Accepted Manuscript Chemotherapy-induced-peripheral neuropathy, gait and fall risk in older adults following cancer treatment Timothy F. Marshall, PhD, Genevieve Pinto Zipp, PT, EdD, Fortunato Battaglia, MD, PhD, Rebecca Moss, MD, Stephanie Bryan, PhD PII:
S2311-3006(16)30197-5
DOI:
10.1016/j.jcrpr.2017.03.005
Reference:
JCRPR 57
To appear in:
Journal of Cancer Research and Practice
Received Date: 20 December 2016 Revised Date:
24 March 2017
Accepted Date: 29 March 2017
Please cite this article as: Marshall TF, Zipp GP, Battaglia F, Moss R, Bryan S, Chemotherapy-inducedperipheral neuropathy, gait and fall risk in older adults following cancer treatment, Journal of Cancer Research and Practice (2017), doi: 10.1016/j.jcrpr.2017.03.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Authors
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Timothy F. Marshall, PhD1,2 Genevieve Pinto Zipp, PT, EdD, 2 Fortunato Battaglia, MD, PhD, 2 Rebecca Moss, MD3 Stephanie Bryan, PhD4 1
Kean University, School of Physical Therapy Seton Hall University, Department of Interprofessional Health Sciences & Health Administration 3 Rutgers, Cancer Institute of New Jersey 4 Saint Peter’s University, Department of Health & Physical Education
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Chemotherapy-Induced-Peripheral-Neuropathy, Gait and Fall Risk in Older Adults Following Cancer Treatment
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Corresponding Author
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Timothy F. Marshall, Ph.D. Assistant Professor School of Physical Therapy, DPT Program Kean University 1000 Morris Ave. Email:
[email protected] Phone: 908-737-6177
This Paper has not been presented at a meeting. There were no funding sources for this research. Abstract Word Count: 220 Paper Word Count: 2,998 Tables: 2
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Title
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Running head: EFFECTS OF CIPN ON GAIT AND FALL RISK
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Chemotherapy-Induced-Peripheral Neuropathy, Gait and Fall Risk in Older Adults Following Cancer Treatment
This Paper has not been presented at a meeting. There were no funding sources for this research.
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Abstract Word Count: 230 Paper Word Count: 3,013 Tables: 2
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 2 ABSTRACT
Background/Objective: Cancer patients undergoing chemotherapy often experience
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chemotherapy-induced peripheral neuropathy (CIPN), which reportedly causes gait disturbances that may increase their risk for falls. The purpose of this study was to investigate whether CIPN is associated with spatial-temporal gait adaptations and fall risk in post-treatment adult cancer
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survivors.
Method: This study enrolled 16 subjects between 50-70 years of age, including 8 subjects with
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CIPN and 8 subjects with age and morphologically-matched controls. Gait velocity, step length, step time, base of support, swing time, single support time, and double support time as measured by GAITRite. Fall risk was assessed utilizing the Timed Up and Go (TUG) test.
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Results: Overall, gait velocity (110.75 cm/s, SD = 26.79, p = .006) was significantly slower, and step length (53.92 cm, SD = 23.55, p = .005) was significantly shorter in those subjects with CIPN. Additionally, CIPN participants had a significantly higher TUG Score (12.33 s, SD =
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6.25, p = .001) compared to the controls (6.62 s, SD = 1.10).
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Conclusion: Our investigation suggested that gait speed and step length are key indicators for fall risk. Compared to controls, cancer patients with CIPN may display slower gait velocities, shorter step length, and are at an increased fall risk as indicated by TUG scores. The presence of CIPN appears to increase fall risk, which may easily be assessed in a clinical setting using the TUG test.
Keywords: Cancer, Chemotherapy, Peripheral neuropathy, Falls, Gait
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 3 1. Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is generally classified as a series of neuromuscular symptoms, both sensory and motor in nature, that result from nerve damage
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caused by the neurotoxic effects of chemotherapy drugs for the treatment of cancer1,2. It is
postulated that chemotherapy agents will often inflict their neurotoxic effects on various parts of the axon, decreasing somatosensory feedback and causing many of the typical CIPN
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symptoms4,5,6,7,8.Symptoms of CIPN may be acute, mild or severe, transient or chronic,
depending upon the treatment regime and dose of the agents, and may manifest in a variety of
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ways, involving sensory and motor symptoms2,3,4. Sensory signs and symptoms may include numbness, tingling, burning, pain, ataxia, loss of deep tendon reflex, and reduced sense of touch, vibration, and proprioception. Motor symptoms may include weakness, balance disturbances, and difficulty performing fine motor skills and a diminished or absent deep tendon reflex2,4,5,6,7.
