-up, were extracted. In cases where direct effect size data were unavailable for randomised controlled trials, the effect size was calculated using the following formula: d = (M1- M2)/SDpooled, where M1 and M2 represent the means of the outcomes in the experimental and control groups, respectively, and SDpooled is the pooled standard deviation of the outcomes from both groups.55,56 Effect sizes were interpreted as small (Cohen’s d, d = 0.2), medium (d = 0.5), or large (d = 0.8).57 Statistical analysis using Review Manager 5.4 was performed for those interventions with two or more RCTs with moderate to strong quality. Statistical significance was set at p<0.05. Continuous data were analysed using the mean difference (MD) and standard mean difference (SMD), also with 95% CI. Heterogeneity was assessed based on both the chi-squared test and the I2 statistic. The classification of observed effects based on timing was as follows: “immediate” effects were identified if the outcomes were evaluated immediately after the completion of the intervention or between week 0 and week 4 post-intervention. “Short-term” effects referred to those assessed between four and 12 weeks post-intervention, while “long-term” effects were measured more than 12 weeks after the intervention.

Certainty of Evidence
The certainty of evidence for the outcomes was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE).58 There were five criteria to consider when assessing the overall certainty of evidence: risk of bias, inconsistency, indirectness, imprecision and publication bias. The overall certainty was categorized as either very low, low, moderate or high.

Results

Study Selections
A total of 1914 records were recorded during the initial search. After removing duplicates and screening the titles and abstracts, 50 articles were included in the full-text reading phase. Subsequently, 37 studies were excluded based on the following criteria: (1) less than 50% of the study samples comprised patients with CRC or those without CIPN (number of studies, n=11), (2) wrong study design (n=18), and (3) irrelevant outcome measurements (n=1). Finally, 13 studies were included in this systematic review.59–71
Figure 1 shows a PRISMA flowchart for study selection.

Characteristics of Included Studies
Table 2 summarises the characteristics of the included studies, published between 2011 and 2024. Among the reviewed studies, nine studies employed RCTs,59–62,64,66,69,71 while the remaining four utilised quasi-experimental designs.63,65,67 Six of them were pilot studies.59,60,65,66,69,70 The included studies were conducted in various countries or regions, including Europe (Germany, n=1; Sweden, n=1), North America (USA, n=2; Canada, n=1), East Asia (China, n=1; Korea, n=1; Japan, n=2), and the Middle East (Turkey, n=3; Iran, n=1).

Characteristics of Participants
In total, 638 participants with gastrointestinal cancer were included in this review. Approximately 90% of them were patients with CRC. The proportion of male participants and female participants was similar (49.1% vs. 50.9%). The median proportion of patients with CRC in studies with various gastrointestinal cancers was 78.3% (Interquartile Range, IQR=14.85%).60,61,63,65,66 Twelve studies involved participants undergoing treatment.59–69,71

Characteristics of Interventions
Six studies examined different types of exercise programs, including multimodal exercise (n=3),64,70,71 hand-foot exercise (n=1),61 and aerobic exercise (n=2).63,66 The duration of the multimodal exercise interventions varied from six to 12 weeks, with sessions held two to four times per week.64,70,71 The Hand-foot exercises were suggested for eight weeks with a frequency of at least three days per week.61 Aerobic exercises were conducted over two to eight weeks, with a frequency of three to five times per week.63,66 When commencing the exercise programs, two studies incorporated nurse-led interventions guided by theoretical frameworks such as motivational interviewing66 and information-motivational-behavioural-skills models,64 which aim to enhance exercise motivation, adherence, and self-efficacy in cancer patients.72–75 All exercise interventions were supervised by nurses or exercise specialists except in one study.62
Furthermore, the other seven studies examined the effects of acupuncture (n = 1), use of herbs (n=2), massage therapies (n = 2), henna (n = 1) and therapeutic ultrasound (n= 1) for CIPN. One study investigated the effects of five weekly sessions of genuine acupuncture administered by registered personnel.69 Two studies examined the effect of Goshajinkigan, a Japanese herb, on the improvement of CIPN during treatment.67,68 Two studies assessed the impact of massage therapies, specifically aromatherapy massage and foot reflexology, on acute CIPN,62,65 with intervention durations ranging from four to six weeks and frequencies of one to three times per week, conducted by qualified professionals. The study on aromatherapy massage applied the Theory of Unpleasant Symptoms to explain concurrent symptoms with CIPN and to guide nursing interventions targeting influencing factors.76–78 One study tested the use of henna application during chemotherapy days for durations of eight to ten hours across two chemotherapy cycles to address acute CIPN.60 Another examined the effects of a two-week therapeutic ultrasound intervention on chronic CIPN.59

