Physical therapy for deficits associated with chemotherapy induced peripheral neuropathy in children with cancer: a systematic review

Introduction

Background

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, often long lasting, and severe side effect in children with cancer, resulting from the administration of neurotoxic chemotherapy agents such as vinca alkaloids (e.g., vincristine) and platinum compounds (e.g., cisplatin) (1-3). Peripheral neuropathies may result from the damage caused by neurotoxic agents, often in the dorsal root ganglia (4-6). The damage from neurotoxic agents causes degeneration and death of axons, myelin sheaths, or cell bodies (3,7), which may lead to long-term functional abnormalities and structural lesions in both peripheral and central nervous systems (7).

Pathophysiological mechanisms of CIPN differ between children and adults given the differences in the myelination of peripheral nerves, composition of the immune system, and central nervous system neuroplasticity (8-10). Consequently, the clinical manifestations are also different in children. Vincristine-induced motor neuropathies are more commonly seen in children, presenting as muscle weakness, foot drop, ataxia, and impaired gait (11,12).

CIPN usually presents in a bilaterally symmetrical distribution, manifesting first in the lower extremities in a stocking-pattern, followed by the upper extremities in a glove-pattern of distribution (3,7,13,14). CIPN primarily affects small-diameter sensory nerve fibers, causing symptoms such as pain, temperature perception loss, or dysesthesia (14). Impairments are also seen in large-diameter sensory fibers, resulting in a loss of proprioception, decreased vibratory sense, decreased deep tendon reflexes, balance deficits, numbness, and loss of fine touch (3,7,14,15). Secondary deficits include motor impairments such as distal muscle weakness and atrophy progressing to foot drop (3,13-16). These deficits lead to balance and coordination impairments, muscle contractures, upper-limb functional deficits (e.g., grabbing a pencil, zipping up clothes, eating with utensils), skeletal malalignment, and abnormal gait patterns (e.g., slowed gait speed) (3,7,14,15,17,18).

CIPN symptoms and deficits can appear early in therapy and persist for many years following chemotherapy completion (19). Lavoie Smith et al. (20) found that 78% of children with acute lymphoblastic leukemia (ALL) presented with CIPN during the first year of treatment, with the prevalence peaking in the first 2 to 4 months of cancer treatment. Two cross-sectional studies have shown that 30% to 40% of children with ALL receiving neurotoxic chemotherapy, experience peripheral nerve deficits at 2 to 3 years post-treatment (21,22), and 12% to 40% of long-term survivors continue to experience neurological impairments 10 years following completion of cancer treatment (23,24).

Rationale and knowledge gap

Research has documented that children with cancer report CIPN as one of the most distressing symptoms experienced (3). Associated sequelae may lead to limitations in daily activities (e.g., running), as well as restrictions in participation (e.g., sports); all of which can negatively affect the quality of life of children and adolescents (17).

Physical therapy (PT) for CIPN plays an important role by helping to prevent deformities, promote patient safety, maintain or restore function, and maximize independence in daily life activities (25,26). Recent reviews evaluating the effects of exercise on CIPN symptoms in children reported that research is largely preliminary, with most studies at a pilot stage, uncontrolled, or not randomized (27-29). Although there is a paucity of high-quality studies evaluating CIPN as a clinical entity in the pediatrics population, there are studies that have been conducted examining PT interventions for impairments and symptoms associated with, or resulting from CIPN (27-30). For example, research evidence supports the benefits of rehabilitation interventions to address decreased ankle range of motion (ROM) and foot drop—impairments resulting from CIPN (31). Therefore, exploring literature investigating therapeutic interventions for CIPN-related deficits may better inform PT management and future research in pediatric oncology.

Objective

The aim of this systematic review is to synthesize the research evidence on PT interventions for symptoms and deficits associated with CIPN in children with cancer. We present this article in accordance with the PRISMA reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-24-42/rc).

Methods

The review protocol was registered in PROSPERO (CRD42023429838).

