Treatment of Breast Cancer-related Lymphedema With a Negative Pressure Device

Study Overview
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Brief Summary
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This study will be a 4 to 6 week randomized, controlled, assessor blinded, trial comparing a negative pressure massage device (intervention group), to the standard manual lymph drainage massage (control group), in breast cancer patients with chronic upper extremity lymphedema.

Detailed Description
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Lymphedema (LE) is a protein-rich interstitial swelling caused by reduced lymph transport secondary to lymphatic system damage from cancer treatments. 1 in 5 women will develop LE following breast cancer treatment. These women have greater restrictions in activity and poorer quality of life (QOL) and are more prone to cellulitis than women without LE. LE is incurable and progressive. Persistent lymph stasis creates a condition of chronic inflammation that contributes to fibrosis and fatty deposition in the subcutis of the affected limb. The fibro-adipose changes associated with chronic LE make it less responsive to treatments that primarily target limb volume. Treatments are needed that can improve these skin and subcutaneous tissues changes, as well as reduce limb volume. This 4 to 6 week randomized controlled pilot feasibility study will enroll 80 women with chronic arm LE, and will evaluate a novel negative pressure massage device that mobilizes skin and subcutaneous tissue. This negative pressure treatment provides vertical (lifting) and horizontal stretching of the skin and underlying fascial structures, which increases the subcutaneous space for lymphatic circulation, improves lymph flow, and has the potential to decrease fibrosis. This treatment will be compared to the standard of care massage: manual lymphatic drainage. Women will be randomly assigned to either the negative pressure massage device (intervention group), to the standard manual lymph drainage massage (control group) Objectives: To evaluate recruitment and retention rates; to determine rates of adverse events; and to determine effect sizes for limb volume, tissue induration; and patient reported outcomes of arm function, QOL, and body image in response to treatment

Official Title
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Treatment of Breast Cancer-related Lymphedema With a Negative Pressure Device: A Feasibility Study

Conditions
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Lymphedema, Secondary, Lymphedema of Upper Limb

Intervention / Treatment
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* Device: PhysioTouch
* Other: Manual Lymph Drainage (MLD)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: To be included women must be: Be over 18 years of age; Have had cancer treatment that included a surgical procedure, radiation therapy (RT), and/or chemotherapy (CTX); Have completed active cancer treatment at least 1 year prior to study enrollment; Have been diagnosed with lymphedema (LE) at least one year prior to study enrollment; Have arm lymphedema on one side only; Have confirmed LE based on bioimpedance measurements with an L-Dex® score of >7.1 (note - this is very mild lymphedema); Have stable arm LE. LE will be considered stable if during the 3 months prior to study enrollment there was no arm infection requiring antibiotics, no change in ability to perform activities of daily living related to LE, and no subjective report of significant persistent changes in limb volume; Be mentally and physically able to participate in the study; Be able to attend the sessions at the University of California, San Francisco (UCSF) Parnassus campus; Read and understand English; Be able to understand a written informed consent document and the willingness to sign it EXCLUSION CRITERIA Women cannot have: Bilateral upper extremity LE; Current infection or lymphangitis involving the affected arm; Current recurrence of their breast cancer (BC) (local or distant) Pre-existing LE prior to their BC diagnosis; A condition that precludes measurement of LE using Bioimpedance Spectroscopy (BIS), including pregnancy; Current venous thrombosis in either upper extremity or be on current anticoagulant therapy; Extremity edema due to heart failure

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Negative Pressure<br>PhysioTouch (negative pressure massage) treatment 3 times a week for 4 weeks to the lymphedematous upper limb | Device: PhysioTouch<br>* The PhysioTouch is a hand-held device that administers negative pressure under the treatment head, and gently pulls the underlying skin and subcutaneous tissue into the suction cup. This suction produces a stretch to the skin and in the subcutaneous tissue space. This action is thought to facilitate lymphatic flow from the interstitium into the lymphatic vessels, and mobilizes the superficial fascia.<br>|
