Japanese Journal of Clinical Oncology Advance Access originally published online on September 5, 2008
Japanese Journal of Clinical Oncology 2008 38(10):670-674; doi:10.1093/jjco/hyn090
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© The Author (2008). Published by Oxford University Press. All rights reserved
Autologous Bone Marrow Stromal Cells Transplantation for the Treatment of Secondary Arm Lymphedema: A Prospective Controlled Study in Patients with Breast Cancer Related Lymphedema
Department of Vascular Surgery, Shandong Provincial Hospital, Shandong University, Shandong, China
For reprints and all correspondence: Xing Jin, Department of Vascular Surgery, Shandong Provincial Hospital, 324 Jingwu Road, Jinan 250021, Shandong Province, China. E-mail: jinxingjn{at}yahoo.cn
Received July 9, 2008; accepted August 7, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgementsReferences |
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Objective: To determine the short- and long-term effect of bone marrow stromal cells (BMSCs) transplantation as a treatment for breast cancer-related lymphedema. To contrast it with complex decongestive physiotherapy (CDT).
Methods: Fifteen women with lymphedema, who had undergone breast cancer surgery and/no radiotherapy 5 years before, served as the experimental group and received BMSC transplantation; 35 patients were measured as the control group treated with CDT. They were kept on follow-up for 1 year.
Results: Two patients in the CDT Group failed to keep follow-up. Before treatment, patients had average volume of edema in the affected arm of 1166.2 ml in BMSC Group and 1091.0 ml in the CDT Group. With therapy, there was an average decrease in lymphedema volume of 730.7, 887.9 and 958.6 ml in the BMSC Group and 714.8, 657.9 and 571.3 ml in the CDT Group after 1, 3 and 12 months, respectively. Before treatment, the percentage of lymphedema was 28.6% in the BMSC Group and 26.8% in the CDT Group. After treatment, there was a decrease of 64.6, 78.5 and 81.0% in the BMSC Group and 67.2, 60.4 and 54.5% in the CDT Group after 1, 3 and 12 months, respectively. When asked to quantify subjectively their pain on a numeric scale from 0 to 5, the average score of these patients was 3.4 in the BMSC group and 4.0 in the CDT Group. The average score was reduced to 1.6, 0.8 and 0.6 in the BMSC Group and to 1.2, 1.7 and 1.6 in CDT Group after 1, 3 and 12 months, respectively.
Conclusions: Autologous BMSCs transplantation for the treatment of breast cancer related lymphedema is effective and feasible.
Key Words: bone marrow stromal cells • lymphedema • transplantation • breast cancer • complex decongestive physiotherapy
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgementsReferences |
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Breast cancer is one of the most common malignancies among women worldwide. Upper extremity lymphedema has affected between 8 and 80% of all the patients who undergo surgery and/or radiation treatments (1–3). And despite application of breast-conservation therapy and sentinel lymph node biopsy techniques, the incidence of lymphedema remains 4.5–30% (4,5). This complication places these patients at the risk of several morbidities, such as developing recurrent cellulitis, experiencing decreased range of motion, pain and psychological distress etc. (6).
Lymphedema means fluid and protein accumulate in the extravascular and interstitial spaces. Secondary lymphedema is much more common than primary lymphedema. Surgical procedure and the irradiation often cause the destruction of lymphatic vessels, the removal of lymph nodes and tissue scarring. The lymphatic vessels that remain become dilated and overloaded and their valves become incompetent. This change makes the lymph system more and more insufferent (7).
To manage this common but sometime serious complication, various types of conservative and surgical treatments have been tried, such as the complete (or complex) decongestive physiotherapy (8–11), lymphatic venous anastomosis (12), weight reduction (13), liposuction (14), lymph node transplantation (15), omental transposition (16) etc. These treatments, however, are either not very effective, or difficult to perform.
At present, the blockage or destruction of the lymphatic system is the real cause of edema, and the best management should be regeneration and reconstitution of lymphatic vessels. Stem cells have been commonly clinically used to cure ischemic diseases and other insufficiencies of function (17–20). It has been well documented that stem cells can differentiate into vascular endothelial cells and other functional cells, including lymphatic endothelial cells. The aim of this study was to determine the effect of bone marrow stromal cells (BMSCs) transplantation as a treatment for breast cancer-related lymphedema.