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The exact cause of CIPN remains elusive. It is postulated that chemotherapy agents will often inflict their neurotoxic effects on various parts of the afferent nerve, such as the axon, mitochondria, voltage-gated channels, as well as the cell body, and dorsal root ganglion neurons.
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The cumulative neurotoxic impact of chemotherapy may cause many of the CIPN symptoms as well as a decrease of somatosensory feedback 4-8.
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Intact somatosensory systems are essential to fluid and stable ambulation. The literature
supports the proposition that somatosensory systems contribute to the modulation of spinal pattern generators, modulation of motor commands, and the perception and control of movements by providing information about mechanical stimuli, temperature changes, potential damage to the skin, body and limb movement and position, and velocity and muscle activation. Cutaneous sensory receptors provide information about the body’s orientation within the
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 4 immediate environment and provide information necessary for reflexive responses9,10. Cumulatively, sensory receptors within the somatosensory aide in the modulation of gait11. Abnormalities in gait parameters such as cadence, stride length, swing, double support,
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stride length variability, and swing time variability, may increase the risk of falling12,13. Falling is a significant event for the elderly population, as falls have been linked to serious injuries and disabilities, loss of independence, and increased mortality14. In 2005, 1.8 million individuals
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over the age of 65 went to the emergency room to be treatment for a fall-related injury. It is estimated that 60% of individuals over the age of 60 will be diagnosed with cancer. As the age
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of cancer patients treated with chemotherapy increases, with a 10-40% incidence of CIPN in patients treated with neurotoxic agents, there is a growing need to identify individuals at risk of falls in order to prevent subsequent injuries and complications15.
Although CIPN is prevalent in cancer patients undergoing chemotherapy, researchers
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have not explored changes in spatiotemporal gait parameters in cancer patients between 50-70 years of age undergoing chemotherapy which may impact their fall risk16. Hence, the aim of this study was to investigate the effect that presence of CIPN may have on spatiotemporal gait
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parameters and fall risk in breast and colon cancer patients who have completed their chemotherapy treatment for cancer.
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2. Participants and methods 2.1 Participants
This study included a convenience sample of 8 participants between 50-70 years of age
with a histologically confirmed stage 2-3 breast or colorectal cancer diagnoses, with a confirmed treatment plan consisting of taxane-based or oxaliplatin-based chemotherapy. Participants also had a confirmed diagnoses of chemotherapy-induced peripheral neuropathy according to the
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 5 Peripheral Sensory Neuropathy category of the Common Terminology Criteria for Adverse Events (CTCAE), version 4. Using a quasi-experimental design, 8 age-and-morphologicallymatched-subjects were recruited to compare to the group of breast and colon cancer patients.
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They were recruited from the same community to match the recruited cancer patients in order to assess differences in spatiotemporal gait parameters. Hence, the present study contained a total of 16 participants and two groups: a control group, which consisted of 8 healthy, disease-free,
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age and morphologically matched controls, and an intervention group, which consisted of 8 breast or colon cancer patients diagnosed with CIPN. Individuals voluntarily provided written
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informed consent and completed the Seton Hall University and Saint Michael’s Medical Center’s Institutional Review Board-approved research protocol. Individuals meeting any of the following criteria were excluded: a history of peripheral neuropathy (i.e., hereditary peripheral neuropathy associated with nutritional agents and paraneoplastic syndrome-related neuropathy), or diseases
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that may contribute to peripheral nerve damage such as diabetes, renal insufficiency, alcohol abuse, vitamin B12 deficiency, HIV, and vasculitis, brain or spinal cord metastases, orthopedic problems that affect balance, or vestibular system or visual disease, use of a walking aide, and
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lastly, participated in 150 min of light-to-moderate intensity exercise per week over the past year. 2.1 Outcomes and statistical analysis
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Following the signing of the informed consent forms, demographic and biometric data
was collected, including the subject’s cancer diagnosis, name of the chemotherapy agent received, age, sex, height, and weight. The patients’ right and left leg lengths were measured (from the greater trochanter to the floor) using a standardized, flexible cloth tape, and entered into the GAITRite software for data processing.