Characteristics of Comparators
Usual care, waitlist, and active control groups were adopted as interventions for the control groups in the reviewed studies. Among the six studies assessing the effectiveness of physical activity on CIPN, three employed written pamphlets detailing CIPN and exercise recommendations for the control groups.64,66,71 Other studies provided usual care,61,63 or varied exercise intensities70 to their control groups. In a study examining acupuncture, the control group received sham acupuncture.69 Participants in the control group received usual care or infusion of Ca/Mg in studies examining the effect of Goshajinkigan.67,68 Studies investigating the effects of massage and henna primarily adopted usual care as the control intervention.60,62,65 Written exercise information was provided to the control group in the study examining therapeutic ultrasound.59

Outcomes and Instruments
Most studies measured outcomes before and immediately after the interventions,59–66,69–71 while three studies investigated the short-term effect, in which outcomes were measured within 12 weeks after the cessation of the interventions.59,65,71 One study adopting genuine acupuncture measured the outcomes before and after each session of acupuncture instead of before and after the completion of the entire program.69 Studies investigating the effect of Goshajinkigan measured the CIPN intensity after the intervention only.67,68

Chemotherapy-Induced Peripheral Neuropathy
Most studies assessed CIPN using self-report measures (N =10). The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group—Neurotoxicity (FACT/GOG-Ntx),59,63,71 The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-CIPN 20)59,62,66 and the Chemotherapy-induced Peripheral Neuropathy Assessment Tool (CIPNAT)60,61,64 are commonly adopted. Other self-reported measures included Neuropathy Total Symptom Score-6 (NTSS-6),70 Utah Early Neuropathy Scale,70 Common Terminology Criteria for Adverse Events (CTCAE),68 Visual analogue scales of neuropathic pain and unpleasant sensation69 and Douleur Neuropathique 4 questions.65 One study measured the frequency of peripheral neuropathy instead of using the self-reported measures.67 Functional tests and sensory tests were adopted to evaluate CIPN in two studies.59,63 Two studies utilized both self-reported measures and sensory tests for the measurement of CIPN.59,63

Quality of Life
Six studies used self-reported measurement tools to assess the QoL. Four studies utilized the European Organization for the Research and Treatment of Cancer QLQ-Core 30 (EORTC QLQ-C30).61,62,64,66 One study also adopted the European Organization for the Research and Treatment of Cancer QLQ-Colorectal cancer (EORTC QLQ-C29) for the measurement of QoL together with EORTC QLQ-C30.60 Other studies adopted Euro-QoL VAS69 and FACT-G subscale in FACT/ GOG-Ntx.59

Balance
Three studies reported balance problems using different measurements, including GGT-Reha,71 Short Physical Performance Battery (SPPB),70 modified clinical test of sensory interaction on balance, and single-leg test.59

Pain
Three studies evaluated pain using the Brief Pain Inventory (BPI)63 and Numeric Rating Scale (NRS)61,65 in patients with CRC and CIPN.