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PATIENTS AND METHODS |
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Patients
All 50 patients enrolled in the study were inpatients receiving lymphedema therapy in the vascular surgery ward of Shandong Province Hospital. They had all undergone a breast cancer surgery and/no radiotherapy 5 years before. Chosen by lot [those who took number 1 were assigned into the BMSC Group and those who took 2 and 3 were into complex decongestive physiotherapy (CDT) Group.], 50 patients were randomly assigned into the BMSC group (15 patients, receiving BMSC transplantation) and the CDT group (35 patient, treated with only CDT). All patients underwent complete physical examination, and their characters, such as weight, age, history of breast cancer etc., were recorded. This study was approved by the Institutional Review Board of the Shandong Province Hospital and written informed consent was obtained from all participants.
Observation
Pain in arm and/or chest wall was assessed. Patients were asked to quantify their pain on a numerical scale from 0 to 5, with 0 being no pain at all and 5 being severe, constant pain.
The volume measurements were done according to Kuhnke's ‘disk model' described by Kurz (21). The circumferences (C) of the arms were measured at 4-cm intervals beginning at the wrist and ending at the shoulder. Then the volume (V) was calculated using the formula (
= 3.1416):
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This is a modified truncated cone formula that can approximate and volumes compare in these patients. When the last section was not 4 cm enough, we take the value as 
. x varies from 0 to 4. So the modified formula will be:
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The volume of edema was calculated as the difference between the affected and unaffected arms. The percentage of edema in the arm was then calculated with the following formula: [(VI – VN)/VN] 100, where VI is the volume of the edema arm and VN is the volume of the normal arm. The percentage of change in the edema arm was calculated by the following formula: [(VT – VI)/ (VI –VN)] 100, where VT is the post-treatment volume of the edema arm, VI the initial volume of the edema arm and VN the volume of the normal arm. The volume of edema of the affected arm was measured at the start of treatment and at 1 and 3 months and 1 year after. When the weight of the patient changes little, the volume of the normal arm can be considered a constant quantity or it should be measured again.
Complex Decongestive Physiotherapy
CDT consists of four components. The first is manual lymphatic drainage (MLD), which causes volume reduction by removing excess fluid and protein. The second is compression therapy, applied to mobilize the edema fluid after each MLD session for 23 h/day, including weekends. The third and fourth components are remedial exercises for the arm and shoulder, and deep breathing to help promote venous and lymphatic flow (22).
Transplantation of BMSC
Patients in the BMSC group should receive a diagnostic bone marrow aspiration at the beginning of the treatment. Only patients with bone marrow hyperplasy actively could remain in the study. Then a therapeutic bone marrow aspiration followed. Bone marrow (50 ml in 10 000 IU of heparin) was obtained from the iliac crest. The aspirate was centrifuged on a Ficoll density gradient to isolate the mononuclear cells, which were washed and resuspended in heparin-treated plasma. Before injection, the mononuclear cells were filtered and subjected to quality-control procedures.
During extraction of BMSC, the patient was admitted into the operating room and prepared to receive transplantation. We chose brachial plexus anesthesia or general anesthesia, depending on the condition of the patient. The operating group had become ready before the BMSC was used so that transplantation could be performed immediately, avoiding the cells being kept for too long and dying. Range of transplantation was around of the axillary, including affected chest wall and part of upper arm. Injection sites were 1 cm away from each other and the needle went into the muscles of thorax or subcutaneous tissue. In one injection site, 0.5 ml BMSC was injected.
After the intensive phase, patients in both groups were measured for a custom garment and instructed to wear the garment daily while awake and to remove it at bedtime. Patients were interviewed by telephone at 3 and 12 months after treatment.
Statistical Analysis
The t test was used to evaluate the difference. The level of significance was chosen at P < 0.05. All data were calculated and evaluated using SPSS 12·0·1 (SPSS, Chicago, IL, USA).
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgementsReferences |
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Two patients in the CDT Group failed to keep follow-up. Other patients’ conditions were all examined and recorded.
Effect on Lymphedema Volume
The volume of lymphedema in the affected limb was calculated as previously described. Before treatment, the average volume of edema of the affected arm was 1166.2 ± 500.1 and 1091.0 ± 484.8 ml (P = 0.5562) in the BMSC and CDT Groups, respectively (Fig. 1).
