Direct, local cell transplants have been tested for effects on cancer-related lymphedema. Stromal cells obtained from the bone marrow are stem cells that can differentiate into various cell types, potentially including lymphatic cell types. In the process of stromal cell transplantation, autologous stromal cells were transplanted around the axillary region and affected areas of the chest wall in patients who had previous breast cancer surgery and radiation therapy to evaluate effect on lymphedema. Stem cell transplants have also been tested for this purpose.
Effectiveness Not Established
Cormier, J.N., Rourke, L., Crosby, M., Chang, D., & Armer, J. (2012). The surgical treatment of lymphedema: A systematic review of the contemporary literature (2004-2010). Annals of Surgical Oncology, 19(2), 642–651.doi: 10.1245/s10434-011-2017-4
To examine peer-reviewed literature evaluating the surgical treatment of lymphedema
- Databases searched were MEDLINE, CINAHL, Cochrane Library, PapersFirst, ProceedingsFirst, Worldcat, PEDro, National Guidelines Clearing House, ACP Journal Club and Dare (2004–2010).
- Search keywords were not stated.
- Studies were included in the review if they were related to lymphedema and involved eight or more patients.
- Studies were excluded if they were not refereed articles.
- The total number of references retrieved was not stated.
- Studies were evaluated using an adapted checklist using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) scale.
- The final number of studies was 19.
- Sample range across all studies was 9–1,800, with larger samples in retrospective descriptive studies
- Key sample characteristics were not provided.
Findings were grouped according to the type of procedure: excisional (8 studies, 4 involving liposuction), lymphatic reconstruction (8 studies of lymphatic venous anastomosis [LVA]), and tissue transfer (4 studies involving lymph node transfer, stromal cell transplant, lymphatic tissue transplant, and lymph node transplant). Reduction in lymphedema volume was greatest after excisional procedures (91.1%). Lymphatic reconstruction was associated with 54.9% reduction, and tissue transfer with 47.6% reduction. Overall, surgical procedures did not appear to eliminate the need for compression therapy. Follow-up duration and methods of lymphedema measurement varied substantially across studies. Quality scores for studies ranged from 2–12 across all procedure types and tended to vary considerably within surgery type grouping as well. Studies were done in both upper and lower extremities, though most LVAs were done in lower extremities. The majority of studies did not comment on postoperative complications. Authors noted that a growing body of evidence supports the use of surgical procedures for prevention of lymphedema.
Evidence related to the effectiveness of various surgical procedures for lymphedema is somewhat limited, and the ability to generalize findings also is limited given the wide variation in study quality, sample sizes, measurement methods, and lack of long-term follow up information. Surgical procedures have not been shown to eliminate the need for ongoing conventional therapies for lymphedema.
This review is limited by a lack of full information on search results, with consort type of flow charting, lack of information about disease types, and patient characteristics.
Results of surgical procedures appear to show some promise for reducing lymphedema volumes. However, current evidence is too limited to generalize and more information is needed regarding postoperative complications or long-term results. Surgical intervention has not been shown to eliminate the need for ongoing conservative and conventional interventions as well.
Penha, T. R., Ijsbrandy, C., Hendrix, N. A., Heuts, E. M., Voogd, A. C., von Meyenfeldt, M. F., & van der Hulst, R. R. (2013). Microsurgical techniques for the treatment of breast cancer-related lymphedema: A systematic review. Journal of Reconstructive Microsurgery, 29(2), 99–106.doi: 10.1055/s-0032-1329919
To summarize available literature on lymphatic microsurgery for breast cancer-related lymphedema
- Databases searched were PubMed and MEDLINE (2000–2012).
- Search keywords were lymphedema, microsurgery, surgical treatment, breast cancer, lymph node transfer, lymphovenous anastomosis, and lymph vessel transplantation.
- Studies were included in the review if they involved breast cancer treatment examining the effectiveness of microsurgical intervention.
- Studies were excluded if they involved primary lymphedema, lower extremity lymphedema, or mixed upper and lower extremity lymphedema.
- The total number of references retrieved were not reported.
- The checklist from the American Society of Plastic Surgery for therapeutic studies was used for quality assessment.
- The final number of studies included was 19 case reports involving a total of 191 patients.
- The sample range across all studies was 6–127.
- All patients had a breast cancer diagnosis.
Phase of Care and Clinical Applications:
Patients were undergoing the active antitumor treatment phase of care.
- Four retrospective case series (n = 52) reported results of composite tissue transfer. Findings were rate of reduction in circumference, reduction in pain, reduced incidence of cellulitis, and improvement in quantitative lymph flow.
- Two studies (n = 139) reported on lymph vessel transplantation. Outcomes included volume reduction and a case of donor site edema.
- Four prospective case series evaluated microsurgery. Findings from these studies were mixed. Studies differed in terms of including patients with early nonfibrotic lymphedema or chronic lymphedema. A number of significant methodological limitations in the evidence were reviewed.
- Derivative microsurgery was associated with relief of neuropathic pain in two studies for 50%–100% of patients.
- Three studies of inguinal lymph node transfer reported discontinuation of postoperative conservative therapy of variable rates for 3–24 months. Results were better with shorter duration of lymphedema. Minimal adverse effects were reported overall.
Very limited evidence exists regarding the efficacy of microsurgical techniques for the prevention and management of upper extremity lymphedema in patients with breast cancer who had axillary lymph node excision. The best findings were seen with inguinal lymph node transfer. Consistent positive findings and minimal reported adverse effects were reported. However, high quality-evidence is lacking.
Findings are limited because of the low number of studies, small samples, and lack of high-quality research. Additionally, follow-up duration varied, and most studies did not report rates related to the ability to discontinue conservative management for lymphedema.