Search strategy and selection criteria

Search strategies were developed with the assistance of a medical librarian at the University of Alberta, and the filter by Glanville et al. (32) was used to find clinical trials. Searches were executed in five electronic databases: Medline, Embase, CINAHL, CENTRAL, and Scopus (Appendix 1). Additional searches were also conducted for reference lists of relevant articles, grey literature, and clinical trial websites. Literature published up to February 2024 was reviewed for inclusion. No language restrictions were applied.

Retrieved articles were imported into COVIDENCE (33). One author (P.A.O.) first screened the titles and abstracts for articles irrelevant to the topic. Titles and abstracts were then screened for potential full-text review by two authors (P.A.O., M.M.A.O.). Two authors (P.A.O., M.M.A.O.) reviewed eligible full articles. Disagreements on inclusion were resolved by discussion and consensus, or if necessary, a third reviewer (M.L.M.) was consulted to reach consensus. Articles were included if they met the following PICOS criteria:

• P (population): children aged 0 to 19 years with any type of cancer.
• I (intervention): PT interventions for CIPN or its associated deficits, including therapeutic exercise, manual therapy, electrophysical agents, gait and balance retraining, joint mobilization, proprioception, coordination, or orthoses (i.e., splints, ankle-foot orthoses, ankle straps).
• C (comparison intervention): standard care, placebo, no PT, or comparison treatment.
• O (outcomes): CIPN symptoms and deficits, ROM, muscle strength, motor function, balance, gait, functional mobility, foot posture, pain, and adverse events (34-43). Further information is provided in Table 1.
• S (study design): randomized controlled trial (RCT) or controlled clinical trial (CCT).

Studies were excluded if the intervention aim was to increase physical activity levels or fitness alone, and did not address a CIPN deficit, symptom, or impairment.

Data collection

Two review authors (P.A.O., M.M.A.O.) extracted the characteristics for each study using a data extraction form, and a third reviewer (M.L.M.) reviewed the extracted data. Authors resolved disagreements by consensus, or when necessary, a third review author (M.L.M.) resolved the discrepancies. In cases of missing data or relevant information, study authors would have been contacted. Extracted data included information on the trial design, sample size, characteristics of participants, objectives of the study, type of intervention(s) and comparison groups, duration of intervention, outcomes assessed, and study results.

The primary outcome of interest of this review was CIPN symptoms and deficits as measured by one of the following outcomes: the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-CIPN twenty-item scale (QLQ-CIPN20), Pediatric Modified Total Peripheral Neuropathy Score (ped-mTNS), Total Neuropathy Score-Pediatric Vincristine (TNS-PV), Total Neuropathy Score (TNS), sensory testing (monofilament testing, nerve conduction testing), or another valid instrument designed to capture deficits relating to CIPN. Secondary outcomes of interest included ROM, measured by goniometry; muscle strength, measured by manual muscle testing, dynamometry, or another valid instrument; motor function, assessed by the Bruininks Osteretsky Test of Motor Proficiency Second Edition (BOT-2), Peabody Developmental Motor Scales (PDMS-2), or another valid instrument; balance, assessed using the Single Leg Stance, Flamingo Balance Test, The Berg Balance Test, or another valid instrument; gait, assessed by observational or computerized analysis, or another valid instrument; functional mobility, assessed by the 6-minute walk test (6-MWT), 2-minute walk test (2-MWT), 9-minute walk test (9-MWT), Timed Up and Go test (TUG), Timed Up and Down Stairs (TUDS), or another valid instrument; foot posture, assessed by the Foot Posture Index (FP1-6) or another valid instrument; pain, measured by the visual analog scale (VAS) or another valid instrument; and adverse events, resulting from the PT intervention including falls, fractures, soft tissue injuries, and worsening of symptoms (e.g., increased pain) that led to study withdrawal.

Data analysis

We did not pool the data from the included trials due to heterogeneity among study populations, as well as chosen outcomes, interventions and comparisons. Therefore, as per protocol, we conducted a descriptive analysis of the outcomes.

Quality appraisal

The methodological quality of the RCTs and CCTs was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB 2) assessment to ensure consistency in reporting as the clinical trials followed the same RCT methodology. Two review authors (P.A.O., M.M.A.O.) independently assessed the risk of bias in the studies using the RoB 2 tool (44), rating each risk-of-bias item as ‘low risk of bias’, ‘some concerns’, or ‘high risk of bias’. Disagreements were resolved by discussion, or if necessary, a third reviewer (M.L.M.) was consulted to reach consensus. The third author (M.L.M.) also reviewed the RoB 2 assessments.