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With therapy, this was reduced to an average volume of 435.5 and 376.2 ml, 285.2 and 433.4 ml, 274.3 and 519.7 ml in the BMSC and CDT Groups after 1, 3 and 12 months, respectively. There was an average decrease in lymphedema volume of 730.7 ± 262.7 and 714.8 ± 255.6 ml (P = 0.8447), 887.9 ± 323.5 and 657.9 ± 277.8 ml (P = 0.0151), 958.6 ± 442.5 and 571.3 ± 219.3 ml (P = 0.0001) in BMSC and CDT Groups after 1, 3 and 12 months, respectively (Fig. 2).
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Effect of CDT on Percentage of Lymphedema
The percentage of edema in the affected arm was measured as previously described. Before treatment, the percentage of lymphedema was 28.6 ± 7.7% in the BMSC Group and 26.8 ± 6.7% in the CDT Group, respectively (P = 0.4173, Fig. 3).
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After treatment, there was a decrease of 64.6 ± 8.5% and 67.2 ± 12.6% (P = 0.2324), 78.5 ± 11.1% and 60.4 ± 9.5% (P < 0.001), 81.0 ± 7.8% and 54.5 ± 14.2% (P < 0.001)in the amount of lymphedema percentage in the BMSC and CDT Groups, respectively, after 1, 3 and 12 months (Fig. 4).
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Effect on Pain
One of the primary complications of cancer-related lymphedema is chronic pain. In this study, 28 (58.3%) of 48 patients had pain associated with their lymphedema. Among these, there were 10 (66.7%) patients in the BMSC Group and 18 (54.5%) patients in the CDT Group (P = 0.4298). When asked to quantify their pain subjectively on a numeric scale from 0 to 5 (0 being free of pain and 5 being very severe, debilitating pain), the average score of these patients was 3.4 ± 1.8 in the BMSC group and 4.0 ± 1.1 in the CDT Group (P = 0.2952). The average score was reduced to 1.6 ± 1.1 and 1.2 ± 1.1 (P = 0.3922), 0.8 ± 0.9 and 1.7 ± 1.2 (P = 0.0424), 0.6 ± 0.7 and 1.6 ± 1.3 (P = 0.0353) after 1, 3 and 12 months, respectively (Fig. 5). Patients in both BMSC and CDT Groups had significant reduction of the pain scale after treatment. The average score was greatly reduced (P < 0.001).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgementsReferences |
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Lymphedema is an important and common complication of the treatment of breast cancer. There is no effective cure for it, although many techniques have been developed. CDT is a received therapy, which can reduce lymphedema volume and limb girth (23,24). We can see, however, that the results were just acceptable but not inspiring. More effective treatments are urgently needed.
This study showed that the patients in either the BMSC Group or the CDT Group had a reduction in lymphedema volume and pain scale, but patients in the BMSC Group had a better long-term cure result. Although they have to undergo a minor operation, they gain a chance of avoiding the tedious and more expensive CDT.
Stem cells are now commonly clinically used to cure different diseases. The stem cells were obtained from the patients themselves without culture in vitro. Puzzling ethical problems thus avoided. Most of the patients were afflicted with lymphedema for a long time and needed an effective therapy badly. Because the length of stay was greatly shortened, medical cost in the transplantation of BMSC was cheaper by far than that of CDT. However, there were two problems in our study. One was regarding differentiation, activity and sum of the stem cells. We counted the stem cells of each patient before transplantation using flow cytometer, and documented that the total number of stem cells of each patient was at the level of 3–10 x 109. At the same time, we are performed an experimental study of therapeutic BMSCs transfected with VEGF-C gene transplantation in the treatment of animal secondary limb lymphedema, so as to determine its effect, look for the best way and study the mechanism of the treatment. The other problem was whether transplantation of the stem cells affects the patients’ primary disease, that to say, whether it promotes relapse and metastasis of breast cancer. It was the reason that we enrolled only those patients who had undergone a breast cancer surgery and/no radiotherapy 5 years before. No relapse or metastasis has been found in this study.
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CONCLUSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgementsReferences |
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Autologous BMSCs transplantation for the treatment of breast cancer-related arm lymphedema is effective and feasible. It can greatly reduce the volume and percentage volume of lymphedema, and reduce the amount of pain caused by edema. It works as efficiently as CDT initially, but gives better long-term result than the latter. However, this study has not offered patients’ conditions after 1 year and there were not enough cases, therefore further studies are needed to determine the results and adverse reactions of this therapy. Lymphoscintigraphy should be performed before and after treatment to document formation of new lymphatic vessels.
Conflict of interest statement
None declared.
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Acknowledgements |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgementsReferences |
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We thank the participants and the supporting medical staff for making this study possible.
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References |
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