Microsurgical techniques for the prevention of lymphedema are promising; however, further high-quality research studies with long-term follow-up are needed.
Research Evidence Summaries
Hou, C., Wu, X., & Jin, X. (2008). Autologous bone marrow stromal cells transplantation for the treatment of secondary arm lymphedema: A prospective controlled study in patients with breast cancer related lymphedema. Japanese Journal of Clinical Oncology, 38(10), 670–674.doi: 10.1093/jjco/hyn090
To determine the short- and long-term effects of bone marrow stromal cells (BMSC) transplantation for breast cancer-related lymphedema and to compare and contrast BMSC transplantation with complex decongestive physiotherapy
Intervention Characteristics/Basic Study Process:
Patients in the complex decongestive physiotherapy group underwent manual lymphatic drainage, compression therapy, remedial exercises for arm and shoulder, and deep breathing to promote venous and lymphatic flow. Patients in the BMSC transplant group underwent bone marrow aspiration from the iliac crest, were admitted, and underwent brachial plexus or general anesthesia with range of transplantation being around the axilla, chest wall, and upper arm of the affected extremity. After the intensive phase, all patients were measured for and wore custom garment during waking hours. Patients were interviewed via telephone at 3 months and 12 months after treatment.
- The study sample (N = 50) was comprised of the control group (n = 35) and the intervention group (n = 15).
- Patients on an in-patient unit were enrolled and followed for one year.
- All patients had were female and had underwent breast cancer surgery without radiation five years earlier.
The study took place in a single site in China.
The study used a controlled trial design.
- Pain was assessed on numerical scale from 0–5.
- Volume measurements were performed according to Kuhnke’s Disk Model, measuring the circumferences of the arms at 4 cm intervals beginning at the wrist and ending at the shoulder.
- 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.
- The percentage of change in the edema arm was calculated by the 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.
Both groups of patients experienced a reduction in pain and lymphedema volume. Patients in the BMSC transplant group had better long-term results. At three months (p = 0.0151) and at 12 months (p = 0.0001) patients in the BMSC group had significantly greater reduction in edema in the affected limb.
Autologous BMSC to treat breast cancer-related upper-extremity lymphedema was effective in the study at one year.
- The study size was small, with less than 100 participants.
- Study cites need for lymphoscintigraphy pre- and post-treatment to evaluate formulation of new lymphatic vessels.
- They study had no random assignment.
The study adds evidence to the effectiveness of complex decongestive physiotherapy in this population, which requires compliance with therapy, education, and support for patients and families.
Maldonado, G.E., Perez, C.A., Covarrubias, E.E., Cabriales, S.A., Leyva, L.A., Perez, J.C., & Almaguer, D.G. (2011). Autologous stem cells for the treatment of post-mastectomy lymphedema: A pilot study. Cytotherapy, 13(10), 1249–1255.doi: 10.3109/14653249.2011.594791
To establish the efficacy of using autologous stem cells (ASC) for the treatment of lymphedema associated with axillary lymph node dissection, define the possible complications, and compare outcomes with compression sleeve therapy
Intervention Characteristics/Basic Study Process:
Twenty patients were randomly assigned to the ASC group or the control group. The ASC group received subcutaneously administered granulocyte-colony-stimulating factor (300 mg per day) for three days prior to the procedure. On procedure day, 100 ml bone marrow was harvested from east posterior iliac crest while the patient was under conscious sedation. The product was centrifuged and, under laminar flow hood, plasma was removed and transferred to sterile test tube. Cells were isolated, and CD34 cells were counted using a flow cytometer. A specimen for microbe and 0.5–1 ml of cell suspension containing 20% albumin and normal saline was administered by intramuscular injection at 30–50 sites of the affected limb, depth of 1 cm, with 25 g needle. Injection range included around the axillary and affected chest wall and part of the upper arm during the first four weeks. Use was discontinued for the following four weeks and then used again for another four weeks. Patients were not allowed to use any other modality of treatment for lymphedema, including manual lymph drainage, exercise drug therapy, or skin products. The control group was given a four-hour practice session on correct use of compression sleeve of 15–20 mmHg.
- The study sample (N = 20) was comprised of female patients with unilateral lymphedema secondary to mastectomy and axillary node dissection.
- Mean age of participants was 50–56 years.
- All patients had not had active cancer in the past five years.
- Patients were excluded from the study if they were older than 75 years, had hypercoagulable states, cardiovascular disease, or bilateral mastectomies.
The study took place at the University Hospital of the School of Medicine of the Universidad Autonoma de Nuevo Leon in Mexico.
Phase of Care and Clinical Applications:
The study has clinical applicability for late effects and survivorship.
The pilot study randomly assigned 10 women to either the ASC group or control group.
- Patient's weight was recorded.
- Limb volume measurements were taken of bilateral upper extremities in four areas, calculating mean by summation.
- Arm volume was determined by trunked cone principle were obtained weekly for 12 weeks.
- Patients were evaluated for pain, sensory loss, and arm mobility.
After 12 weeks, the ASC group had decreased pain, improved sensitivity, and improved mobility as compared to the control group. Volume reductions were similar between the two groups, with the control group being more user dependent.
The study does not provide sufficient evidence to determine potential efficacy of stem cell transplant to manage lymphedema.
- The study had a small sample size, with less than 30 participants.
- Sample characteristics present a risk of bias.
- Measurement validity and reliability is questionable.
- The findings are not generalizable.
- The intervention is expensive, impractical, or requires training.
It is important to be aware of studies being conducted. The study has limited practical value in the United States today, but as ASC becomes a more accepted and standard of care, awareness of the decreases in pain and increased sensitivity and mobility may be of benefit.