Results

Description of studies

Search results

The searches of the five electronic databases, reference lists of relevant articles, grey literature, and clinical trial websites retrieved a total of 4,742 references (Figure 1). Titles and abstracts screening resulted in 39 full-text studies assessed for eligibility. Thirty studies did not meet the eligibility criteria, resulting in nine studies included in the review.

Figure 1 Systematic review flow chart.

Study designs

Of the nine studies included in the review, six studies were RCTs (31,45-49), one was a pilot RCT with preliminary results only (50), one was a CCT (51), and one was a pilot CCT (52). The secondary analysis (53) of a CCT (51) was included in the review (Table 2). Ongoing studies were excluded from the analyses and were reported in the ‘Ongoing studies’ section.

Participants

A total of 439 participants were included in the studies. Five studies included children diagnosed with ALL (31,45-47,49), two studies included children with any type of cancer (48,50), and two studies included children scheduled for/receiving hematopoietic stem cell transplant (51,52). Ages varied across the studies, from 4 to 19 years, and sample sizes ranged from 7 participants to 107 participants.

Outcomes

We did not find any studies that included a measure of CIPN symptoms and deficits as per our primary outcome; however, all studies included at least one outcome that assessed an impairment associated with, or impacted by CIPN. Secondary outcomes included measures of endurance/functional capacity (31,45,47,51); motor proficiency (45,46,48,52); functional mobility (31,47,51,52); active ankle ROM (31,45,47); hand-grip strength (45,47,51); knee extension strength (45,47,52) ankle dorsiflexion strength (45,47,52); lower body strength (31,51); passive ankle ROM (46,52); pain intensity (50,53); pain threshold (50); and balance (49). Only three studies provided data on adverse events and these studies reported that no adverse events occurred due to the intervention (47,51,52).

Interventions

The locations of PT interventions evaluated across the studies comprised hospital-based programs (49,50,52), and a combination of in-hospital and home-based programs (31,45-48,51). Most of the studies (n=6) included an exercise program within their intervention, comprising strength training, ROM, and aerobic/endurance exercises (31,45-47,51,52). Some studies added additional components to tailor interventions such as a behaviour change component and exercises for gross motor skills (45), education on motor impairments (46), manual stretching and functional exercises (47), rehabilitation counseling indications (52), and relaxation exercises (51). One study included graded motor imagery and neural mobilization interventions (50), one included task-oriented rehabilitation interventions including functional activities for fine and gross motor skills (48), and one included gait training and balance training interventions (49).

Duration of interventions ranged from 4 weeks to 2.5 years, with a frequency of daily sessions to monthly sessions. Frequency of sessions varied across the studies as some included more than one intervention with different frequency of sessions. Six studies evaluated interventions with a frequency ranging from 2 to 5 days per week (31,45,47,49,50,52), and three studies comprised interventions that were delivered and/or recommended on a daily basis (46,48,51). Two studies evaluated long-term interventions lasting 2 (46) and 2.5 years (45).

