Can Exercise Interventions Improve or Reduce CIPN symptoms?

Can Exercise Interventions Improve or Reduce CIPN symptoms?

Findings from a Systematic Review

By Rebekah Friday

Senior Honors Thesis School of Nursing

The University of North Carolina at Chapel Hill

March 18

, 2020

Approved:

____

_________________________

Ashley Leak Bryant, PhD, RN

Honors Advisor

Abstract

Chemotherapy induced peripheral neuropathy (CIPN) is a crippling side effect of some types of chemotherapy and there are currently minimal treatment options. Symptoms of CIPN can be a limiting factor in length of treatment and can even arise after one completes

chemotherapy. Interventions such as balance and endurance exercises have been researched to see if they can decrease or limit the severity of CIPN symptoms. It is currently recommended that cancer patients exercise during and after treatment, but balance and endurance exercises in particular are especially important for patients with CIPN. These exercise interventions are a low risk, credible method for patients with CIPN to potentially decrease their symptoms and risk of falls. Future research for additional interventions that target CIPN symptoms is warranted.

Case Study

Erin just celebrated her one-month anniversary of completing her chemotherapy. Over the last month, Erin has begun to notice changes in her fingers and feet. Her oncologist had warned her about a potential side effect called chemotherapy induced peripheral neuropathy (CIPN) seen in some patients who receive the chemotherapeutic agent Carboplatin. Her oncologist had told her that even after finishing her treatment, this side effect could still arise.

She is afraid that he is right. Erin now feels tingling and numbness in her hands and feet.

Occasionally, she gets a pain in her feet that she would describe as an electric shock. She is

having a harder time buttoning her shirts and opening jars. Even after her treatment, she feels

like the side effects will just never end. Erin asks her oncologist about potential treatment for

these symptoms and he recommends exercise. This systematic review addresses CIPN and its

associated symptoms. Throughout this review, readers will learn about CIPN and the different

exercise interventions that have the potential to decrease symptoms of the condition. Questions that correspond with this case study can be found in Appendix A.

Introduction

Chemotherapy induced peripheral neuropathy (CIPN) is a serious side effect of some types of chemotherapies in which the peripheral nerves, the nerves outside the brain and spinal cord, are damaged. Chemotherapeutic agents that are likely to cause CIPN include platinum drugs, including cisplatin, carboplatin, oxaliplatin; taxanes, including paclitaxel, docetaxel, and cabazitaxel; and plant alkaloids, including vinblastine, vincristine, vinorelbine, and etoposide (American Cancer Society, 2019). Some immunomodulating drugs such as thalidomide,

lenalidomide, and pomalidomide and proteasome inhibitors such as vortezombin, carflizombin, and ixazomib are also known to cause CIPN (American Cancer Society, 2019).

Functions of peripheral nerves that can be affected these treatments include the nerves’

ability to carry sensations to the brain and to control one’s arms and legs (American Cancer

Society, 2019). Symptoms can vary depending on the type of chemotherapy and whether the

sensory nerve fibers, motor nerve fibers, autonomic nerve fibers, or all of the types of fibers are

affected. When sensory nerve fibers are affected, common symptoms include paresthesia,

numbness, tingling, altered touch sensations, impaired vibration, balance problems, and painful

sensations (Johns Hopkins Medicine, n.d.; Zajaczkowska et al., 2019). These painful sensations

are often described as spontaneous burning, shooting, or electric shock-like pain (Zajaczkowska

et al., 2019). When motor nerve fibers are affected, common symptoms include weakness of

muscles in the hands and feet, gait and balance disturbances, and impaired movements (John

Hopkins Medicine, n.d.). Autonomic nerves fibers can also be affected, and their involvement

can result in orthostatic hypotension, constipation, and altered sexual or urinary function

(Zajaczkowska et al., 2019). The symptoms can last from weeks to years after the completion of treatment and be severe enough to be a limiting factor for treatment, while also altering patient’s quality of life.

The American Cancer Society’s list of CIPN symptoms will be what defines CIPN symptoms for this systematic review. These symptoms include tingling, which can be described as a “pins and needles feeling,” a burning or warm feeling, numbness, discomfort or pain, decreased ability to feel hot and cold, and cramping in the feet (American Cancer Society, 2019).

While the authors of this systematic review understand that CIPN can greatly influence balance, for the purpose of this review, the interventions effectiveness will be based on improvement in the above symptoms, and balance will not be considered. Still, CIPN can also lead to falls, which can lead to serious complications. It was found that women with CIPN are 1.8 times more likely to fall than women without CIPN (Winters-Stone, et al., 2017).

Currently, there are limited therapeutic options for CIPN and no way to prevent the condition. More research is needed to find additional remedies. One developing field involves the effects of exercise on CIPN symptoms. The primary outcome of this systematic review is to look at existing research concerning adults with CIPN and how exercise can improve or reduce CIPN symptoms either during chemotherapy or post-chemotherapy. A secondary outcome of this review is to examine what the literature states about exercise interventions and its impact on falls in this patient population.

Background

The terms exercise and physical activity will be used interchangeable throughout this

review. The World Health Organization (WHO) considers exercise to be subcategory of physical

activity (2017). Exercise is planned, structured, repetitive, and purposeful and has a goal of

improving or maintaining an aspect of one’s physical fitness (World Health Organization, 2017).