Quality of the Included Studies
Table 3 shows the methodological quality ratings of the included studies evaluated using the EPHPP criteria. Three studies were rated as “strong”;62,66,71 three studies were rated as “moderate”;59,60,64 and seven studies were rated as “weak”61,63,65,67–70 in overall quality. A low participation rate contributed to a “weak” rating in “selection bias” in four studies.61,63,69,70 All randomised controlled trials were rated as “strong”;59–62,64,66,69–71 and four quasi-experimental studies were rated as “weak” in study design.63,65,67,68 For the “confounder” domain, the low percentage of controlled confounders and unclear information about the differences in baseline characteristics between groups contributed to a “weak” rating in two studies.69,70 Eight studies with participants not being blinded were rated as “weak” in the “blinding” domain.59–61,63–65,67,68 Most studies received the “strong” rating in the “data collection” domain as the measurement tools were reliable and valid.59–66,68–71 The lack of reporting of the dropout reasons and the dropout rate contributed to the “weak” rating in two studies in the “withdrawal” domain.63,67,68

Intervention Effects
Table 4 summarizes the effects of integrative approaches on the primary outcome (CIPN) and the secondary outcomes.

Intervention Effects on Primary Outcome—CIPN/OIPN

Multimodal Exercise
Multimodal exercise, which consisted of endurance, strength, balance, and flexibility exercises, demonstrated consistent and significant improvement in OIPN symptoms and OIPN interference in patients with CRC.64,70,71 A fixed-effects model was used for the statistical analysis because there was no significant heterogeneity (Chi-square= 1.57, p=0.21, I2=36%, Figure 2). Compared to control groups receiving booklet education, multimodal exercise demonstrated a significant pooled effect for the improvement of CIPN symptoms and interference, regardless of the delivery modality (random-effect model, SMD= −0.71, 95% CI −1.36, −0.07, p=0.03).64,71 The certainty of evidence was downgraded to low due to serious risk of bias and imprecision from the small sample size. (Table 5). An eight-week multimodal exercise program demonstrated a sustainable effect with moderate effect size (ES=0.58; p=0.31) lasting up to four weeks.70 A study investigating the effect of high-intensity training with multimodal components on OIPN in patients with CRC demonstrated greater improvement in neuropathy symptoms than those in the moderate-intensity aerobic exercise group; however, no statistical significance analysis was performed due to the small sample size and poor methodological quality.70 This study was not included in the pooled effect size calculation due to the overall weak quality of quality assessment.

Hand-Foot Exercise
One study suggested that an eight-week hand-foot exercise program demonstrated significant improvement in OIPN symptoms in patients with CRC compared with the control group receiving usual care (ES= 194; P<0.001).60

Aerobic Exercise
Aerobic exercise programs did not demonstrate significant improvement in self-reported OIPN.63,66 An eight-week MI-walk intervention did not improve the sensory OIPN and motor OIPN compared with patients receiving written pamphlets about exercise recommendations (p>0.99).66 Additionally, another study found that patients with CRC receiving two-week rehabilitation exercise showed significant worsening of neuropathy (p<0.05) compared with patients receiving usual care.63 However, the rehabilitation exercise program was demonstrated to have significant immediate improvement of OIPN interference, for example, the 6-hole shirt test (ES=1.081, p<0.05), walking 50 steps test (ES= 0.936, p<0.05), and coin test (ES= 0.72, p<0.05) compared with usual care.62

Use of Herbs
The use of Goshajinkigan (7.5 mg) per day along with oxaliplatin-based chemotherapy reduced the worsening of acute OIPN symptoms in patients with CRC. Two studies suggested that patients with CRC receiving Goshajinkigan experienced less frequent OIPN symptoms and deterioration of OIPN compared with the control group receiving chemotherapy alone (p<0.05).67,68 Furthermore, the combination of Goshajinkigan and infusion of Ca/Mg did not demonstrate any significant between-group differences in the frequency of OIPN symptoms.68 In terms of the curative, effective, and stabilising management of OIPN symptoms, there was no significant effect in patients with CRC receiving Goshajinkigan compared with those receiving usual care (p>0.05).67

Acupuncture
One study investigated the immediate effects of genuine acupuncture on acute OIPN, finding significant improvement in facial pain (ES= 0.371, p =0.018) and unpleasant facial sensations (ES= 0.35; p =0.036) among patients with CRC compared to those receiving sham acupuncture.69 However, no significant changes were observed in hand pain (p =0.461), foot pain (p =0.431), or unpleasant foot sensations (p =0.189).69 Contrary to expectations, sham acupuncture resulted in significantly better improvement in unpleasant hand sensations (p =0.002) compared to genuine acupuncture.69 The study did not assess the short-term effects of OIPN.