| Active Comparator: Manual Lymph Drainage<br>Manual lymph drainage (MLD) treatment 3 times a week for 4 weeks to the lymphedematous upper limb | Other: Manual Lymph Drainage (MLD)<br>* MLD is a practitioner-applied manual massage technique designed to decrease limb volume in patients with lymphedema by enhancing movement of lymph fluid, resulting in reductions in interstitial fluid.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment Rates | The recruitment rate is defined as the number of women who were screened and then enrolled on the study divided by the the total number of women screened overall. | At 4 weeks | 
| Percentage of Participants Who Completed All Study Visits | Retention rates for both arms of this study were evaluated. The numbers of women who completed the study will be recorded. Reasons for drop out will be ascertained. | At 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Limb Volume | Arm circumferential measurements of both limbs and hands were taken twice, using a spring-loaded tape measure. The hand was measured in two locations. Upper extremity measurements were taken at 10 centimeter (cm) intervals from the ulnar styloid of the wrist up to a total distance of 40 cm. Circumferences were measured using the procedures outlined by Cornish et al. Limb volume was calculated using the formula for volume of a truncated cone and reported in millilitre (ml) | At Baseline | 
| Mean Limb Volume | Arm circumferential measurements of both limbs and hands were taken twice, using a spring-loaded tape measure. The hand was measured in two locations. Upper extremity measurements were taken at 10 centimeter (cm) intervals from the ulnar styloid of the wrist up to a total distance of 40 cm. Circumferences were measured using the procedures outlined by Cornish et al. Limb volume was calculated using the formula for volume of a truncated cone and reported in millilitre (ml) | At 4 weeks | 
| Mean Lymphedema Index (L-DEX®) Ratio Scores | Bioimpedance spectroscopy (BIS) measurements were taken using a single channel BIS, tetrapolar device (LDex device, ImpediMed, San Diego, CA) to evaluate upper limb bioelectrical impedance. Impedance ratios (unaffected/affected limb) are calculated and converted to L-Dex ratio score. With development of lymphedema, impedance of extremity decreases and L-Dex ratio therefore increases. An L-Dex ratio score of 10 is equivalent to impedance ratio of 1.139 (which is = to 3 standard deviations (SD) from mean normative BIS data) for at-risk dominant arms & 1.066 for at-risk non-dominant arms, respectively. Each 1 standard unit in L-Dex is equivalent to impedance ratio of 0.03. Using this arbitrary scale relevant to normative standards, a patient is determined to have arm lymphedema if L-Dex ratio score exceeds 7.1, which is 2 SD above mean normative data for BIS impedance ratios. Higher L-Dex ratio score means higher impedance ratio between limbs, which means more volume in affected limb. | At Baseline | 
| Mean L-DEX® Scores | Bioimpedance spectroscopy (BIS) measurements were taken using a single channel BIS, tetrapolar device (LDex device, ImpediMed, San Diego, CA) to evaluate upper limb bioelectrical impedance. Impedance ratios (unaffected/affected limb) are calculated and converted to L-Dex ratio score. With development of lymphedema, impedance of extremity decreases and L-Dex ratio therefore increases. An L-Dex ratio score of 10 is equivalent to impedance ratio of 1.139 (which is = to 3 standard deviations (SD) from mean normative BIS data) for at-risk dominant arms & 1.066 for at-risk non-dominant arms, respectively. Each 1 standard unit in L-Dex is equivalent to impedance ratio of 0.03. Using this arbitrary scale relevant to normative standards, a patient is determined to have arm lymphedema if L-Dex ratio score exceeds 7.1, which is 2 SD above mean normative data for BIS impedance ratios. Higher L-Dex ratio score means higher impedance ratio between limbs, which means more volume in affected limb. | At 4 weeks | 