Physical activity is defined in a broader sense than exercise. Any movement produced by skeletal muscles that requires energy expenditure is categorized as physical activity (World Health Organization, 2017). In the 2018 Physical Activity Guidelines for Americans released by the Office of Disease Prevention and Health Promotion, it is clarified that all exercise is considered as physical activity but not all physical activity as exercise (U.S. Department of Health and Human Services, 2018). In this review, exercises will be categorized into balance exercises and endurance exercises. The interventions found in the studies of this review all involve balance, endurance, or multimodal exercises that meet the definition of exercise above.

It is also important to state that the current exercise guidelines for cancer survivors encourage them to engage in exercise to improve physical fitness, restore physical functioning, improve quality of life, and decrease cancer related fatigue (Campbell et al., 2019; Schwartz et al., 2017; Segal et al., 2017). It is recommended that for optimal outcomes, cancer survivors engage in, “moderate-intensity aerobic training at least three times per week, for at least 30 minutes, for at least 8-12 weeks”. Resistance training twice a week of at least 2 sets of 8 to 15 repetitions, along with aerobic training has also presented similar benefits (Campbell, et al., 2019). For this this review, exercise interventions that specifically target CIPN symptoms were selected.

Methods Search Strategy

The author of this article conducted a systematic literature search on the computer to

gather studies published from 2014-2019. The following search terms were used for searches on

PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Scopus:

chemotherapy induced peripheral neuropathy, exercise, and falls. We manually found 4 articles

in Google Scholar using the same search terms.

Inclusion and Exclusion Criteria

All retrospective, prospective, cross-sectional, exploratory, qualitative, longitudinal, and randomized, controlled trial (RCT) studies that had an intervention of physical activity, exercise, or balance were eligible for inclusion. The search was restricted to studies written in English that had human participants with cancer and ages 18 and older. The resulting studies were examined to see if methods that measured CIPN symptoms, as defined in the introduction, were included.

Exclusions included systematic reviews, case reports, study protocols, expert opinions, dissertations, or abstracts (see Figure 1).

The comprehensive search resulted in 92 articles from the databases, including the manual additions from Google Scholar. Of those, 38 were duplicates and removed. Fifteen more studies were excluded based on obvious irrelevance based on title and abstract screening. The remaining 39 articles were fully screened. Twenty-nine articles were excluded because they did not meet the inclusion or exclusion criteria. A final sample included 10 articles, and the matrix (see Appendix A) was assembled.

The entire systematic search was rerun on January 17

, 2020 without the search term fall.

This was to ensure that the search captured all of the necessary studies for this topic. One new article, which had not been published at the time of the original search, was added to yield a total of 11 articles for this systematic review.

Data Extraction

After the search and elimination of duplicates and irrelevant articles, two authors (ALB

and RF) reviewed the remaining 39 articles. These studies were checked for inclusion criteria.

The authors examined the type of study, the characteristics and location of the sample

population, and ensured the inclusion of an exercise intervention that targeted CIPN symptoms.

Studies were categorized as utilizing balance interventions, endurance interventions, or multimodal interventions.

Findings

General Characteristics of CIPN studies

Characteristics of the 11 reviewed studies are summarized in Appendix A. Ten studies used the terminology of chemotherapy induced peripheral neuropathy (CIPN) and 1 study used the term peripheral neuropathy for patients as they underwent chemotherapy. Thirteen different measures were used to assess CIPN symptoms. Frequently, a combination of measures was used to assess the results of the intervention on both the subjective and objective symptoms of CIPN.

These measurement tools consisted of the Total Neuropathy Score (TNS), including the clinical version (TNSc) and modified version (mTNS), the European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire Concerning Neuropathic Symptoms (EORTC-QLQ-CIPN20), the Functional Assessment of Cancer Therapy/Gynecology Oncology Group (FACT&GOG), including the Neurotoxicity Subscale (FACT&GOG-NTX) and the Trial Outcome Index (FACT-TOI), the CIPN Rasch Built Overall Disability Score (CIPN-R-ODS), the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), the Chemotherapy Induced Peripheral Neuropathy Assessment Tool (CIPNAT), the Nerve

Conduction Velocity (NCV) test, quantitative sensory testing, the Pain-DETECT, a standardized

clinical battery test, clinical sensory testing, tuning fork assessments, and a patient-reported scale

in which CIPN symptoms were ranked from 1-10.

All studies were published within 5 years of the search date. Three studies were prospective longitudinal, 7 were RCTs, and 1 was a secondary analysis of an RCT. Research about this topic is being performed globally as 6 studies were conducted in Germany, 2 studies in India, and 1 study each in the United States, Canada, and Australia. Sample sizes ranged from 27 to 355 participants with mean ages ranging between 48 and 70 years.

Although each of the study participants in all 11 studies underwent chemotherapy, their chemotherapy status during the studies’ interventions varied. Three studies included participants who were all post-chemotherapy. Three studies implemented their interventions all during chemotherapy. One study provided the intervention during chemotherapy and continued the intervention post-chemotherapy. Three studies encompassed a mix of patients who were either post-chemotherapy or currently undergoing chemotherapy. One study did not report the chemotherapy status of their participant population.