Massage Therapy
Two studies examining massage therapies demonstrated immediate and significant improvement in acute OIPN in patients with CRC.62,65 A four-week foot reflexology improved the sensory (ES=0.58, p=0.01), motor (ES=0.49, p=0.031) and autonomic (ES= 0.48, p=0.034) aspects of OIPN compared with usual care.62 Additionally, patients with CRC receiving a six-week aromatherapy massage perceived significant improvement in OIPN symptoms (p<0.05) compared to those receiving usual care.65 However, the effects did not sustain (p>0.05) two weeks after the completion of the intervention.

Henna
One study reported that patients with CRC receiving oxaliplatin experienced significant improvements in overall peripheral neuropathy symptoms (p <0.05, Effect size: np2 = 0.160), sensory symptoms (p <0.05, np2 = 0.17), fine motor function (p =0.001, np2 = 0.142), general activity (p <0.05, np2 = 0.269), and interference (p <0.05, np2 = 0.284) following a four-week henna application compared to usual care.60 However, no significant improvement was observed in motor symptom subscales (p =0.344).60 The study did not assess the short-term effects of CIPN.

Therapeutic Ultrasound
One study demonstrated the mixed effects of therapeutic ultrasound on chronic OIPN in patients with CRC.59 Compared with patients with CRC receiving pamphlets about exercise recommendations, patients had significant improvement in overall neuropathy symptoms measured by FACT/GOG-Ntx (ES= 0.594, p=0.012), neurotoxicity symptoms (ES= 0.789, p=0.003) and sensation of upper extremities vibration (ES= 0.241, p=0.03) after the two-week therapeutic ultrasound, however, there were no significant impacts of neuropathy severity measured by EORTC QLQ CIPN-20 (p>0.05) and sensation of temperature (p>0.05) and lower extremity vibration (p>0.05).59 The sustainable effects on all OIPN aspects were not significant four weeks after the intervention (p>0.05).59

Intervention Effects on Secondary Outcomes

Quality of Life
Five studies examined the effects of exercise, massage and acupuncture on the QoL.61,62,64,66,69 Multimodal exercise, hand-foot exercise, massage, and acupuncture demonstrated potential benefits on QoL in patients with CRC with OIPN.61,62,64,68 The app-based multimodal exercises significantly improved the QoL (ES= 1.266, p=0.003) among non-metastatic CRC patients.64 Patients with CRC receiving hand-foot exercise perceived significant improvement in QoL by using EORTC-QLQ C30 (ES=0.89; p<0.05) compared with the control group receiving usual care, while there was no significant between-group effect demonstrated by using EORTC-QLQ CR29 in which the measurement focused more on the lower anterior resection of rectum symptoms, stoma care and sexual interests.61 However, there was no significant effect of MI-walk, which is an aerobic exercise, on QoL in patients with advanced CRC (p>0.99).66 Apart from exercise, the reflexology improved the QoL in different aspects, including functional status (ES= 1.00, p<0.001), symptom management (ES=1.5, p<0.001) and global health status (ES=1.26, p<0.001) compared to usual care.62 The improvement of QoL was also demonstrated in patients with CRC receiving acupuncture (MD 10 vs 2),69 however, no statistical analysis on this measure was presented. However, therapeutic ultrasound demonstrated no significant impact on QoL in weeks 2 (p=0.09) and 6 (p=0.8) in the comparison between the two groups.59