| Mean Skin Induration Score | The SkinFibroMeter (Delfin Technologies, Finland) was used to measure tissue induration. The SkinFibroMeter consists of a 1 mm long indenter and a force sensor. The device is gently pressed against the skin. The indenter imposes a constant deformation when the reference plate is in full contact with the skin. The skin and the underlying superficial subcutis resist the deformation. Measurements will be taken bilaterally at 5 locations: the first dorsal web space; the medial forearm halfway between the ulnar styloid and medial epicondyle; the lateral forearm halfway between the radial styloid and the lateral epicondyle; the medial arm 3 inches proximal to the medial epicondyle; and the lateral arm 3 inches proximal to the lateral epicondyle. Five recordings were taken at each location and a mean score was calculated.The induration value in Newtons (N) is recorded. | At Baseline | 
| Mean Skin Induration Score | The SkinFibroMeter (Delfin Technologies, Finland) was used to measure tissue induration. The SkinFibroMeter consists of a 1 mm long indenter and a force sensor. The device is gently pressed against the skin. The indenter imposes a constant deformation when the reference plate is in full contact with the skin. The skin and the underlying superficial subcutis resist the deformation. Measurements will be taken bilaterally at 5 locations: the first dorsal web space; the medial forearm halfway between the ulnar styloid and medial epicondyle; the lateral forearm halfway between the radial styloid and the lateral epicondyle; the medial arm 3 inches proximal to the medial epicondyle; and the lateral arm 3 inches proximal to the lateral epicondyle. Five recordings were taken at each location and a mean score was calculated.The induration value in Newtons (N) is recorded. | At 4 weeks | 
| Mean Degrees of Shoulder Range of Motion | Active shoulder flexion and abduction range of motion (ROM) was assessed, with patients supine, using a goniometer and standardized procedures reported by Norkin and White. Bilateral ROM was assessed. Two measurements will be taken for each motion and a mean obtained, for each, bilaterally. Findings are recorded in degrees. | At Baseline | 
| Mean Degrees of Shoulder Range of Motion | Active shoulder flexion and abduction range of motion (ROM) was assessed, with patients supine, using a goniometer and standardized procedures reported by Norkin and White. Bilateral ROM was assessed. Two measurements will be taken for each motion and a mean obtained, for each, bilaterally. Findings are recorded in degrees. | At 4 weeks | 
| Mean Grip Score | Grip strength was assessed using a Jamar hydraulic hand dynamometer (Patterson Medical, Bolingbrook, IL). Patients will be tested in sitting with the feet flat on the floor, the arm at the side with the elbow flexed to 90 degrees. The patient was instructed to maximally squeeze the handle and hold for a count of 3. The peak-hold needle will automatically record the highest force exerted. Two trials for each extremity will be done and a mean grip score (in kilogram of force) calculated. A higher score indicates a greater grip strength. | At Baseline | 
| Mean Grip Score | Grip strength was assessed using a Jamar hydraulic hand dynamometer (Patterson Medical, Bolingbrook, IL). Patients will be tested in sitting with the feet flat on the floor, the arm at the side with the elbow flexed to 90 degrees. The patient was instructed to maximally squeeze the handle and hold for a count of 3. The peak-hold needle will automatically record the highest force exerted. Two trials for each extremity will be done and a mean grip score (in kilograms of force) calculated. A higher score indicates a greater grip strength. | At 4 weeks | 
| Mean Karnofsky Performance Status (KPS) Score | Participants rated their functional status using the single item KPS scale with a range from 0 (dead) to 100 (I feel normal; I have no complaints or symptoms), in increments of 10 (0,10,20, 30 , 40...). The lower the Karnofsky score, the worse the impairment. | At Baseline | 
| Mean Karnofsky Performance Status (KPS) Score | Participants rated their functional status using the single item KPS scale with a range from 0 (dead) to 100 (I feel normal; I have no complaints or symptoms), in increments of 10 (0,10,20, 30 , 40...). The lower the Karnofsky score, the worse the impairment. | At 4 weeks | 
| Mean Self-Administered Comorbidity Questionnaire (SCQ) Scores | The SCQ consists of 13 common medical conditions that are simplified into language that could be understood without any prior medical knowledge. Patients were asked to indicate if they had the condition using a yes/no format. If they indicate that they had a condition, they are asked if they received treatment for it (yes/no; proxy for disease severity) and did it limit their activities (yes/no; indication of functional limitations). • For each condition, a patient can receive a maximum of 3 points. Because there are 13 defined medical conditions and 2 optional conditions, the maximum achievable total score is 45 points as all items were available for use. | At Baseline | 