Interventions in these studies included endurance training, balance training, resistance and strength training, sensorimotor training, whole body vibration, and closed kinematic chain exercise. For the purpose of this review, exercise interventions are categorized into balance exercise, endurance exercise, and multimodal exercise. Endurance exercises are comprised of both cardiovascular exercises and resistance exercises. The multimodal approach, in which both balance and endurance training are part of the intervention, is the most common intervention.

Endurance exercises will include both resistance training and cardiovascular training.

Balance Exercise Interventions

Three studies resulted from the systematic search that utilized only balance exercises as the intervention to improve CIPN symptoms. Details of these 3 studies are found in Appendix B.

Balance exercise interventions included closed kinematic chain exercises, home based muscle

strengthening and balance exercises, sensorimotor training, and whole body vibration. Fernandes

& Kumar implemented an intervention of 15 sessions of closed kinematic chain (CKC) exercises over a 3 week period (2016). Dhawan et al. studied the effects of a 10 week, daily, home-based muscle strengthening and balance exercise regimen (2019). Streckmann et al. compared the effects of sensorimotor training (SMT) and whole-body vibration (WBV) over 6 weeks (2019).

For this review, whole body vibration is considered a balance exercise as it targets similar mechanisms as SMT and SMT consists solely of balance exercises (Streckmann, 2019). Sample sizes were 30, 40, and 45 and the chemotherapy status of the patients varied. Fernandes and Kumar (2016) did not report their patient chemotherapy status, Steckmann et al.’s (2019) patients were all status post chemotherapy, and Dhawan et al.’s (2019) subjects all underwent chemotherapy during the intervention.

Different instruments were used to measure CIPN symptoms including a standardized clinical test battery for objective CIPN symptoms, FACT GOG-NTx for subjective CIPN

symptoms, Pain-DETECT, mTNS score, CIPNAT, RLS performa, NCV, and LANSS pain scale.

CKC exercises were found to cause a 52% change in mTNS scores from a pre-test score of 13±1

to a post-test score of 6±0.9 (Fernandes and Kumar, 2016). After CKC exercises, patients also

reported decrease tingling sensation and pain with an increase in pinprick and vibration senses in

their lower limbs (Fernandes and Kumar, 2016). Streckmann found that WBV and SMT helped

improve sensory and associated motor symptoms and subjective symptoms (2019). WBV targets

an improvement in pain, while SMT helps tendon reflexes and subjective symptoms. Although

only 68% of the participants in Dhawan’s intervention adhered to the exercise regime, the

balance exercises were found to help discomfort in the patients’ hands and feet (p = 0.02) and

decrease pain (2019). Incidence of neuropathic symptoms and neuropathy interference between

the control group and intervention group post-test both had p values of less than 0.0001 (Dhawan, 2019). Balance exercise interventions were found to be associated with some improved CIPN symptoms.

Endurance Exercise Interventions

One study found in the literature search looked solely at the effects of endurance training on CIPN symptoms. Klecker based their study of the Exercise for Cancer Patients (EXCAP) recommendations. For six weeks, patients participated in a progressive walking plan and

progressive therapeutic band workout (Klecker, 2018). All 355 patients underwent chemotherapy during the intervention and the data was extracted from this study was a secondary analysis of an RCT. Details about the exact exercise regimen are in Table 2. This intervention’s effectiveness was measured by patient reported CIPN symptoms of numbness and tingling and hot/coldness in their hands and feet over the most recent 7 days on a 1-10 scale. Post-intervention, both groups reported more severe CIPN symptoms, but the intervention group reported less severe CIPN than the control group by almost 0.5 units. So, while endurance exercise was not found to completely prevent or eliminate all CIPN symptoms, the results of the study showed that endurance

exercises helped decrease the severity of CIPN symptoms.

Multimodal Exercise Interventions

Seven studies that utilized multimodal approaches for their exercise interventions were

found for this review. To be considered a multimodal approach, the intervention must include at

least one of both balance training and endurance training. Details of these multimodal exercise

interventions can be found in Table 2. Six different studies contained two different types of

endurance training, cardiovascular exercise and strength/resistance exercise, along with balance

training (Bland et al., 2019, Kneis et al., 2020, Zimmer et al., 2018, Streckmann et al., 2014,

Schonsteiner, et al., 2017, and McCrary et al., 2019). The number of participants in these multimodal exercises ranged from 29 to 131 patients. Interventions lasted from 6 weeks to 36 weeks. Resistance workouts, in which the fitness regimen was defined, involved weights in 2 studies and a mixture of weights and resistance bands in 2 studies (McCary et al., 2019,

Streckmann et al., 2014, Zimmer, et al., 2018, Bland, et al., 2019). All 7 studies involved some form of cardiovascular training including walking, incline walking, a cross trainer, a treadmill or a stationary bike.

Balance interventions were found to be similar throughout these studies, and included repetitive of stabilizing tasks and leg stances. The exception was whole-body vibration. The chemotherapy status of the patients varied. Two studies contained patients who were all post- chemotherapy (Kneis, et al., 2019, McCrary et al., 2019). Two studies implanted their

interventions during chemotherapy and continued their interventions post- therapy (Vollmers et al., 2018, Steckmann et al.,). Two studies had a mixture of patients during their chemotherapy and post-chemotherapy (Zimmer et al, 2018, Schonsteriner et al, 2017). Many different

instruments were used to measure CIPN symptoms including EORTC-QLQ-CIPN-20, NtxS and TOI of the FACT&GOG, TNSc, CIPN-R-ODS, quantitative sensory testing, a tuning fork, and a clinical sensory test. Common findings reported in both Bland’s study and Schonsteriner’s study include that the multimodal exercises helped improve numbness in one’s toes and feet and improve vibration sensations. Commonly, it was reported that strength improved, while symptoms and pain.

