Home-Based Physical Activity Intervention for Taxane-Induced CIPN

Breast Cancer Female Clinical Trial

— B-HAPI  

Official title:

Home-Based Physical Activity Intervention for Taxane-Induced CIPN

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04621721
• Other study ID #: Pro00040035
• Secondary ID: 1R01CA229681-01A
• Status: Recruiting
• Phase: N/A
• Start date: August 14, 2020
• Est. completion date: September 30, 2024

Study information

• Verified date: July 2020
• Source: University of South Florida
• Contact: Constance Visovsky
• Phone: 8139743831
• Email: cvisovsk[@]usf.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This two-group, randomized control trial (RCT) will test the effects of a home-based, 16 week gait/balance training plus resistance (exercise bands) exercise program as compared to an educational cancer survivorship attention control condition to address persistent taxane-induced peripheral neuropathy in 312 patients treated for invasive breast cancer with taxanes at 1 year or more after completion of therapy. Assessments of lower extremity muscle strength, gait/balance, nerve conduction, neuropathy symptoms, and quality of life (QOL) will be performed.

The proposed exercise intervention addresses gait/balance impairments and motor (resistance) components of taxane-induced peripheral neuropathy. The mechanism by which the intervention achieves the proposed outcomes is though 1) increasing endoneurial blood flow to peripheral nerves and mitochondria resulting in reduction in neuropathic symptoms (including pain) and clinical manifestations of peripheral neuropathy, while improving gait/balance in those with persistent neuropathy; 2) The subsequent increase in nutrient supply allows the mitochondria to function more efficiently, and may alleviate the neuropathic manifestations of taxane-induced peripheral neuropathy. 15

This is the first study proposing to test the home-delivery of an exercise intervention specifically aimed at persistent (long-term) taxane-induced neuropathy. If successful, this study will provide the only evidence-based intervention for patients suffering from persistent neuropathy from neurotoxic chemotherapy. Additionally, the home-delivery format makes this intervention easily translated into clinical practice.

Specific Aims:

In a sample of patients who completed a taxane-containing chemotherapy regimen (> 1 year) for breast cancer and who have a persistent neuropathy (VAS score of > 3) the specific aims of this RCT are:

1. To test the efficacy of a 16-week -delivered program of gait/balance training plus resistance exercise, compared to an educational attention control condition in increasing muscle strength, improving gait/balance and nerve conduction parameters, decreasing the severity of taxane-induced peripheral neuropathy symptoms, and increasing quality of life.

2. To evaluate for differences in muscle strength, gait/balance, sensory (sural) and motor (peroneal) nerve conduction, peripheral neuropathy symptoms, and quality of life (QOL) between patients who receive the exercise program, compared to those in an educational attention control condition controlling for age, BMI, taxane cycles and intervals, neuropathic pain, neuropathy/pain medications, current resistance exercise participation and falls/near falls experienced.

Description:

The use of taxanes in breast cancer chemotherapy regimens is considered standard first line therapy.1 However, taxanes are known to induce peripheral neuropathy, from 59-87% for paclitaxel and from 11-64% for docetaxel. 2-4 Sensory manifestations can include pain; numbness, tingling, & burning; diminished proprioception, and decreased vibration and touch sensation. 5-6 Motor symptoms such as lower extremity muscle weakness and impaired balance has been reported. 7 Currently, peripheral neuropathy remains a significant toxicity resulting in taxane chemotherapy dose reductions or discontinuation, with no evidence-based preventative or treatment strategies are available. 8 Taxanes induce sensory and motor neuropathy by inducing both mitochondrial and vascular dysfunction.9 In rodents, treatment with taxanes resulted in swollen, vacuolated axonal mitochondria that are functionally impaired, producing a chronic energy deficit.10 In addition, toxic effects to the endothelial cells of the vasa nervorum (small arterioles that supply peripheral nerves) in the dorsal root ganglia attenuates blood flow to neurons, resulting in endothelial cell death. 11 These findings suggest that both mitochondrial impairment and vascular damage are major mechanisms that underlie the development of taxane-induced peripheral neuropathy, manifesting as sensory manifestations and neuropathic pain. 9-12

Mitochondrial and vascular dysfunctions lead to sensory loss and reduced muscle strength, functions dependent upon cellular mitochondria to generate energy in the form of ATP (adenosine triphosphate). Thus, mitochondrial dysfunction results in the loss of energy-generating capability, and vascular impairment deprives muscle and nerve cells of oxygen-rich nutrients, further impairing neuronal function. A limited number of human and animal studies have demonstrated that exercise stimulates endothelium-dependent vasodilation and vascular endothelial growth factor (VEGF) expression, increasing endoneurial blood flow and energy generating capacity through mitochondrial protein synthesis and glycolysis, 13, 14

The proposed exercise intervention addresses gait/balance impairments and motor (resistance) components of taxane-induced peripheral neuropathy. The mechanism by which the intervention achieves the proposed outcomes is though 1) increasing endoneurial blood flow to peripheral nerves and mitochondria resulting in reduction in neuropathic symptoms (including pain) and clinical manifestations of peripheral neuropathy, while improving gait/balance in those with persistent neuropathy; 2) The subsequent increase in nutrient supply allows the mitochondria to function more efficiently, and may alleviate the neuropathic manifestations of taxane-induced peripheral neuropathy.