Balance
Three studies examined the effects of exercise interventions and therapeutic ultrasound on the improvement of balance in patients with CRC with OIPN.59,70,71 Compared with therapeutic ultrasound, exercise programs improved the balance problem in patients with CRC experiencing OIPN.70,71 The eight-week multimodal excise improved the balance on an unstable surface (ES=0.801, p=0.025) among patients with advanced CRC receiving oxaliplatin together with a sustainable effect 4 weeks after intervention (ES=0.644, p=0.025), compared with waitlist group.71 MICE demonstrated greater improvement in balance than HIIT (MD 0.8 vs 0.00).70 Yet, therapeutic ultrasound had no significant impact on balance in patients with CRC experiencing CIPN between groups immediately after the intervention or in the short-term (p>0.05).59

Pain
Three studies showed the positive benefits of exercise and massage in the management of pain for patients with CRC experiencing OIPN.61,63,65 The two-week rehabilitation exercise program reduced pain (ES=0.435, p<0.05) among patients with CRC experiencing OIPN compared to those receiving usual care.63 Furthermore, the eight-week hand foot exercises improved pain significantly (ES=2.04; p<0.001).61 In addition to exercise, aromatherapy massage significantly reduced pain in patients with CRC receiving chemotherapy (p<0.05) compared with usual care; however, the effect did not sustain two weeks after aromatherapy massage (p>0.05).65

Adverse Effects
Three studies examined whether there were any adverse effects of the interventions.65,69,71 Patients receiving genuine acupuncture reported the side effects of bleeding (10%), tiredness (20%), dizziness (9%), and pain (6%).69 Another two studies reported aromatherapy massage and multimodal exercise had no adverse effects on participants during the studies.65,71

Discussion
This review aimed to assess the effects of integrative approaches on OIPN, QoL, pain, and balance and to investigate the adverse effects of these interventions in patients with CRC. Finally, 13 studies were included in this review. This review highlights the potential efficacy of multimodal exercise in managing CIPN/ OIPN, pain, balance problems, and QoL in patients with CRC.64,70

Intervention Effects on CIPN/ OIPN
This review suggests that multimodal exercise may provide short-term benefits for OIPN in patients with CRC.64,70,71 This review, along with others,79–81 suggests a positive impact of multimodal exercise interventions on both acute and chronic CIPN. The potential mechanisms underlying the efficacy of multimodal exercise may involve both the biological and psychophysiological pathways. Multimodal exercises that combine endurance, resistance, and balance training offer several benefits. Endurance exercise has been shown to mitigate neuropathy by improving mitochondrial function, promoting anti-inflammatory effects, increasing neurotrophic factors, enhancing blood flow, and stimulating the release of endorphins.82,83 Additionally, resistance and balance exercises increase brain-derived neurotrophic factors, which help prevent axonal degeneration and reduce neuropathic impairment.84,85 Given that the long-term effects of multimodal exercise have not been examined in previous studies, further research is necessary to evaluate its sustained efficacy in patients with CRC.
Compared to multimodal exercise, aerobic exercise alone did not demonstrate significant effects for managing OIPN in this review.63,66 Previous reviews and meta-analyses reported that exercise with multiple components is more effective than aerobic exercise alone for the management of OIPN in cancer patients,79–81 however, subgroup analysis of the effect of various types of exercise was not conducted. Although one study included in this review reported improvements in functional performance, as measured by tasks such as the 6-hole peg test, 50-step walking test, and coin test,63 the short duration of the intervention (two weeks) and the lack of detailed information regarding data collection time points introduce uncertainty as to whether these improvements can be directly attributed to aerobic exercise. The performance of these functional tests may have been influenced by the timing of oxaliplatin infusion, as patients with CRC often experience severe OIPN symptoms during the first seven days following infusion.11,86 Therefore, future studies should carefully consider the timing of data collection to minimise potential confounding factors.
Hand-foot exercise demonstrated positive outcomes of CIPN in patients with CRC.61 It is an exercise targeting the peripheral nerve region of the extremities to improve OIPN.61 The effects of hand-foot exercise were further supported by positive outcomes in another RCT on breast cancer patients experiencing CIPN.87 However, the limitations of available studies, especially in patients with CRC, may need further research to conclude the effectiveness of hand-foot exercise in patients with CRC experiencing OIPN.
This review suggested that Goshajinkigan was effective in the prevention of worsening OIPN in patients with CRC receiving chemotherapy; however, there was no significant reduction in the intensity of OIPN.67,68 Another systematic review and meta-analysis has also demonstrated that Goshajinkigan has prophylactic effects on CIPN during treatment instead of reducing the severity of CIPN.88
While this review has also suggested the potential benefits of other integrative interventions, such as massage therapies and the application of henna, for the management of OIPN in patients with CRC, the evidence for these interventions is uncertain due to the lack of existing reviews and the limited number of studies. The included studies have demonstrated the efficacy of aromatherapy massage and foot reflexology in the relief of acute OIPN in patients with CRC.62,65 Although the included studies62,65 and current primary studies89,90 have supported the improvement of CIPN by massage therapies through the improvement of oxygenation and blood flow to tissues and the release of hormones associated with analgesia,91 the lack of reviews and the heterogeneity of studies may not show promising evidence for the management of OIPN among patients with CRC. Furthermore, the included study60 is the only study investigating the efficacy of henna for OIPN, underscoring the need for further research to validate these initial findings.
The efficacy of therapeutic ultrasound for managing OIPN in patients with CRC remains uncertain due to inconsistent findings and the limited number of available studies, as highlighted in this review.59 The self-reported CIPN symptoms varied depending on the measurement tools and neurological assessments used, which diminishes the reliability of the positive effects of therapeutic ultrasound observed in patients with CRC experiencing OIPN.59 Furthermore, no other studies have specifically examined the efficacy of therapeutic ultrasound for CIPN in patients with cancer, underscoring the need for further research to clarify its potential benefits.
Similarly, this review, along with the limited available evidence, suggests that acupuncture may not be an effective treatment for OIPN in patients with CRC. While acupuncture has shown some benefit for facial neuropathy, OIPN in patients with CRC primarily affects the limbs, making this treatment less applicable.69 Additionally, sham acupuncture or “pseudoacupuncture”, demonstrated significant effects in the hands,69 which may indicate that the observed improvements in neuropathy are not directly attributable to acupuncture. A systematic review and meta-analysis further supported this conclusion, showing no significant pooled effect of acupuncture on CIPN in patients with cancer (p = 0.1).92 Therefore, acupuncture may not be effective in managing CIPN in patients with CRC.