Falls Report

Of the 11 studies in this review, 3 had no mentioning of falls or fall risk (Dhawah et al.,

2019; Kleckner, et al., 2018; Schonsteiner, et al., 2017). Of the remaining 8 articles, 4 studies

mentioned falls or falls risk only in their introductions (Fernandes & Kumar, 2016; Kneis et al., 2020; McCrary et al., 2019; Bland et al., 2019). These four introductions supported the concept that CIPN may lead to a higher risk of falls. This risk can be due to gait and balance deficits caused by CIPN (McCrary et al., 2019). Symptoms such as absent tendon reflexes, impaired dorsiflexion, loss of sensitivity and proprioception, and decreased strength of the muscles around the ankle joint could be improved by exercise interventions, decreasing one’s fall risk (Fernandes

& Kumar, 2016; Streckmann, et al., 2019).

In the remaining 4 studies, 1 study talked about falls only in their discussion (Zimmer, et

al., 2018). The other 3 studies mentioned falls in both their introductions and conclusions

(Streckmann, et al., 2019; Vollmers, et al., 2018; Streckmann, et at., 2014). These 4 studies also

connected the presence of CIPN with a higher risk of falls. While these studies collected data on

the symptoms of CIPN which cause falls, no study measured fall rates before and after the

interventions. During a multimodal exercise intervention, Streckmann, et al., did measure

perturbed mono-pedal stance, which stimulates stumbling (2014). It was found that 54% of the

patients in the control group were unable to maintain balance once therapy started and would

have fallen. The intervention group stayed stable at all times, showing a strong connection

between multimodal exercise and a decreased fall risk (Streckmann, et al., 2014). In particular,

sensorimotor training was the exercise intervention most associated with decreased risk of falls

(Streckmann, et al., 2019; Vollmers, et al., 2018; Streckmann, et al., 2014). Posturometry was

supported as a good diagnostic tool for measuring balance and identify patients who have a

higher fall risk (Vollmers, et al., 2018; Streckmann, et al., 2014). More data could be collected

on this topic if the research performed by the authors of this paper focused on balance deficits of

CIPN, rather than the other symptoms of CIPN.

Discussion

This review addresses potential benefits of balance, endurance, and multimodal exercises for patients with CIPN during and post chemotherapy. The primary outcome was to examine which interventions improved or reduced the CIPN symptoms of tingling, burning, numbness, discomfort or pain, decreased ability to feel hot and cold, and cramping in the feet. Through this review, it was found that different exercise interventions often help decrease CIPN symptoms regardless of the stage of treatment. Bland, et al. tested the same exercise intervention during chemotherapy for one group and after chemotherapy for another group (2019). No difference in the groups’ EORTCT-QLQ CIPN20s was found at any time, but exercise was shown to have the potential to reduce CIPN symptoms and help patients adhere to their treatment plans (Bland, et al., 2019). Balance exercises in particular were often connected with decreased pain (Fernandes and Kumar, 2016; Streckmann, et al., 2019, Dhawan, et al., 2019). Common cardiovascular exercises utilized were walking on treadmills and outside and using a stationary bike or elliptical machine. Free weights, weights machines, and bands were used as forms of resistance workouts.

These resistance workouts helped prevent strength loss (Vollmers, et al., 2018). While CIPN symptoms occur and get worse with chemotherapy regardless of the exercise intervention, intervention groups often reported less severe or more stable symptoms compared to control groups (Klecker, et al., 2018, Zimmer, et al., 2018). Endurance workouts often helped sensory symptoms, while balance workouts often helped improve functional status (Kneis, et al., 2020).

A multimodal approach was most commonly used. Streckmann, et al. helped show the

importance of including balance exercises in an exercise regime (2019). In a population that had

been previously engaging in endurance and strength training, but was not seeing any beneficial

effect on their CIPN symptoms, interventions of SMT and WBV led to an improvement in

sensory and associated motor symptoms (Streckmann, et al., 2019). For optimal results, multimodal approaches should include balance exercises. In general, exercise is a low risk method for patients with CIPN to improve physical fitness and sensory function and possibly decrease their CIPN symptoms.

In another systematic review that studied exercise interventions on patients with CIPN while they underwent therapy, Duregon et al. also supported the use of exercise as a feasible and effective way to counteract some limitations of CIPN (2018). A multimodal approach of

endurance, strength, and balance can be particularly useful. Duregon et al. recommended a combination of aerobic exercise, total body strength training, and proprioceptive training in a program which would last longer than 36 weeks (2018). The exercise interventions involved in this review such as the CKC exercises and endurance, balance, and sensorimotor training can also be considered physical therapy interventions. When examining these interventions for their impact on balance, function, quality of life, and symptoms of CIPN, Brayall et al., agreed that such interventions can help reduce CIPN symptoms (2018). The interventions can be helpful for both patients undergoing treatment and for patients once they are done with their treatment (Brayall et al., 2019). It is important to consider that CIPN symptoms can still increase and become more severe despite exercise interventions, but that exercise is still recommended for cancer patients to improve their lives (Campbell et al., 2019).

