Early Detection of Taxane-Induced Neuropathy in Women With Breast Cancer

Study Overview
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Brief Summary
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Purpose: The purpose of the study is to test a new way of measuring nerve damage in women with breast cancer receiving chemotherapy drug paclitaxel (Taxol).

Detailed Description
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Purpose: The study has four aims; The primary aim of the study is to determine whether women who are receiving either weekly Taxol (80-100 mg/m2) or bi-weekly Taxol (i.e.,dose-dense; 175 mg/m2) show deficits in axon-reflex mediated vasodilation (AMV) over the course of six weeks of Taxol therapy similar to those that have been reported in patients with diabetic and genetically-inherited neuropathies. The second aim of the study is to determine whether women who are receiving either weekly or dose-dense Taxol develop changes in AMV before developing signs & symptoms of chemotherapy-induced peripheral neuropathy (CIPN) in a way that supports using changes in AMV as an early detection method for small-fiber CIPN. A third (exploratory) aim of the study is to determine whether any changes in AMV detected during the study are significantly correlated with self-reported CIPN in a way that would support using changes in AMV as a confirmatory marker for CIPN. A final (exploratory) aim of the study is to describe the size of axon reflexes and axon flares in women receiving weekly Taxol before they start their pre-Taxol anthracycline & cyclophosphamide (AC) therapy.

Official Title
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Early Detection of Taxane-Induced Neuropathy in Women With Breast Cancer

Conditions
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Peripheral Neuropathy

Intervention / Treatment
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* Procedure: Axon Reflexes
* Procedure: Axon Flares
* Procedure: Self-Reported Signs & Symptoms of CIPN