Intervention Effects on QoL
The efficacy of multimodal exercise64 and hand-foot exercise61 on the improvement of QoL in patients with CRC experiencing OIPN has been supported by the included studies as shown in this review; however, aerobic exercise alone did not demonstrate any significant impact on QoL improvement.66 This finding is consistent with the results of a systematic review and network meta-analysis, which showed that the combination of strength and balance exercises in a home-based setting has the greatest improvement in QoL in cancer patients with CIPN.93 Multimodal exercise appears to improve QoL in cancer patients experiencing CIPN by directly improving neuropathy itself. Additionally, this review suggests that acupuncture and massage therapies may improve QoL in patients with CRC experiencing acute OIPN.62,69 A systematic review also showed a positive effect of acupuncture on QoL in cancer patients.91 While acupuncture reduces neuropathic pain, thereby potentially enhancing QoL; its direct impact on CIPN remains unconfirmed. Conversely, a review indicated that massage therapies might not effectively relieve suffering or improve QoL in advanced cancer patients.94 Further research is necessary to elucidate the efficacy of these therapies in improving QoL in patients with CRC experiencing OIPN.

Intervention Effects on Balance Problem
Exercise interventions have shown promising evidence for improving balance in patients with CRC experiencing OIPN, as observed in this review.70,71 These findings align with a meta-analysis which demonstrated that cancer patients in exercise intervention groups had significantly better balance than those in control groups.79 The included study71 further suggested that a multimodal exercise program produced a sustained short-term improvement in advanced balance tests among patients with CRC experiencing OIPN. Exercise enhances muscle strength in the lower extremities, which likely contributes to improved balance.95 However, the long-term effects of exercise interventions on balance, particularly in patients with CRC, have not been explored in the included studies or previous reviews. Further research is necessary to assess the long-term efficacy of exercise interventions to address the balance issues in patients with CRC experiencing OIPN. In contrast, this review found no evidence suggesting that therapeutic ultrasound has any effect on improving balance in patients with CRC experiencing OIPN in the study.59 Additionally, there are currently no studies indicating that therapeutic ultrasound improves balance or posture in cancer patients. Future studies should investigate the potential role of therapeutic ultrasound in addressing balance problems in patients with CRC who experience OIPN.