| Mean Self-Administered Comorbidity Questionnaire (SCQ) Scores | The SCQ consists of 13 common medical conditions that are simplified into language that could be understood without any prior medical knowledge. Patients were asked to indicate if they had the condition using a yes/no format. If they indicate that they had a condition, they are asked if they received treatment for it (yes/no; proxy for disease severity) and did it limit their activities (yes/no; indication of functional limitations). • For each condition, a patient can receive a maximum of 3 points. Because there are 13 defined medical conditions and 2 optional conditions, the maximum achievable total score is 45 points as all items were available for use. | 4 weeks | 
| Mean Norman Questionnaire (NQ) Scores | The NQ was originally developed and validated as a phone interview questionnaire to describe the signs and symptoms of breast cancer-related lymphoedema. Participants report subjective differences in the size of the hands, lower arms, and/or upper arms between their right and left sides. For each site difference, the reported score can range from 1 (very slight difference) to 3 (very noticeable difference). The total score can range from 1 (very slight difference at 1 site) to 9 (very noticeable difference at all 3 sites). Higher scores indicate a greater noticeable difference between the two arms | At Baseline | 
| Mean Norman Questionnaire (NQ) Scores | The NQ was originally developed and validated as a phone interview questionnaire to describe the signs and symptoms of breast cancer-related lymphoedema. Participants report subjective differences in the size of the hands, lower arms, and/or upper arms between their right and left sides. For each site difference, the reported score can range from 1 (very slight difference) to 3 (very noticeable difference). The total score can range from 1 (very slight difference at 1 site) to 9 (very noticeable difference at all 3 sites). Higher scores indicate a greater noticeable difference between the two arms | At 4 weeks | 
| Mean Norman Questionnaire (NQ) Scores | The NQ was originally developed and validated as a phone interview questionnaire to describe the signs and symptoms of breast cancer-related lymphoedema. Participants report subjective differences in the size of the hands, lower arms, and/or upper arms between their right and left sides. For each site difference, the reported score can range from 1 (very slight difference) to 3 (very noticeable difference). The total score can range from 1 (very slight difference at 1 site) to 9 (very noticeable difference at all 3 sites). Higher scores indicate a greater noticeable difference between the two arms | At 4 months | 
| Mean Disability of Arm, Shoulder, Hand Questionnaire (DASH) Scores | The DASH is a 30-item self-report questionnaire measuring upper limb symptoms and ability to perform common functional activities in people with musculoskeletal disorders of the upper limb. The disability/symptom questions are scored 1 thru 5, with 1=being no difficulty and 5=being unable to perform. At least 27 of the 30 items must be completed for a scaled score to be calculated. The assigned values for all completed responses are simply summed and averaged, producing a raw score between 1 and 5. This value is then transformed to a score out of 100 to create a DASH disability/symptom score = [(sum of (n) responses) - 1] x 25, where n is equal to the number of completed responses. Each scaled score cut point is scored as 0 (no disability), 25 (mild disability), 50 (moderate), 75 (severe) and 100 (unable to perform activities). Higher scores indicate greater limitation. | At Baseline | 
| Mean Disability of Arm, Shoulder, Hand Questionnaire (DASH) Scores | The DASH is a 30-item self-report questionnaire measuring upper limb symptoms and ability to perform common functional activities in people with musculoskeletal disorders of the upper limb. The disability/symptom questions are scored 1 thru 5, with 1=being no difficulty and 5=being unable to perform. At least 27 of the 30 items must be completed for a scaled score to be calculated. The assigned values for all completed responses are simply summed and averaged, producing a raw score between 1 and 5. This value is then transformed to a score out of 100 to create a DASH disability/symptom score = [(sum of (n) responses) - 1] x 25, where n is equal to the number of completed responses. Each scaled score cut point is scored as 0 (no disability), 25 (mild disability), 50 (moderate), 75 (severe) and 100 (unable to perform activities). Higher scores indicate greater limitation. | At 4 weeks | 