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Women with Breast Cancer: Age 18-85 Able to read, write, and understand English Diagnosed with histologically-confirmed, first-time, non-metastatic breast cancer (stage I-IIIB) No prior exposure to neurotoxic chemotherapy or radiation at the time of enrollment, Will be receiving weekly paclitaxel (Taxol® or generic paclitaxel, 80- 100mg/m2) or bi-weekly Taxol (i.e., dose-dense; 175 mg/m2) as a part of their cancer treatment regimen OR Will be receiving an anthracycline and cyclophosphamide (AC) followed by weekly paclitaxel (Taxol® or generic paclitaxel, 80-100mg/m2) or bi-weekly Taxol (i.e., dose-dense; 175 mg/m2) as a part of their cancer treatment regimen; Inclusion Criteria for Healthy Controls: Aged 18-85 Can read, write, and understand English Exclusion Criteria: A history of cardiovascular disease, hypertension, or peripheral arterial/vascular disease; Current use of (1) medications/supplements to control blood pressure (e.g. beta-blockers, nitrates, calcium channel blockers, Phosphodiesterase-5 (PGE5) inhibitors) or (2) the use of statins for cholesterol; Suspected or diagnosed diabetes (with the exception of gestational diabetes); Pre-existing neuropathy, neuropathic pain, or nerve injury; Pain or significant arthritis in the toes of either foot; Current skin disease or fungal infection of the feet; Significant damage or deformity to the feet that would alter blood flow or make it impossible to measure/interpret findings; Diagnosed or suspected vasospastic disease such as Raynaud's syndrome; Current use of tobacco/tobacco-containing products; Diagnosis of restless leg syndrome or other movement disorders that would prevent accurate data from being able to be collected. In-Study Restrictions: No caffeine- or alcohol-containing products for 12 hours prior to their study visit; No food for at least one hour prior to blood flow monitoring; No non-steroidal anti-inflammatory drugs (NSAIDS) for 24 hours prior to study visits unless directed by a physician to do so. (Note: These restrictions are designed to improve the rigor and quality of the data, but non-compliance will not be grounds for study exclusion; adherence to these restrictions will be monitored during self-report).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Women with Breast Cancer (WBC)<br>Defined as women who: Are 18 to 85 years old at the time of enrollment; Have histologically-confirmed, first-time, non-metastatic breast cancer (Stage I-IIIB); Have no history of neurotoxic chemotherapy or radiation treatment at the time of enrollment; Will be receiving weekly paclitaxel (Taxol® or generic paclitaxel), 80-100mg/m2, or bi-weekly (i.e., dose-dense) Taxol, 175 mg/m2, as a part of their treatment regimen OR Will be receiving an anthracycline and cyclophosphamide (AC) therapy followed by weekly or bi-weekly (i.e., dose-dense; 175 mg/m2) paclitaxel (Taxol® or generic paclitaxel, 80-100mg/m2); Are willing to participate in up to four study sessions. | Procedure: Axon Reflexes<br>* *Axon reflexes will be evoked in the palmar surface of the right great toe using local skin heating with a 0.33 cm2 heat probe using the following protocol: Baseline: Heating the skin of the toe for a minimum of 5 minutes at 33*C. Heat Ramp: Increasing the heat in the heat probe to 42*C at approx. 0.1*C/10 sec. Skin Heating: Heating the skin of the toe for 30 minutes 42*C. Heat Ramp: Increasing the heat in the heat probe to 44*C at 0.1*C/10 sec.. Skin Heating: Heating the skin for an additional 5 minutes at 44*C. The size of the axon reflex during this skin heating protocol will be imaged using Laser Doppler Flowmetry (LDF). In the case that participants develop CIPN on their left side only, the left toe will be substituted.<br>Procedure: Axon Flares<br>* Axon flares will be generated on the palmar surface of the right great toe using the same local skin heating protocol described above, and imaged using a laser speckle contrast imager (LSCI) (also known as full-field laser perfusion imager, or FLPI).<br>* Other names: LDIflare, Heat-Evoked Axon Flare;Procedure: Self-Reported Signs & Symptoms of CIPN<br>* Self-reported signs & symptoms of CIPN such as the presence and location of (1) tingling, (2) numbness, and (3) neuropathic pain, along with information about (4) deficits in vibration thresholds, and (5) loss of deep tendon reflexes will be assessed at each study visit using the 5-item, modified Total Neuropathy Score (mTNS).<br>|
| Healthy Female Controls (HCs)<br>Defined as women who: Are 18 to 85 years old at the time of study enrollment; Can read, write, and understand English, Are willing to participate in three planned study sessions. | Procedure: Axon Reflexes<br>* *Axon reflexes will be evoked in the palmar surface of the right great toe using local skin heating with a 0.33 cm2 heat probe using the following protocol: Baseline: Heating the skin of the toe for a minimum of 5 minutes at 33*C. Heat Ramp: Increasing the heat in the heat probe to 42*C at approx. 0.1*C/10 sec. Skin Heating: Heating the skin of the toe for 30 minutes 42*C. Heat Ramp: Increasing the heat in the heat probe to 44*C at 0.1*C/10 sec.. Skin Heating: Heating the skin for an additional 5 minutes at 44*C. The size of the axon reflex during this skin heating protocol will be imaged using Laser Doppler Flowmetry (LDF). In the case that participants develop CIPN on their left side only, the left toe will be substituted.<br>Procedure: Axon Flares<br>* Axon flares will be generated on the palmar surface of the right great toe using the same local skin heating protocol described above, and imaged using a laser speckle contrast imager (LSCI) (also known as full-field laser perfusion imager, or FLPI).<br>* Other names: LDIflare, Heat-Evoked Axon Flare;Procedure: Self-Reported Signs & Symptoms of CIPN<br>* Self-reported signs & symptoms of CIPN such as the presence and location of (1) tingling, (2) numbness, and (3) neuropathic pain, along with information about (4) deficits in vibration thresholds, and (5) loss of deep tendon reflexes will be assessed at each study visit using the 5-item, modified Total Neuropathy Score (mTNS).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in the mean size of axon reflexes between healthy women and women with breast cancer BEFORE starting Taxol. | Hypothesis: (Cross-Sectional): There WILL NOT be a significant difference in the mean size of axon reflexes (expressed as a %CVCmax) in the great toe between healthy women and women with breast cancer before they start Taxol (i.e., Day 1). Definitions/Notes: The mean size of axon reflexes will be determined by averaging the peak laser doppler values (in tissue perfusion units (TPUs)) that occur during a stable 30-90 second period after increasing the probe temperature to 42*C. The maximum circulatory vascular conductance (%CVCmax) for each participant will be determined by dividing the raw TPU values by the participant's mean arterial blood pressure (MAP) during the axon reflex. The size of axon reflexes for each group will be then calculated by averaging the %CVCmax values corresponding to each individual's axon reflex for each group at that time point. Differences between groups in the size of axon reflexes at Day 1 will be compared using two-tailed t-tests, α=0.05. | Day 1 (before participant's 1st Taxol infusion). | 