Findings suggest that studies that comprised shorter supervised and tailored PT interventions showed better results when compared to those examining long-term or unsupervised interventions (31,47-52). Marchese et al. (47) evaluated a 4-month combined in-hospital and home-based PT intervention comprising functional exercises compared to no PT exercises and advice. Results showed statistically significant improvements in ankle dorsiflexion ROM (P<0.01) and knee extension strength (P<0.01). Sahin et al. (48) examined the effects of a 4-week in-hospital home-based task-oriented rehabilitation program including functional gross and fine motor activities compared to a home-based program. Results showed positive effects in gross and fine motor skills in the intervention group and no effect in the control group. Zakaria et al. (49) investigated the effect of a 3-month in-hospital PT program combining gait and balance training, compared to gait training alone. Results showed significant improvement in balance scores in the intervention group (P<0.001). Tanir et al. (31) evaluated a 3-month combined supervised in-hospital and home-based PT intervention comprising strengthening, ROM, and aerobic exercises compared to no exercise recommendations. Results showed statistically significant improvements in functional capacity and leg strength (P=0.001). Yildiz Kabak et al. (51) investigated the effectiveness of a supervised exercise program during hospitalization combined with a self-administered home-based program 1 month after discharge, compared to recommendations to stay active during hospitalization. Statistically significant between group differences were found favouring the intervention group for functional capacity (P=0.021), lower body strength (P=0.012), and functional mobility (P<0.001) outcomes. Rossi et al. (52) evaluated the preliminary effectiveness of a hospital-based rehabilitation program in addition to rehabilitation counseling in maintaining motor performance, compared to rehabilitation counseling only. Although, no statistically significant differences were found for the primary outcome—motor performance—participants maintained their motor function and ankle ROM. Casanova et al. (50) investigated the effect of a 4-week graded motor imagery and neural mobilization intervention on neuropathic pain, compared to pharmacological management alone. Preliminary results (n=7) showed a non-significant but positive trend for improvement in pain intensity.

Studies that evaluated long-term interventions starting from diagnosis and finalizing upon cancer treatment completion, reported low adherence to the interventions (45,46). Hartman et al. (46) investigated the effect of a 2-year exercise program comprising education on motor deficits resulting from chemotherapy in addition to a PT program to maintain function and mobility. Results showed low adherence to the intervention, and the exercise program was not found to be more beneficial than standard of care. Cox et al. (45) evaluated the effects of a 2.5-year combined in-hospital and home-based motivation-focused exercise program. The authors reported low adherence to the intervention with no improvements in outcomes when compared to usual care.

Risk of bias assessments

All studies were classified as high-risk of bias (44). All studies had at least one category scored as ‘high-risk’, with the most common bias due to lack of blinding of participants and investigators to the intervention (Figure 2). While this bias is not always possible to mitigate in PT studies, many other categories were of high or unclear risk.

Figure 2 Cochrane risk-of-bias tools for randomized trials assessment.

Ongoing studies

A total of five ongoing clinical trials (n=3) and registered protocols (n=2) were retrieved from the search. PT interventions being evaluated comprise sensorimotor training (54,55), structured active play activities for gross motor function (56), foot orthotics and splints (57), and goal directed exercise therapy (58). Three out of the five ongoing studies include CIPN symptoms as an outcome measured using the Ped-mTNS score (54,55,58) (Appendix 1).

Discussion

The primary finding of this review is that no studies were found that evaluated CIPN as a clinical entity. Moreover, our results are similar to recent reviews evaluating the effects of exercise for CIPN symptoms in that no high-quality studies evaluating exercise or therapeutic interventions specific to CIPN symptoms were found (27-29). As reported by Streckmann et al. (28), the paucity of research in this area may be due to the under-reported statistics on its incidence and prevalence, and the limited evidence-based knowledge on assessment and treatment options in the pediatric population (2,7).

CIPN is commonly seen in children receiving neurotoxic chemotherapy drugs, with prevalence rates reported in up to 100% of pediatric cancer patients (2), lasting years following completion of cancer therapy (21-24,59). To date, there is no consensus on a standardized CIPN assessment in pediatric oncology. Given the high incidence of CIPN in children with cancer, a standardized CIPN evaluation should be included as part of the routine PT assessment to allow an early detection and management of its deficits (60), even in cases where the frequency of vincristine doses has been reduced.

Consensus on an agreed upon set of outcomes that should be measured and reported in all clinical trials (a core outcome set) for CIPN in children with cancer would be helpful to compare findings across studies (61). Reliable and validated pediatric-specific CIPN tools exist that can be used clinically. The ped-mTNS is one of the most commonly reported tools used to assess CIPN in children as it comprises a comprehensive set of questions on sensory, motor, and autonomic functions, as well as physical tests comprising light touch, pin and vibration sensation, distal muscle strength, and deep tendon reflexes (62). This tool requires a handheld Biothesiometer to measure vibratory thresholds, and this type of equipment may not be widely accessible. However, given the large range of outcome measures and a lack of gold standard CIPN measure, at minimum, use of the ped-mTNS test may allow for comparison of results across studies.

