Treatment of Breast Cancer-Related Lymphedema with Adipose-Derived Regenerative Cells and Fat Grafts: A Feasibility and Safety Study

Abstract

Breast cancer-related lymphedema (BCRL) is a debilitating late complication with a lack of treatment opportunities. Recent studies have suggested that mesenchymal stromal cells can alleviate lymphedema. Herein, we report the results from the first human pilot study with freshly isolated adipose-derived regenerative cells (ADRC) for treating lymphedema with 6 months follow-up. Ten BCRL patients were included. ADRC was injected directly into the axillary region, which was combined with a scar-releasing fat graft procedure. Primary endpoints were change in arm volume. Secondary endpoints were change in patient reported outcome and safety. The study is registered with ClinicalTrials.gov (NCT02592213). During follow-up, a small volume reduction was noted but was not significant. Five patients reduced their use of conservative management. Patient-reported outcomes improved significantly over time. ADRCs were well tolerated and only minor transient adverse events related to liposuction were noted. In this pilot study, a single injection of ADRC improved lymphedema based on patient-reported outcome measures, and there were no serious adverse events in the 6 months follow-up period. In addition, half of the patients reduced their use of conservative management. ADRC therapy is a promising interventional therapy for alleviating lymphedema, but results need to be confirmed in randomized clinical trials. Stem Cells Translational Medicine 2017;6:1666-1672.

Keywords: Adipose-derived regenerative cells; Fat graft; Lymphedema; Regenerative medicine.

© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Figures

Figure 1

Patient overview. (A): Representative photo of breast cancer‐related lymphedema in the left arm compared with the healthy contralateral side. (B): Table showing baseline characteristics of included patients. Patient ID 02 was excluded due to non‐protocolled treatment as described in the manuscript. Abbreviations: +, yes; ‐, no; BMI, body mass index; CT, chemotherapy; ISL stage, International Society of Lymphology stage; Pt. ID, patient identification; RT, radiation therapy.

Figure 2

The procedure and cell characterization. (A): Approximately 300 mL of lipoaspirate was harvested for adipose‐derived regenerative cell (ADRC) isolation. (B): ADRC were isolated using the automated Celution IV system yielding a 5‐mL cell suspension in about 2 hours. (C): During surgery, 20–30 mL of lipoaspirate was injected in the axilla in a fan‐shaped pattern to loosen scar tissue. (D): Immediately following ADRC isolation, the cell suspension was injected subcutaneously in the axilla. Flow cytometric evaluation of ADRC surface markers was performed on fresh cells and analyzed for CD34 (E), CD90 (F), CD31 (G), CD73 (H), CD45 (I), CD235a (J). The stromal stem cell subpopulation was defined as CD235a‐CD45‐CD31‐CD34+ (K) and the endothelial progenitor cell subpopulation was defined as CD235a‐CD45‐CD31+CD34+ (L).

Figure 3

Patient reported outcome evaluation. Patient‐reported outcome was evaluated after 1, 3, and 6 months following treatment. There was a significant improvement in patient reported outcomes based on the degree of heaviness (A): as well as tension (B): in the arm measured on numerical rating scales (0–10) as well as the DASH questionnaire (C). Abbreviations: DASH, disabilities of the arm, shoulder and hand; IQR, interquartile range.

Figure 4

Volumentric outcome evaluation. (A): Volume was calculated manually by circumference measurements at five points along the arm and measurement of the distance between each point. A transient significant reduction in arm volume was seen after 1 month but results were insignificant after 3 and 6 months. (B): Volume was also assessed by DXA after 3 and 6 months after treatment. A subregion was drawn around the arm and based on known densities of bone, fat, and lean tissue types, the volume was calculated. Similar to the circumference measurements, volume change over time assessed by DXA also showed a small non‐significant decrease at the 3 and 6 month time points. Abbreviation: DXA, dual‐energy x‐ray absorptiometry.