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 6 Following standard protocol, fall risk was assessed using the valid and reliable Timed Up and Go test (TUG), which is a mobility test used to measure basic mobility skills17. The measurement outcome for TUG is the time it takes to rise up out of a chair, walk 3 meters away
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from the chair, walk 3 m back to the chair, and return to the seated position; the time it takes to complete this task is recorded. Previous research indicates that a time of greater than 10.7 s indicates risk for falls18. The TUG has been shown to have a sensitivity of 90%, and specificity
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of 88.5% as well as a high diagnostic accuracy at 88.9% when a modified cutoff score of 10.7s is applied18.
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After the completion of the TUG test, the GAITRite system was used to compute spatiotemporal gait parameters. The GAITRite system is an electronic pathway which is 8.2 m in length and resembles a carpet runner; the active area is 61 cm wide and 732 cm long, and contains 27,648 sensors placed 1.27 cm apart and are activated by mechanical sensors. Data from
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the activated sensors are collected by a series of onboard processors and transferred to the computer through a serial port17. The GAITRite system has been shown to be a valid and reliable tool for assessing spatiotemporal gait parameters. Walking speed, cadence, step length
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and step time variables have been shown to have intra-class correlation coefficients (ICCs) between 0.92 - 0.99, and repeatability coefficients (RCs) between 1.0 - 5.9% of mean
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values. Step length and step time variables have also been shown to have good agreement, with ICCs between 0.91 - 0.99 and RCs between 2.6 - 7.8%).17 For each trial, participants were instructed to initiate walking from a non-sliding standing
spot marked 2 meters before the beginning edge of the GAIT Rite carpet. This allowed walking to be initiated from the same location at every trial, and also permitted a steady state of ambulation to be achieved prior to stepping on the GAITRite walkway. Participants negotiated
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 7 the entire length of the 5.18-m GAITRite carpet walkway at a steady pace while looking straight ahead. Three trials were performed by each participant without environmental distractions. The independent variable was the presence of CIPN. There were multiple dependent
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variables, which included the participants’ TUG score and spatiotemporal gait parameters
obtained from the GAITRite system. Thus, the research question was answered using a one-way Multiple Analysis of Variance (MANOVA). An alpha level of 0.05 was used19. While the
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sample size may appear to be small, a post-hoc analysis indicated that the present study was powered at .87, indicating that the sample size of 16 was sufficient to detect a difference between
3. Results 3.1 Participant characteristics
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the two groups if in fact there was an effect to be detected19.
There were 16 subjects between the ages of 50 - 70 that participated in the study, and 8
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aged and morphologically matched subjects (age, height, weight BMI) served as study controls. Eight of the participants had a histologically confirmed stage 2–3 breast or colorectal cancer diagnosis and were treated with either taxane- or oxaliplatin-based chemotherapy. Presence of
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CIPN was confirmed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
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Both the CIPN group and control group had 6 females and 2 males; five of the
participants had breast cancer and 3 had colon cancer. Of the types of chemotherapy received by those with CIPN, 1 participant received paclitaxel, 4 received taxanes, and 3 participants received oxaliplatin. There were no significant differences between the participant characteristics of the two groups other than the presence of chemotherapy-induced peripheral neuropathy (p>.05).
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 8 3.2 Fall Risk The mean TUG time for the CIPN participants was 12.33 s (SD = 6.25), whereas the mean TUG time for the control was 6.62 s (SD = 1.10). TUG time was found to be significantly different
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between the control group and the CIPN group, X² (1) = 11.29, p = .001; n² = 0.69. 3.3 Spatial temporal gait parameters
The mean and standard deviations for the spatiotemporal gait parameters are displayed in Table
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2. Of the spatial temporal gait parameters analyzed, only gait velocity and step length were
significantly different. The gait velocity of those with CIPN (110.75 cm/s, SD = 26.79) was
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significantly slower than that the controls (147.79, SD = 11.69), X² (1) = 7.46 p = .006; n² = 0.43 The mean step length for the CIPN group (53.92 cm per step; SD = 23.55) was significantly shorter that the step length for the controls (77.15 cm per step; SD = 5.28), X² (1) = 8.04, p = .005, n² = 0.47.