Intervention Effects on Pain
Exercise intervention and massage therapy have demonstrated potential effects on pain management in patients with CRC experiencing OIPN.61,63,65 The potential benefit of exercise for pain relief in cancer patients with neuropathy problems is also supported by a systematic review and meta-analysis.79 Exercise is believed to reduce neuropathic pain by promoting the release of anti-inflammatory cytokines.79,96 In addition to exercise, aromatherapy massage has been shown to have notable effects on the management of paraesthesia pain.65 However, no existing studies have suggested similar findings. Therefore, more evidence is required to determine the impact of massage therapy on neuropathic pain management in patients with CRC.

Adverse Effects of Interventions
Three studies examined whether there were any adverse effects of the interventions in this review.65,69,71 Study investigating acupuncture reported several side effects, and the efficacy of acupuncture for managing OIPN in patients with CRC is inconclusive.69 Further research on the safe use of acupuncture on OIPN should be considered. While most non-pharmacological interventions are non-invasive, monitoring both the benefits and potential side effects of these treatments, particularly for vulnerable populations such as patients with cancer, is essential.97,98 Future studies should address the adverse effects of interventions for cancer-related symptom management.

Lack of Psychological Interventions for the Management of CIPN in Patients with CRC
There are no existing two-arm studies investigating the effect of psychological interventions, such as cognitive behavioural therapy (CBT) and psychoeducation, for managing OIPN in patients with CRC, while existing reviews have found that psychological interventions may mitigate painful CIPN in cancer patients. Tanay et al found that psychoeducation focusing on the CIPN knowledge, self-management resources and symptom reporting reduces the CIPN symptoms in cancer patients.44 Another review found that cancer patients receiving CBT may have a positive impression of change of symptom severity; however, there is no statistically significant difference in pain interference and perception of neuropathy pain severity compared with patients receiving usual care.28 Therefore, future studies examining the effect of psychological interventions on OIPN in patients with CRC are required.

Study Strengths and Limitations
One of the strengths of this review is that it draws a robust conclusion about the efficacy of different integrative interventions for CIPN with the inclusion of RCTs and quasi-experimental studies. Additionally, subgroup analysis of each intervention, especially various types of exercise programs, suggested the promising efficacy of multimodal exercise compared with other types of exercise, which other existing reviews did not address. However, this review has some limitations. The major limitation of this review was the lack of evaluation of the pooled effects of different interventions owing to the heterogeneity of the included studies. Second, the language of the included studies was limited to English and Chinese, which limited the number of available studies. Third, CIPN is associated with psychosocial symptoms such as anxiety and depression,18–20 however, these symptoms were not evaluated in this review. Last but not least, five out of thirteen reviewed studies enrolled participants with different gastrointestinal cancers and did not report the subgroup findings of the patients with CRC, despite over 60% of participants were patients with CRC in those studies.60,61,63,65,66 Therefore, those findings might not solely reflect the effects of interventions for patients with CRC.

Conclusion
This review examined the effects of integrative approaches for managing CIPN in patients with CRC and found that multimodal exercise significantly improved CIPN symptoms in these patients, which may suggest healthcare providers should consider this component in a CRC-specific survivorship plan. Goshajinkigan may prevent the worsening of the CIPN symptoms rather than mitigating CIPN symptoms. Additional research is needed in the future to investigate the effectiveness of hand-foot exercise, massage and henna applications and their short-term effects for managing CIPN. Additionally, exercise was the sole intervention to demonstrate positive effects on pain, balance, and quality of life in patients with CRC experiencing CIPN. This review also highlighted the lack of evidence regarding the long-term effects of integrative interventions.