Our review revealed that short-term, supervised, tailored therapeutic interventions showed positive benefits on functional outcomes affected by CIPN such as ankle dorsiflexion ROM, motor performance, lower extremity strength, functional mobility, functional capacity, and balance. Smaller studies also have shown benefits of PT interventions such as prescription of orthoses for drop foot deficits resulting from CIPN. Tanner et al. (63) examined the feasibility of an ankle foot orthosis in children with non-central cancers experiencing peripheral muscle weakness and results showed positive trends in step length (P=0.028), dorsiflexion strength (P=0.046), and ankle dorsiflexion ROM (P=0.027). Tanner et al. (64) conducted a longitudinal, descriptive study to evaluate the feasibility of a proactive PT program ’stoplight’, targeting the main impairments resulting from ALL chemotherapy treatment in children. The intervention utilizes a prospective surveillance model to facilitate routine screening of CIPN and functional deficits in children receiving neurotoxic agents. The ’stoplight’ program offers education and preventive care interventions early after diagnosis, as well as tailored rehabilitation sessions for children demonstrating significant CIPN deficits. Thereafter, Tanner et al. (65) conducted a quasi-experimental, between-subject study to investigate the sustained benefits of the ’stoplight’ program on body function and activity limitations in survivors of ALL who completed the program and compared them with a historical control group of children. Results showed benefit from the program for motor performance and physical activity levels 1.5 years after cancer treatment completion.

Findings from this review suggest that interventions that were shorter in time, tailored to the child’s deficits, and comprised functional activities resulted in positive benefits for specific outcomes related to CIPN, in addition to good adherence to the interventions. These results are consistent with current research recommendations that support tailoring rehabilitation programs for CIPN impairments (25), with a focus on maintaining function and independence in daily activities (25). PT programs may focus on strengthening exercises to maintain and optimize muscle strength, stretching to preserve muscle length and minimize the risk of ROM loss, desensitization techniques to promote sensory processing and decrease pain, balance and gait retraining to optimize mobility, and bracing to support the affected extremities and maintain ROM (25,66). On the other hand, PT interventions that were longer in duration showed poor adherence, which may be due to the increased burden to families. Programs of shorter frequency and with continued PT support to maintain long-term ‘movement’ habits, may be better accepted by families. Tailoring PT interventions to the child’s health status and interests may help with addressing barriers to adherence (46).

Although this review did not identify high quality research studies that included CIPN as an outcome, five ongoing studies were identified, with some comprising play-based sensorimotor interventions for children with central nervous system cancers and ALL. Sensorimotor interventions have shown to be beneficial for adults with CIPN; however; it is still unknown if findings are transferrable to the pediatric population (28). Nonetheless, smaller scale, uncontrolled studies have examined the effects of novel therapeutic approaches such as whole body vibration for children during (67) and after receiving chemotherapy (68).

Results from this systematic review indicate that research evidence on PT interventions for CIPN and its associated deficits in childhood cancer survivors is limited in scope and quality. Preliminary research shows positive benefits for some outcomes related to CIPN, but given the high risk of bias and heterogeneity across interventions, it is not possible to provide clear recommendations. Current ongoing studies exploring CIPN-specific interventions may provide needed insights to advance the field.

This systematic review presented some limitations. First, we only included studies that have been published. Therefore, our results may not reflect all the studies that have been conducted but are unpublished. Second, studies did not report data on the type, doses, and frequency of the neurotoxic chemotherapy drugs administered to children, limiting our ability to compare interventions relative to cancer treatment. Third, given the heterogeneity across studies in study populations, interventions, and group comparisons, we were unable to pool the results to provide recommendations for clinical practice.

Conclusions

Preliminary research evidence suggests benefit from therapeutic interventions to improve deficits in ankle dorsiflexion ROM, motor performance, lower extremity strength, functional mobility, functional capacity, and balance—all of which are commonly associated with CIPN. Further research with closer attention to methodological quality is warranted.

Acknowledgments

We acknowledge Liz Dennett, the Medical Librarian at the University of Alberta, for her assistance with the development of the search strategies.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-24-42/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-24-42/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-24-42/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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