| Mean Patient-Reported Outcomes Measurement Information System® (PROMIS) Physical Function for the Upper Extremity (UE) | The PROMIS for the Upper Extremity is reliable and addresses disability with physical activities that involve upper limb activities. The instrument items include 5 response options, from 1 not at all to 5 very much. Total scores range from 0 to 100. PROMIS UE scores are scored using a T-score metric, with higher scores indicate higher levels of physical functioning of the upper extremity. | At Baseline | 
| Mean Patient-Reported Outcomes Measurement Information System® (PROMIS) Physical Function for the Upper Extremity (UE) | The PROMIS for the Upper Extremity is reliable and addresses disability with physical activities that involve upper limb activities. The instrument items include 5 response options, from 1 not at all to 5 very much. Total scores range from 0 to 100. PROMIS UE scores are scored using a T-score metric, with higher scores indicate higher levels of physical functioning of the upper extremity. | At 4 weeks | 
| Mean Scores on the Participant Version of the Patient-Reported Outcomes Measurement Information System (PROMIS®-29) (Version 2) | The PROMIS 29 v2.0 profile assesses pain intensity using a response scale for each item ranging from 0 (no pain) to 10 (worst imaginable pain) on seven health domains (physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance), with four items per domain and one question which addresses pain intensity item. PROMIS-29 domains are scored using a T-score metric, with higher scores indicate higher levels of functioning. | At Baseline | 
| Mean Scores on the Participant Version of the Patient-Reported Outcomes Measurement Information System (PROMIS®-29) (Version 2) | The PROMIS 29 v2.0 profile assesses pain intensity using a response scale for each item ranging from 0 (no pain) to 10 (worst imaginable pain) on seven health domains (physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance), with four items per domain and one question which addresses pain intensity item. PROMIS-29 domains are scored using a T-score metric, with higher scores indicate higher levels of functioning. | At 4 weeks | 
| Mean Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores | The FACT-B is a self-report instrument that measures multidimensional quality of life (QOL) in patients with breast cancer. The FACT-B consists of 37 questions that address physical, social, emotional, and functional well-being, with specific questions relevant to women with breast cancer. Each item has a score range of 0 (Not at all) to 4 (Very much), with a total score ranging from 0-148 The higher the score, the better the QOL reported by the participant. | At Baseline | 
| Mean Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores | The FACT-B is a self-report instrument that measures multidimensional quality of life (QOL) in patients with breast cancer. The FACT-B consists of 37 questions that address physical, social, emotional, and functional well-being, with specific questions relevant to women with breast cancer. Each item has a score range of 0 (Not at all) to 4 (Very much), with a total score ranging from 0-148 The higher the score, the better the QOL reported by the participant. | At 4 weeks | 
| Mean Body Image Scale (BIS) Score | The 10-item Body Image Scale was developed by Hopwood et al. in 2001 to measure affective, behavioral, and cognitive body image symptoms. Patients can indicate body image symptoms on a 4-point scale (0 not at all to 3 very much). The total score ranges from 0 to 30 and can be calculated by summing up the 10 items. A higher score means a higher level of body image disturbance | At baseline | 
| Mean Body Image Scale (BIS) Score | The 10-item Body Image Scale was developed by Hopwood et al. in 2001 to measure affective, behavioral, and cognitive body image symptoms. Patients can indicate body image symptoms on a 4-point scale (0 not at all to 3 very much). The total score ranges from 0 to 30 and can be calculated by summing up the 10 items. A higher score means a higher level of body image disturbance | At 4 weeks | 
| Mean Functional Assessment of Chronic Illness Therapy (FACIT) - Treatment Satisfaction - General (TSG) Scores | Satisfaction with treatment will be evaluated at the 4-week assessment using the Functional Assessment of Chronic Illness Therapy (FACIT) - Treatment Satisfaction - General (TSG) (FACIT-TSG- Version 4). The FACIT-TSG is a copyrighted 8-item questionnaire, with each item score ranging from 0 (not at all) to 4 (very much). Total scores range from 0 to 32 with higher scores indicating greater satisfaction with treatment. | At 4 weeks |