The secondary outcome this review was to explore how interventions affect falls risk in

this patient population. According to these articles, CIPN may affect patients’ gait and balance

which can lead to a higher risk of falls. Exercise interventions, especially sensorimotor training,

can help decrease this risk (Streckmann, et al., 2019; Vollmers, et al., 2018; Streckmann, et al.,

2014). To accurately evaluate the risk of falls in CIPN patients, providers should collect fall data at each clinic visit. In this fashion, patients at higher risk can be properly monitored and assisted.

Implications for Nursing Practice

CIPN is a common side effect for cancer survivors who have been treated with platinum drugs, taxanes, plant alkaloids, some immunomodulating drugs, and some proteasome inhibitors.

To help patients prepare psychologically and physically for treatment, nurses need to be educated about CIPN. Nurses need to know the chemotherapies that cause CIPN, CIPN’s signs and

symptoms, potential treatments that could decrease side effects, and coping strategies. Nurses can teach about self-care strategies, can measure the effectiveness of exercise interventions on CIPN, and can help create future research studies that investigate the prevention and

management of CIPN (Dhawan, et al., 2019). Nurses can also inquire about patients’ fall histories. They can help other health care professionals realize how CIPN symptoms can place patients at risk of falling, so that precautions can be taken. In general, per current cancer

guidelines, nurses can support patients exercising during and after treatment in order to increase their health and quality of life (Campbell, et al., 2019). More specifically, this review shows that by educating patients about particular forms of exercise, nurses can help them reap these benefits by improving CIPN symptomatology.

Conclusion

Future studies on exercise interventions on CIPN symptoms could focus on the ideal

timing for exercise interventions, test specific workout regimens with different ratios of balance

and endurance training, and make exercise interventions specific to different types of cancer, if

that is found to be helpful. As more people are being treated with chemotherapy, more people

will be developing CIPN. This is concerning because of the limited treatment options for this

condition. Future work is warranted to develop more interventions that target CIPN symptoms.

Cancer patients should exercise for their health, but especially need to be encouraged to engage in multimodal exercise programs. In this way, patients can potentially help prevent or decrease the severity of CIPN symptoms and decrease their risk of fall.

Lessons Learned From Review

Throughout my time in nursing school, we have had limited lectures on the topics of hematology and oncology. We learned about typical side effects of chemotherapy such as alopecia, nausea, vomiting, and fatigue, but I had never learned about CIPN before this project.

This review made me aware of a very serious side effect of chemotherapy that has few treatment options. As a nursing student who has accepted a new graduate RN position on a

hematology/oncology unit, I hope to bring increased awareness to my future colleagues about

encouraging our patients, who will be receiving chemotherapies known to cause CIPN, to engage

in a multimodal exercise. I would be interested in learning about exercise groups or classes at the

YMCA or UNC-affiliated workout facilities offered for cancer patients. It would be beneficial

for programs to be offered in which CIPN symptoms are targeted through multimodal exercise

interventions. The findings of this systematic review will be useful to help provide the best care

possible to the patients on my oncology unit. In Erin’s situation (see case-study above), she is

likely suffering from CIPN. It would be important for her health care professionals to recognize

this so that they can monitor her symptoms and their severity.

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3875-5

Tables Table 1

Summary of Articles Included in Literature Review Study #,

Author

Purpose Sample

Characteristics and Setting

Intervention IG: intervention group

CG: control group

Design and Instruments (for American Cancer Society defined CIPN symptoms)

Findings

Fernandes and Kumar, 2016

Evaluating the effects of closed kinematic chain (CKC) exercises on balance for patients with CIPN

30 patients, whose

chemotherapy status, was not reported, in India.

-13 females and 12 males -All over the age of 30

All 25 participants underwent 15 training sessions over 3 weeks.

Sessions consisted of 7 exercises for 12 minutes each including ROM exercises, toe and heel raises, wall slides, and unipedal balance for time.

Prospective, longitudinal -Modified Total Neuropathy Score (mTNS)

CKC exercises improved patients’

CIPN severity and balance with statistically

significant values. A 52% change was found in mTNS scores from pretest to post test. CIPN symptoms like tingling and pain improved. As muscles around ankle joint become stronger through CKC exercises, balance and risk of falls improves.

Streckmann, et al., 2019

Assessing the impact of sensorimotor training (SMT) and whole-body vibration (WBV) on patients with CIPN

40 patients, all status post chemotherapy, in Germany.

-27 females and 12 males -Ages ranging 47-74 years -Mean ages were 56, 59, 59, and 57 years

All patients had done strength and endurance training prior to

SMT IG: n=10 WBV IG: n=10 Oncological control: n=10 Healthy control:

n=10

For 6 weeks, the 20 patients in the IGs had 2 weekly sessions.

SMT involved balance exercises on progressively more unstable surfaces. WBV

Prospective RCT -Standardized clinical test battery for objective CIPN symptoms -FACT&GOG- Ntx

-Pain-DETECT for neuropathic pain

Balance exercises like SMT and WBV can help decrease CIPN, improving sensory and associated motor symptoms. SMT is superior for

subjective symptoms

and WBV superior

for pain. After the

intervention, CIPN

patients were

comparable to

healthy control

groups in peripheral

deep sensitivity,

this

intervention, which had no reported effect on their CIPN.

involved training on a vibration platform.

pain, and tendon reflexes.