| Differences in the mean size of axon reflexes between healthy women and women with breast cancer DURING Taxol therapy. | Hypothesis (Cross-Sectional): There WILL be a significant difference in the mean size of axon reflexes generated on the palmar surface of the right great toe between healthy controls and women with breast cancer during their initial six weeks of Taxol therapy (i.e., day 14 and 42, respectively). Notes: The mean size of axon reflexes during Taxol therapy will be determined by averaging the size of axon reflexes for participants in each group at day 14 and 42, respectively. Differences between groups in the size of axon reflexes at day 14 and 42 will be compared using two-tailed t-tests, α=0.05. | Day 14 (week two of Taxol therapy) and Day 42 (week six of Taxol therapy). | 
| Differences in the mean size of axon reflexes OVER TIME for women with breast during the initial six weeks of Taxol therapy. | Hypothesis (Longitudinal): There WILL be a significant difference in the mean size of axon reflexes generated on the palmar surface of the great toe of women with breast cancer from (a) day 1 to day 14, (b) day 14 to day 42, and from (c) day 1 to day 42. Note: Differences in mean size of axon reflexes over the course of Taxol therapy will be calculated using repeated-measures analysis of covariance (RM-ANCOVA). | Day 1 (before participant's 1st Taxol infusion), day 14 (week two of Taxol therapy) and day 42 (week six of Taxol therapy). | 
| Differences in the mean size of axon reflexes between healthy female controls OVER TIME the six-week study period. | Hypothesis (Longitudinal): There WILL NOT be a significant difference in the size of axon reflexes on the palmar surface of the great toe of healthy female controls from(a) day 1 to day 14, (b) day 14 to day 42, and from (c) day 1 to day 42. Note: Differences in mean size of axon reflexes over the course of Taxol therapy will be calculated using repeated-measures analysis of covariance (RM-ANCOVA). | Day 1 (before participant's 1st Taxol infusion), Day 14 (week two of Taxol therapy) and Day 42 (week six of Taxol therapy). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in the mean size of heat-evoked axon flares between healthy women and women with breast cancer BEFORE starting Taxol therapy. | Hypothesis (Cross-Sectional): There WILL NOT be a significant difference in the mean size of heat-evoked axon flares generated on the palmar surface of the great toe between healthy women and women with breast cancer before starting Taxol therapy (day 1). Note: A heat-evoked axon flare is defined as the area of increased cutaneous blood flow surrounding heat probe that is at least three standard deviations (3SD) above blood flow measured during prior to local skin heating. The size of each axon flare will be expressed in centimeters squared (cm2). The mean size of axon flares for each group will be calculated by averaging the size of axon flares for healthy women at baseline and the size of axon flares for women with breast cancer at day 1 (before starting Taxol). Differences in the mean size of axon flares between both groups at day 1 will be compared using two-tailed t-tests, α=0.05. | Day 1 (before participant's 1st Taxol infusion). | 
| Differences in the mean size of heat-evoked axon flares between healthy women and women with breast cancer DURING six weeks of study visits. | Hypothesis (Cross-Sectional): There WILL be a significant difference in the mean size of heat-evoked axon flares generated on the palmar surface of the great toe between healthy controls and women with breast cancer DURING Taxol therapy at day 14 and 42 (respectively). Note: Differences in the size of heat-evoked axon flares between healthy women and women with breast cancer at days 14 and 42 (respectively) will be compared using separate, two-tailed t-tests, α=0.05. | Day 14 (week two of Taxol therapy) and Day 42 (week six of Taxol therapy). | 
| Differences in the mean size of heat-evoked axon flares between women with breast cancer DURING their initial six weeks of Taxol therapy. | Hypothesis (Longitudinal): There WILL be a significant difference in the mean size of heat-evoked axon flares generated on the palmar surface of great toe of women with breast cancer receiving Taxol from (a) day 1 to day 14, (b) day 14 to day 42, and from (c) day 1 to day 42. Differences in the size of heat-evoked axon flares during Taxol therapy will be evaluated using repeated-measures analysis of variance (RM-ANOVA). | Day 1 (before participant's 1st Taxol infusion), Day 14 (week two of Taxol therapy) and Day 42 (week six of Taxol therapy). | 
| Differences in the size of heat-evoked axon flares for healthy women during the six-week study period. | Hypothesis (Longitudinal): There WILL NOT be a significant difference in the size of heat-evoked axon flares (in cm2) generated on the great toe of healthy women from (a) day 1 to day 14, (b) day 14 to day 42, and from (c) day 1 to day 42. Differences in the size of heat-evoked axon flares during Taxol therapy will be evaluated using RM-ANOVA. | Day 1 (before participant's 1st Taxol infusion), Day 14 (week two of Taxol therapy) and Day 42 (week six of Taxol therapy). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Taxane, Neuropathy, Chemotherapy-Induced Peripheral Neuropathy (CIPN), Breast Cancer, Local skin heating, Axon reflex, Axon flare, Total Neuropathy Score (TNS), Laser Doppler Flowmetry (LDF), Laser Speckle Contrast Imaging (LSCI), Full-field laser perfusion imaging (FLPI), Paclitaxel, Taxol