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4. Discussion
This is, to our knowledge, one of the first studies to investigate the impact that the presence CIPN has on spatiotemporal gait parameters and fall risk in breast and colon cancer
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survivors who received taxane or platinum-based chemotherapy for the treatment of their cancers. Although falls and unsteady gait are frequently reported by cancer patients who have
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CIPN, researchers have not sufficiently investigated possible changes in the way cancer patients are walking that may increase their risk of falls. The present study found that cancer patients with CIPN displayed slower walking
velocity and shorter step length, resulting in a higher risk of falls, compared to healthy, age and morphologically matched controls. Additional gait patterns such as step time, base of support, swing time, single support time, and double support time, were not significantly different. Also,
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 9 the mean TUG score for CIPN patients was not only significantly greater, but was also above the clinical fall risk cut off of 10.7 s, indicating an apparent fall risk. Due to these findings, additional research studies with larger samples sizes are warranted
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because the number of people surviving a cancer diagnosis is increasing due to new and
innovative screening and treatment techniques20. However, many cancer survivors are dealing with long-term physical and emotional side effects that negatively impact their health and overall
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quality of life12. A common functional impairment experienced by cancer patients who received chemotherapy, especially those who receive platinum and taxane based agents is chemotherapy-
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induced peripheral neuropathy (CIPN), which may be described as paranesthesia-like numbness and/or pain, which occurs in a stocking-and-glove distribution22,23,24. Cancer patients with CIPN often report difficulties in walking, in that they feel unsteady and note a reduced sense of balance 24,25,26
. Impaired sense of balance and gait concerns reported by cancer patients have been linked
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to an increased fall risk, which potentially limits their ability to perform tasks of daily living22,27,28,29. However, little is known about the specific gait impairments that may be caused by CIPN, and if these gait impairments contribute to an increased fall risk25.
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A strong indicator of fall risk is gait velocity, which has been found in other populations other than cancer patients with CIPN, such as the elderly and diabetics with peripheral
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neuropathy. Specifically, gait speeds between 70 - 100 cm/s have been found to be associated with higher fall incidences than when gait speeds are above 100 cm/s13. In the present study, it was found that those subjects with CIPN had an average gait velocity of 110.75 cm/s, which was significantly slower than the control subjects’ walking velocity of 147.79 cm/s. The slower gait velocity demonstrated by those with CIPN in this study is concerning because decreased velocity has been found to be directly associated with an increase in fall
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 10 risks30; this increased risk was underscored by our study subjects’ elevated TUG time. The TUG time for those with CIPN was 12.33 seconds (SD = 6.25), which was significantly greater than the mean TUG time of 6.62 seconds (SD = 1.10) for the control group. These findings are
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particularly noteworthy because the mean TUG time by those with CIPN was well above the score of 10.7 seconds, which researchers suggest is indicative of fall risk18. Therefore, the results further support that those with CIPN are at a higher risk of falling.
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While the TUG test has demonstrated its clinical effectiveness in assessing fall risk, the TUG does not evaluate kinetic differences that are specific to the impairment that may influence
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fall risk31. Thus, the Maximum Step Length (MSL) test can be used in future work as it assesses both dynamic balance and leg strength. Clinically, a decrease in the MSL may indicate an increased fall risk32,33,34. Research indicates that the majority of falls experienced by the elderly and individuals with diabetic peripheral neuropathy will have gait patterns that are consistent
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with shortened step lengths9,35. In the present study, it was found that individuals with CIPN consistently displayed significantly shorter step lengths; individuals with CIPN had a mean step length of 53.92 cm, which was significantly shorter than the control step length of 77.15 cm.
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Thus, the findings in the present study are consistent with the previous literature in that the presence of CIPN increased fall risk, as indicated by the mean TUG scores, which was due to a
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decrease in gait velocity and step length. Several limitations can be noted in the present study. First, the presence of CIPN was
determined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and thus the extent of the damage to peripheral nerves was not quantified nor were the fiber types affected by the chemotherapy agents specified. The level of neurotoxicity and fiber types affected are significant because this suggests that type Ia, type Ib, and type 2 fibers may be the
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 11 primary fibers providing afferent feedback for the reflex arcs involved in gait mediation11. However, the fibers which experience neurotoxicity may be unmyelinated C fibers, and myelinated Aδ fibers are the primary targets of chemotherapy agents23,36.In 2004, Visovsky and
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Daly found that there was no effect on deep tendon reflex using Babinski’s reflex hammer,
which suggests that the type Ia, type Ib, and type 2 afferent nerves that innervate Golgi tendon organs and muscle spindles and their corresponding reflex mechanisms are intact. This is a
are primarily responsible for mediating gait11.