Specific Aims:

In a sample of patients who completed a taxane-containing chemotherapy regimen (> 1 year) for breast cancer and who have a persistent neuropathy (VAS score of > 3) the specific aims of this RCT are:

1. To test the efficacy of a 16-week -delivered program of gait/balance training plus resistance exercise, compared to an educational attention control condition in increasing muscle strength, improving gait/balance and nerve conduction parameters, decreasing the severity of taxane-induced peripheral neuropathy symptoms, and increasing quality of life.

2. To evaluate for differences in muscle strength, gait/balance, sensory (sural) and motor (peroneal) nerve conduction, peripheral neuropathy symptoms, and quality of life (QOL) between patients who receive the exercise program, compared to those in an educational attention control condition controlling for age, BMI, taxane cycles and intervals, neuropathic pain, neuropathy/pain medications, current resistance exercise participation and falls/near falls experienced

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 312
• Est. completion date: September 30, 2024
• Est. primary completion date: July 30, 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 21 Years and older

Eligibility

Inclusion Criteria:

• Female breast cancer survivors (>21) with who completed treatment for invasive breast cancer with taxane-based chemotherapy, and who have a peripheral neuropathy score of > 3 by VAS rating consistent with studies of diabetic peripheral neuropathy.

Exclusion Criteria:

• any disease (e.g. diabetes, HIV) that results in peripheral neuropathy or muscle weakness (such as chronic fatigue syndrome, multiple sclerosis, spinal cord tumors or injuries, stroke,); any disease that would preclude exercise (preexisting cardiopulmonary disease, bone metastasis). Individuals with symptomatic lymphedema or advanced disease at high risk for bone metastases and pathologic fracture will be excluded.

Related Conditions & MeSH terms

• Balance; Distorted
• Breast Cancer Female
• Chemotherapy-induced Peripheral Neuropathy
• Gait Disorders, Neurologic
• Muscle Weakness
• Nervous System Diseases
• Peripheral Nervous System Diseases

Intervention

Behavioral:
• Gait/balance & resistive exercise
Walking forward and back, walking with head motion, static standing, Standing Partial Tandem, Tandem Standing heel to toe, Standing with head turns Single leg stance and March in place. Resistance exercises include: calf raises, lunges, supine leg curls and extensions.

Locations

Country	Name	City	State
United States	University of South Florida	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
University of South Florida	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Participant age	participant will provide their age by self-report	Baseline
Other	Taxane cycles	Number of taxane cycles received and interval since last treatment will be collected.	Baseline
Primary	Gait Change	Gait analysis will be performed using a GAITRite System with 3D motion capture with integrated force platform. Gait variables to be used in analysis are ankle plantar/flexor torque	Change from Baseline to week 16
Primary	Balance Change	Balance analysis will be performed using the Neurocom Balance Master Sensory Organization Test	Change from Baseline to week 16
Primary	Change in Lower Extremity Muscle Strength	Isokinetic dynamometry (Biodex 3.0) Hip flexors, hip abductors, knee flexors, knee extensors, and ankle dorsiflexors will be tested	Change from Baseline to week 16
Primary	Change in Lower Extremity Nerve Conduction	Nerve conduction studies of the sural & peroneal nerve action potentials will be tested by Dr. Vu, USF Department of Neurology.	Change from Baseline to week 16
Primary	Change in Neuropathy Symptoms	FACT-Taxane Additional Concerns subscale53 Addresses symptoms specific to neuropathy. Likert scale: 0 (not at all) - 4 (very much).	Change over time from Baseline to 4 weeks, 8 weeks, 12 weeks, and 16 weeks
Primary	Neuropathy Quality of Life	FACT-Taxane (version 4) 54 A total Quality of Life score can be obtained by summing the subscale scores and will be used for in the data analysis.	Change over time from Baseline to 4 weeks, 8 weeks, 12 weeks, and 16 weeks
Secondary	Change in Neuropathic Pain	Brief Pain Inventory assesses severity of pain, impact of pain on daily function, location of pain, pain medications and amount of pain relief in the past 24 hours	Change over time from Baseline to 4 weeks, 8 weeks, 12 weeks, and 16 weeks
Secondary	Change in Body Mass Index	A portable Tanita Body Composition Analyzer will be used to obtain each participant's weight and body mass index (BMI) through bioelectrical impedance.	Change from Baseline to week16
Secondary	Change in Neuropathy or Pain Medications	Medications used for neuropathy pain will be monitored and documented throughout the study, and coded into drug classifications, and dosage change/no change tracked for analysis	Change over time from Baseline to 4 weeks, 8 weeks, 12 weeks, and 16 weeks
Secondary	Change in Falls or near falls in last month	participant will self-report (yes/no) if they have fallen or had a near fall within the last month.	Change over time from Baseline to 4 weeks, 8 weeks, 12 weeks, and 16 weeks