Lymphedema Progression Screening Using MRI (INFORM)

August 22, 2019 updated by: Manus Donahue, Vanderbilt University

Imaging Noninvasively With Functional-MRI for Onset, Response and Management of Lymphatic Impairment

This study will apply novel, noninvasive structural and functional magnetic resonance imaging (MRI) methods to patients with mild and moderate breast cancer-related lymphedema (BCRL) for the first time to test fundamental hypotheses about relationships between lymphatic compromise and imaging biomarkers that may portend disease progression and individualized therapy response.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Lymphedema is a chronic, debilitating disease caused by lymphatic flow obstruction. Breast cancer-related lymphedema (BCRL) secondary to mastectomy and/or radiation therapy is a growing health concern, with a reported incidence as high as 94% in breast cancer survivors. Behavioral adjustments and aggressive therapeutic management can reduce long-term impairment and optimize quality of life. However, there is currently no standard clinical procedure for identifying patients at greatest BCRL risk and fundamental gaps exist in even our basic knowledge of how the lymphatic system responds to node dissection and subsequent therapy. Specialized imaging methods have demonstrated that reduced lymphatic flow velocity and lymphatic contractility impairment may signify greater BCRL risk, however these approaches frequently require radioactive tracers or exogenous contrast agents which alter the physiological environment and are primarily available only in specialized centers. As such, these methods are simply impractical for routine BCRL monitoring in humans or for reporting clinical trial endpoints.

Recent work has demonstrated that spin labeling, a popular and noninvasive MRI method for measuring perfusion, can be adapted to measure lymphatic fluid flow to axillary lymph nodes. Furthermore chemical exchange saturation transfer (CEST) MRI, a popular method for measuring protein content and pH changes in brain, breast, and liver, can be translated to the lymphatic system to assess sensitive changes in interstitial protein accumulation, a hallmark of lymphedema progression. Recent work has provided motivation for these techniques by demonstrating, using commercially available equipment, that consistent changes in lymphatic properties are detectable in vivo under (i) conditions of cuff-induced lymph flow manipulation, and (ii) in affected vs. unaffected arms of BCRL patients. Here, these methods will be implemented in sequence with standard clinical and MRI measures of lymph structure to expand our understanding of lymph physiology in different stages of BCRL and in response to therapy.

Hypothesis (1). Axillary lymph nodes and vessels, velocity of lymphatic fluid, and interstitial protein accumulation can be visualized in a reproducible manner using noninvasive MRI approaches that are frequently used to measure analogous metrics in brain, breast, and liver.

Aim (1). Turbo-spin-echo, spin labeling, and CEST MRI will be applied to assess lymph collector volume, lymphatic flow velocity, and interstitial protein accumulation, respectively, together for the first time in healthy female volunteers. Intraclass and Spearman's rank correlation coefficients will be calculated to understand the reproducibility and age-dependence of these parameters in uncompromised lymphatic systems.

Hypothesis (2). (2a) The MRI protocol applied in Aim (1) can be used to detect (i) increases in interstitial protein accumulation and (ii) reductions in lymphatic velocity in patients with mild and moderate BCRL, and (2b) these functional metrics will be more variable than limb volume measurements in patients in early BCRL disease stages and following common manual lymphatic drainage (MLD) therapy, thereby demonstrating the utility of these imaging biomarkers for identifying lymphatic dysfunction and monitoring therapy response.

Aim (2). The Aim (1) protocol will be applied to patients in preclinical (Stage 0), mild (Stage I), and moderate (Stage II) BCRL together with volumetric limb measurements before and after MLD therapy. A Wilcoxon rank-sum test will be used to assess differences in parameters between patient volunteers in different BCRL stages as well as pre- and post-MLD therapy. These data will provide an exemplar for how the novel, internal imaging measurements of lymphatic function vary with disease severity and therapy administration.

Hypothesis (3). In preclinical BCRL patients (Stage 0), reduced lymphatic velocity and increased interstitial protein accumulation correlates with elevated two-year BCRL progression risk.

Aim (3). Stage 0 BCRL patients will undergo an identical MRI protocol as outlined in Aim (1) and follow-up disability metrics will be recorded up to two years post-therapy. A multi-parametric analysis will be used to test correlations between the hypothesized imaging biomarkers and BCRL progression, thereby demonstrating to what extent acute MRI may be used to stratify risk in patients at high risk for BCRL.

This work will for the first time translate a noninvasive, multi-modal MRI protocol, which has demonstrated clinical potential in brain, liver, and breast applications, to the human lymphatic system to better characterize lymphatic dysfunction, therapy response, and BCRL risk in the growing breast cancer survivor population.

Study Type

Interventional

Enrollment (Anticipated)

90

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University Medical Center
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • sex=female
  • age=40-70 yrs
  • clinical diagnosis of lymphedema secondary to breast cancer treatment (including node dissection, radiation therapy, and/or sentinel node biopsy).

Exclusion Criteria:

  • Contraindication to MRI
  • Bilateral axillary lymph node removal
  • Primary lymphedema. Individuals on tyrosine kinase inhibitors or calcium channel blockers

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: SCREENING
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
OTHER: Manual lymphatic drainage therapy
Patients will undergo a 50 min manual lymphatic drainage (MLD) therapy session by a certified lymphedema therapist. MLD therapy is performed routinely for standard of care in these patients and consists of light massage to facilitate lymphatic fluid mobility.
Procedure: Manual lymphatic drainage therapy
Patients will undergo a 50 min manual lymphatic drainage (MLD) therapy session by a certified lymphedema therapist. MLD therapy is performed routinely for standard of care in these patients and consists of light massage to facilitate lymphatic fluid mobility.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Lymphedema progression
Time Frame: 2 years
Progression to more advanced stage of lymphedema. Stage 0 to Stage 1 criteria: ≥ 2 cm difference in arm circumference between involved and uninvolved arms. Fibrosis: none or minimal; Pitting: pits on pressure; Elevation: reduces edema; Skin: no change. Stage I to II progression criteria: Stage I circumference criteria with Fibrosis: moderate; Pitting: may be present; Elevation: does not fully reduce edema (minimal to no reduction); Skin: no change. All progression will be determined using the Perometer by a certified lymphedema therapist.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vanderbilt University

Investigators

  • Principal Investigator: Manus J Donahue, PhD, Vanderbilt University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

February 1, 2015

Primary Completion (ACTUAL)

June 1, 2019

Study Completion (ACTUAL)

June 1, 2019

Study Registration Dates

First Submitted

November 18, 2015

First Submitted That Met QC Criteria

November 18, 2015

First Posted (ESTIMATE)

November 23, 2015

Study Record Updates

Last Update Posted (ACTUAL)

August 26, 2019

Last Update Submitted That Met QC Criteria

August 22, 2019

Last Verified

August 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Donahue_Lymphedema

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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