Improvements due to SMT and WBV could contribute to reduced falls.

Dhawan, et al., 2019

Assessing the effectiveness of muscle

strengthening and balancing exercises in reducing CIPN symptoms and improving QOL for cancer patients treated with neurotoxic chemotherapeuti c drugs

45 patients, all during

chemotherapy in Delhi, India.

-38 females and 7 males -Mean age + SD of 50.5 + 7.9 years in the IG and 52.5+

6.6 years in the CG

IG: n=22 CG: n=23 For 10 weeks, the 22 patients in the IG did 30 minutes of daily home-based exercises of muscle strengthening and balance exercises. The 23 in the CG, did standard routine care for 10 weeks.

RCT, longitudinal -CIPNAT

-Nerve conduction velocity (NCV) -LANSS pain scale

Muscle

strengthening and balance exercises can help reduce CIPN pain and improve QOL. Post- intervention, the IG significantly

improved their functional, symptoms, and global health status QOL compared the CG (p<0.05).

A significant reduction in neuropathic pain scores was also found (CIPNAT, p<0.001).

Kleckner, et al., 2018

Examining the effects of

exercise on CIPN symptoms, the factors that predict CIPN symptoms, and the patients’

characteristics that moderate effects of

exercise on CIPN symptoms

355 patients, all during

chemotherapy, in Rochester, NY, USA.

-328 females and 27 males

-Mean ages + the SD of 55.9 + 9.7 years in the IG and 55.6 + 11.8 years in the CG

IG: n= 170 CG: n=185 For 6 weeks, the 170 patients in the IG did daily- home based exercises including progressive walking and resistance exercises. The 185 patients in the CG did standard care for chemotherapy for 6 weeks.

Secondary analysis of an RCT

-Patient reported their CIPN symptoms over the last 7 days on a 1-10 scale (0=

not present and 10=the worse) for:

1. numbness and tingling

2. hot/coldness in hands/feet

Exercise may help decrease CIPN symptoms. Post- intervention, both groups had more severe CIPN symptoms, but IG reported less severe CIPN than CG by almost 0.5 units on the 1-10 scale. For the IG compared to the CG, numbness and tingling

improved by − 0.42

(p = 0.061) and

hot/coldness in

hands/feet by − 0.46

(p = 0.045). A

greater reduction in

CIPN symptoms found for older patients, males, and those with breast cancer.

Kneis, et al.,

2019 Evaluating the effects of balance exercises versus only endurance training on CIPN symptoms and functional performance, focusing on improving CIPN patients’ balance performance

37 patients, all status post chemotherapy in Heidelberg, Germany.

-26 females and 11 males -Ages ranging from 44-82 years (x͂ = 62)

IG: n=18 CG: n=19 All 37 patients underwent two sessions a week for 12 weeks. The 19 in the CG did only endurance training of 30 minutes on a stationary bike.

The 18 in the IG did the same 30 minutes of endurance training along with 30 minutes of balance training.

RCT

-EORTC-QLQ- CIPN-20 -NtxS of FACT&GOG (neurotoxicity scale)

Exercise and balance training both provide benefits for patients with CIPN

decreasing CIPN symptoms via the EORTC-QLQ- CIPN-20 (IG, p=0.007 CG, p=0.027).

Endurance training helps decrease sensory symptoms.

Balance training helps improve functional status.

McCrary, et al., 2019

Evaluating the impact of a multimodal exercise

intervention on CIPN symptoms and related functional deficits for cancer survivors with persistent CIPN symptoms

29 patients, all status post chemotherapy, ranging from 3 to 156 months (x͂= 18.7 months) in Sydney, Australia.

-21 females and 8 males -Ages ranging from 32-79 years (x͂ = 61.6)

All 29 participants underwent 8 weeks of 3-60- minute sessions a week

including resistance, balance, and cardiovascular exercise. 20 minutes of each type of exercise were completed.

Prospective, longitudinal -TNSc

-EORTC CIPN-20 -CIPN-R-ODS for disability related to CIPN

Multimodal exercise can help patients with CIPN as patients reported improvements in CIPN symptoms, balance, and QOL.

Compared to an 8 week control period with no statistically significant changes in CIPN symptoms, CIPN symptoms during intervention improved objectively (CIPN-20, p<0.01) and subjectively (TNSc p<0.01).

Disability due to

CIPN decreased

(CIPN-R-ODS, p=0.03).

Vollmers, et

al., 2018 Determining if sensorimotor exercises have a positive effect on physical and psychological parameters for breast cancer undergoing neurotoxic chemotherapy

36 patients, all during

chemotherapy and post chemotherapy (prior chemo, then 12 and 18 weeks after) in Kiel, Germany.

-All 36 patients were female -Age range of 18 to 75 years -Mean age + SD in the IG was 48.56 ± 11.94 years and 52.39 ± 10.14 years for the CG

IG: n=17 CG: n=19 During

chemotherapy and six weeks post-chemo, the IG participated in moderate strength and endurance training along with

sensorimotor training based on balance training. The CG was solely given an instruction sheet suggesting regular physical activity.

Prospective RCT -EORTC CIPN-20

Sensorimotor training helped improve postural stability related CIPN. Balance improved in the IG (p<0.01) compared to the CG who decreased in postural stability via the Fullerton Advanced Balance Scale.