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significant observation because it is proposed in the literature that these three reflex mechanisms
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Furthermore, the time of onset of CIPN symptoms was not quantified, which is another limitation because individuals may develop compensatory behaviors due to the loss of sensory input caused by CIPN. Gait is the result of afferent information from visual, vestibular, and proprioceptive systems. These three systems do not operate independently; the body uses
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somatosensory information from all bodily sources in order to shape functional movement. When the contribution of somatosensory information is attenuated, or lost, such as in the case of peripheral neuropathy, the vestibular system, which primarily mediates the trunk during gait,
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may provide a greater contribution to posture and balance38,39. This is important to note because the trunk may in fact have a greater influence on gait stability then lower body segments40,41.
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Thus, although CIPN patients may have attenuated somatosensory afferent feedback, more noticeable changes in spatiotemporal gait parameters other than gait velocity were not found due to the intact vestibular information that is critical for trunk control and walking accuracy41. Decreased gait velocities may not only be due to the neurotoxic effect of the
chemotherapy agents but also due to the presence of pain, which is a common CIPN symptom42. It is hypothesized that individuals who are experiencing pain will adapt their motor program to
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 12 protect injured tissues. A recent study that evaluated gait parameters in individuals with foot pain related to gout found that those individuals with gout-related foot pain walked significantly slower43. The presence of pain in the lower extremities is significant because the decrease in gait
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speed may not be solely attributable to the decrease in afferent feedback, but the presence of pain; this is because individuals experiencing pain may undergo motor adaptations to protect the painful/injured tissues, resulting in a decrease in gait velocity44,45,46.
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Lastly, the physical health of the individual was not quantified, which is significant
because it is estimated that 30% of cancer survivors will decrease their physical activity levels
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upon receiving a cancer diagnosis, with up to 70% of cancer survivors not meeting the U.S national recommendations for exercises and physical activity47,48. The participants in the present study had not been engaging in regular physical activity. Thus, cancer patients may experience a deconditioning effect, characterized by a decrease in muscle strength, cardiopulmonary capacity
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and flexibility. In turn, this reduction in physical activity and not the presence of CIPN, may cause a decrease in gait velocity and step length49. In conclusion, breast and colon cancer patients with CIPN between 50-70 years of age
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display slower gait velocities and shorter step lengths compared to age- and morphologicallymatched controls, and thus may be at a higher risk of falls, which was demonstrated by the CIPN
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participating study subjects’ mean TUG score. Gait velocity, step length and the Timed Up-andGo test are key indicators for fall risk13. Preliminary evidence from this present study suggest that a larger study is warranted to further understand the impact that the presence of CIPN has on fall risk.
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 13 Conflict of Interest The authors declare that there are no conflicts of interest
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This study was not supported by grant funding.
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Acknowledgements
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cancer diagnosis. AM J Health & Behavior 2003; 27: 246–256.
48. Blanchard CM, Courneya KS, Stein K. Cancer survivors’ adherence to lifestyle behavior recommendations and associations with health-related quality of life: Results from the American Cancer Society’s SCS-2. J ClinOncol 2008;26: 2198–2204.
TE D
49. Ko S, Stenholm S, Metter E J, et al. Age-associated gait patterns and the role of lower extremity strength: Results from the Baltimore Longitudinal Study of Aging. Arch Gerontol
AC C
EP
Geri 2012;55:474–479.
ACCEPTED MANUSCRIPT EFFECTS OF CIPN ON GAIT AND FALL RISK 19 Table 1 Descriptive statistics of participants
Height (cm) BMI (kg/m2)
Table 2 Gait characteristics
Velocity (cm/s) R Step time (s)
AC C
R HH Base support (cm) R Swing time (s)
R Single support time (s)
R Double support time (s)
.590 .127 .262
Mean
Std. deviation
p-value
CIPN Control CIPN Control CIPN Control CIPN Control CIPN Control CIPN Control CIPN Control CIPN Control
12.33 6.62 110.75 147.79 .55 .52 53.92 77.15 8.77 7.87 .44 .43 .44 .43 .24 .18
6.25 1.10 26.79 11.69 .08 .02 23.55 5.28 3.00 1.97 .04 .02 .05 .03 .07 .04
.001
EP
R Step length (cm)
.771
Participant type
TE D
TUG(s)
p-value
RI PT
Weight (kg)
Std. deviation 7.42 3.77 18.48 8.88 14.35 9.44 6.34 2.37
SC
Age (yrs.)
Mean 61.38 62.25 76.45 72.42 158.05 167.90 27.71 24.85
M AN U
Participant type CIPN Control CIPN Control CIPN Control CIPN Control
.006 .529 .001 .462 .833 .958 .074