Strength training also helped prevent a loss of strength that the CG experienced.

No significant improvement was found in

psychological parameters.

Strec kmann, et at., 2014

Assessing how exercise, particularly sensorimotor training (SMT), effects

lymphoma patients during chemotherapy, with a primary endpoint of how exercise effects QOL

61 patients, all during

chemotherapy and post chemotherapy (prior chemo, then 12, 24, and 36 weeks after), in Freiburg, Germany.

-14 females and 42 males -Ages ranging 19-73 years -Mean ages of 44 years in IG and 48 years in the CG

IG: n=30 CG: n=31 For 36 weeks, the 30 in the IG did 2-60-minute sessions a week of aerobic endurance training, SMT, and strength training. The 31 patients in the CG participated in no exercise during

chemotherapy and limited exercise post chemotherapy.

Prospective RCT -Tuning fork for PNP

Patients benefited from specific exercise program throughout all phases of therapy. PNP diminished 97.5% in IG while no patient in CG reduced PNP (P<0.01). IG

improved their balance while CG’s balance continually declined. Exercise improved QOL and reduced side effects like PNP and balance control.

Zimmer, et

al., 2018 Assessing the

effects of 30 patients, in

Essen, IG: n=17

CG: n=13 Prospectiv

e RCT Multimodal exercise

can help decrease

multimodal exercise program on CIPN,

endurance, strength, and balance control in patients with metastasized colorectal cancer

Germany.

-20 had chemo during study period (IG:

n=10, CG:

n=10) -10 did not have chemo during the study period (IG: n=7, CG:

n=3)

-9 females and 21 males -Ages ranging 50-81 years -Mean ages of 68.53 years in the IG and 70.00 years in the CG

For 8 weeks, the 17 patients in the IG had 2-60- minute sessions a week of resistance, endurance, and balance training.

The 13 patients in the control group were given standard written

directions for fitness.

-The Trial Outcome Index (TOI) of the FACT/GOG-NTX

CIPN and improve balance and strength to increase patients’

QOL. Neuropathic symptoms were stable in the IG, while CG’s

symptoms worsened (TOI, P=0.37). IG improved strength and balance, resulting in improved CIPN symptoms. As patients’ balance improves, the risk of falling decreases.

Schonsteiner , et al., 2017

Evaluating the effects of whole- body vibration (WBV) in addition to an integrated workout program (IP) on CIPN symptoms

131 patients, either during or post

chemotherapy, in Ulm,

Germany -Median months since patients’ last chemo in the IG was 2 months (range:0-98) and CG was 0 months (range:0-51).

-68 females and 63 males -Ages ranging 24-71 years -Mean ages of 69 years in IG and 62 years in the CG

IG: n=66 CG: n=65 Over 15 weeks, the 66 patients in the IG had 15 sessions of WBV and IP. IP consisted of massage, passive mobilization, and alternating training

exercises.

Walking was encouraged. The 65 patients in the CG did everything the IG did except for the WBV.

Prospective, longitudinal -FACT/GOG- NTX

-Quantitative sensory testing including warm and cold detection thresholds

(QST)

WBV with IP can help improve physical fitness and sensory function and decrease symptoms of CIPN. All patients had less symptoms and pain (NTX, P<0.001). WBV particularly

improved patients’

chair rising test and warm-detection- threshold (QST, P=0.02), decreased discomfort and tingling in the feet, and helped increase fitness and balance.

Bland, et al., Evaluating the 27 patients IE: n=12 RCT Between the IE and

2019 effect of exercise on CIPN during versus after taxane-based chemotherapy in women with breast cancer

either during chemotherapy or post

chemotherapy, in Canada.

-All patients were females -Mean age + SD in the immediate exercise (IE) group was 51.0 +8.1 years and in the delayed exercise (DE) group was 49.5 +11 years

immediate exercise

(exercise during chemo followed by a period of no formal training) DE: n=15 delayed exercise (usual care during chemo with exercise intervention after chemo completion) Both groups underwent 8-12 weeks of 3 days a week of supervised aerobic, resistance, and balance training and 2 days a week of home- based aerobic activity.

-EORTC QLQ- CIPN20

-Clinical sensory testing of the lower limbs including vibration sensation via a tuning fork and temporal summation of pain via a pinprick

DE, no differences in CIPN symptoms were reported at any time. Symptoms worsened with cumulative doses and peaked at the end of treatment.

Exercise during chemo did help specific symptoms such as numbness in toes or feet and vibration sensation, but after chemo, no differences were found between groups. At the end of chemo, QOL was higher in the IE versus the DE group but QOL increased in the DE group after their exercise

intervention.

Exercise may help

chemotherapy be

more tolerable.

Summary of Exercise Interventions Author/Study Balance Exercise Fernandes and

Kumar, 2016 Closed Kinematic Chain (CKC) Exercises –15 training sessions over 3 weeks

7 exercises for 12 minutes each including open chain active ankle range of motion exercises, bipedal toe and heel raises, bipedal inversion and eversion, unipedal toe raises and heel raises, unipedal inversion and eversion, wall slides, and unipedal balance for time

Streckmann, et al., 2019

Whole Body Vibration (WBV) – 6 weeks of 2 sessions weekly

4 progressing sets, for 30 seconds to 1 minute, of vibration exercises from 18 to 35 Hz and amplitude of 2-4 mm on a side-alternating vibration platform

Sensorimotor Training (SMT) – 6 weeks, 2 sessions weekly

4 exercises, three times each for 20 seconds, of progressively more difficult balance exercises on progressively unstable surfaces

Dhawan, et al.,

2019 Home based muscle strengthening and balance exercise – 10 weeks of daily exercise

Exercises listed below were completed for a total of 30 minutes a day. 12 total exercises in the lying down, sitting and standing positions.

- Lying: ankle motion, hip abduction, straight leg raise

- Sitting: digit abduction/adduction, wrist motion, elbow flexion and extension, knee flexion and extension, toe tapping

- Standing: one legged stand, toe stand, hip extension, tandem forward walking Endurance Exercise

Kleckner, et al., 2018

Home-based Progressive Walking and Resistance Exercises following the Exercise for Cancer Patients (EXCAP) recommendations – 6 weeks of daily exercise

- Progressive walking prescription: walking daily at low to moderate intense aerobic exercise (60-80% heart rate reserve) with total number of steps measured by a pedometer.

- Progressive therapeutic band prescription: 4 sets of 15 repetitions of 10 band exercises including squat, side

bend, leg extension, leg curl, chest press, row, calf raise, overhead press, biceps curl, and triceps extension along

with four optional exercises. Three different bands of different strengths were provided.

McCrary, et al., 2019

8 weeks of 3-60-minute sessions weekly Resistance: 20 minutes

Two sets of 4 lifting-based exercises with weights Cardiovascular: 20 minutes

Walking, incline walking, or stationary cycling

Balance – 20 minutes

Two sets of 4 leg exercises including two legs and single leg balance moves such as tandem standing and walking and single leg stances with different variations

Vollmers, et al., 2018

2 times a week during patients’ chemo through six weeks after completion of chemotherapy

Resistance: General strength training of upper and lower extremities and a warm-up endurance training. Strength training consisted of 6 different exercises, twice with 20 repetitions of moderate intensity Cardiovascular: Regular physical exercise training

Sensorimotor Exercise

Balance training of both stance and dynamic

movements using one leg stands and smovey exercises on posturomed devices

Streckmann, et at., 2014

36 weeks of 2-60-minute sessions weekly

Resistance: Strength Training: Four resistance exercises carried out for 1 minute at maximum force. Inpatients substituted with a Thera- Band.

Cardiovascular: Aerobic Endurance Training-

Cardiovascular activation on a bicycle dynamometer (60%–70% max heart rate) and 10- to 30-min walk on a treadmill or bicycle

dynamometer (at 70%–80% max heart rate) at the end of the session

Sensorimotor Exercise

Four postural stabilization tasks, progressively

increasing task difficulty as well as surface instability, carried out in three sets. Each set was carried out at 20- s intervals, allowing a 20-s rest between each set and 1 min between exercises to avoid fatigue

Zimmer, et al.,

2018 8 weeks of 2-60-minute sessions weekly Resistance Training – 20 minutes

Circuit training with 5 stations with 2x8-12 repetitions each.

Balance– 15 minutes warm up and 10-15-minute cool down

Balance training: balance pads, balancing on lines

Coordination Practice: cherry pit billows, Brasils

Cardiovascular: Endurance Training - 10 minutes

Cross trainer, bicycle ergometer or walking at 60-70% exercise intensity

Schonsteiner, et al., 2017

15 weeks with 15 set sessions - time dependent on IG or CG IG: WBV + IP

CG: only IP (physical exercise, massage/passive mobilization, walking)

Resistance: Physical Exercises

21 separate exercises that focused on posture and transport movements that were performed daily at home.

Cardiovascular: Walking as frequent and long as possible was encouraged. Steps measured by a pedometer.

Whole body Vibration – IG only

18 minutes of progressive and increasing amplitude and frequency with a cool down on a vibration platform with a seesaw plate

Massage and Passive Mobilization:

Warm up of joints as lower extremities were moved passively for 30 minutes on each side

Kneis, et al., 2020 12 weeks of 2 sessions weekly

IG: 1 hour: 30 minutes endurance and 30 minutes balance training CG: only 30 minutes endurance training

Resistance: Muscular endurance training For main muscle groups

Cardiovascular: 20 minutes of warm-up on a stationary bike at 70- 80% of maximum heart rate

Balance-based exercises: 30 minutes

3 to 8 exercises with 3 repetitions for 20-30 seconds.

-Difficulty was increased by reducing support surfaces, visual input, adding motor/cognitive tasks, and

inducing instability

Bland, et al., 2019 8-12 weeks of 5 days a week Resistance exercise:

5 specific exercises using machines, free weights, or resistance bands to target the primary upper and lower body muscle groups

progressing up to 2 sets of 10 to 12 repetitions

Balance exercise:

-2 single leg standing balance exercises for 6 to 8 repetitions with progressing difficulty from a stable surface with support to unsupported on an unstable surface

-Hand and foot exercises with resistance bands and

balls

up to 35 minutes

Figure 1. Article Selection Process

Appendix A

1) After reading this literature review, do Erin’s symptoms suggest that she may be suffering from CIPN? What other symptoms might she be experiencing or might experience in the future?

2) What should her oncologist recommend her to do as it relates to exercise? What is a potential good exercise regimen for Erin?

3) What are some interventions Erin’s nurses could do to help in order to help Erin

manage her CIPN?