Enabling Early Assessment and Successful Management of Lymphedema in Patients with Cancer

Introduction

Cancer ranks second in mortality and morbidity, just behind cardiovascular disease in the United States (US). Cancer survivorship over the last 40 years has risen dramatically subsequent to improvements in screening and antineoplastic therapies, such as surgery, chemotherapy and radiation. The American Cancer Society (ACS) projects 1.43 million new cancer cases in 2008 and the National Institutes of Health (NIH) estimates the overall cost of this care will be $219.2 billion annually. This figure includes the cost of lost productivity due to illness and premature death.

Incidence prevalence data from the NIH and the ACS have identified more than 100 different types of cancer. Of this lengthy list, breast, prostate, colorectal and lung cancer have the highest number of new cancers and mortality among Americans.

The relative 5-year survival rate for all cancers is 66%. An estimated 10.8 million Americans have been identified as having a past history of cancer, according to ACS figures. Many of these survivors have developed life-long physical impairments secondary to the effects of a primary medical treatment that are designed to ablate local, regional and systemic disease.

One common impairment is secondary lymphedema (LE) or swelling of the limb, which is seen in patients with breast, colorectal, pelvic and skin (melanoma) cancers following primary medial treatment. Secondary lymphedema occurs as a result of trauma from either surgery, radiation or a combination of the two, inhibiting the normal drainage function of the lymphatic system and causing a build-up of fluid in the limb, and eventual swelling. This impairment is often chronic and impacts the ability of survivors to function at home and work, and negatively the survivor’s quality of life. [1]

Incidence rates for lymphedema range from 24 percent to 49 percent for breast cancer after mastectomy, 4-17% after sentinel lymph node biopsy with radiation [1-8] and 5-67% for pelvic cancers. [9-12]

Primary Medical Treatment  

Currently, newly diagnosed cancer patients with solid tumors progress through three levels of primary care. First, surgeons remove the primary tumor and possibly lymph nodes to stage the disease and provide local tumor control. Second, medical oncologists provide chemotherapy to achieve systemic control of the remaining micro-metastatic cells. Third, radiation oncologists administer radiation therapy for local or regional control of any remaining disease.

The focus of this three-tiered approach emphasizes ablation of primary disease, but doesn’t account for co-morbidities associated with these interventions. NIH has estimated indirect morbidity costs (cost of lost productivity due to illness) to be $18.2 billion. Lack of attention to lymphedema is further complicated due to the transference of the patient through three separate disciplines over a 1-year period. In addition, lack of training and expertise in identifying early signs and symptoms of functional impairments contribute to delayed diagnosis and dysfunction. As a result, many cancer survivors develop lymphedema during the course of care.

Current Methods of Diagnosis and Treatment  

In many cases, primary health care providers are unable to diagnose lymphedema until the condition is visibly apparent or until the degree of dysfunction and impairment are so severe that patients can’t function at home or work. A referral to physical therapy often requires an intensive and costly therapeutic program of manual lymph drainage, compression bandaging and custom compression garments in an effort to restore near normal limb girth and skin function. While patients can generally achieve reasonable function through physical therapy interventions, many are resigned to limited functional levels for the rest of their lives.

Medicine has promoted early detection and treatment of cancer from the perspective of a disease model of care, however, it has failed to adequately address lymphedema in the same prospective, proactive fashion. [13]

New Paradigm of Care  

Establishing a baseline of the limb prior to primary medial treatment of cancer appears essential to achieve restorative goals during therapeutic interventions. Some evidence supports efficacy of a prospective model of care. Clinical research trials in the last decade by Armer, Box, and Johansson, investigated various impairments in patients diagnosed with breast cancer. These studies established the importance of early pre-operative baseline assessment of patients providing evidence-based rationale for this concept. [14-16] Scientific investigations using prospectively designed clinical trials to evaluate early interventions to treat lymphedema are essential to establish evidenced-based practices.

One example of this prospective paradigm of cancer care and its potential impact on severity of impairment was demonstrated in a recently published clinical trial. The trial, conducted by the NIH between 2000 and 2005, investigated co-morbidities in a cohort of 196 newly diagnosed breast cancer patients. Preliminary study results indicated the importance of a prospective model of care to reduce the severity of lymphedema and promote the positive therapeutic effects of early intervention. [17]

In addition, given the current downward trends in health care economics, there may be a need to assess benefits and costs of early assessment and treatment of newly diagnosed cancer patients. The potential impact may result in an earlier lymphedema diagnosis, which can reduce severity of dysfunction, lower costs to patients and third-party insurance providers, and improve function in quality of life for cancer survivors.

Advances in Scientific Technologies

There is an extensive body of scientific literature illustrating the application and effectiveness of bioimpedance in medicine to measure total body water, cardiac hemodynamics and renal function.

Studies conducted over the last 15 years specific to lymphedema have provided conclusive evidence supporting the valid and reliable quantification of lymphedema. [18-22] These devices offer clinicians an opportunity to diagnose and treat many impairments earlier in the course of treatment before lymphedema is visibly apparent and prior to later, often irreversible, stages.

In 2007, the US Food and Drug Administration cleared a novel medical device (ImpediMed Limited, Brisbane Australia) for the clinical assessment of unilateral arm lymphedema. The technology employs a low-frequency current that passes through the patient via specifically designed gel-backed electrodes placed on the skin. The procedure is painless, imperceptible to the patient and takes only minutes to perform. The low-frequency current produced travels only through extracellular space due to the high capacitance of lipids contained in the cellular membranes, thus preventing the current from traveling through intracellular space. The first ImpediMed device has been designed to compare impedance, or resistance to the flow of that current, through the patient’s at-risk limb with that of the contra lateral uninvolved limb. The results of that ratio are reported by the device as the Lymphedema Index, or L-Dex™ value. The more extracellular fluid contained in the at-risk arm, the higher the L-Dex value. In a study of healthy women, Cornish et al. established normative ranges which have been standardized into an L-Dex range from -10 to +10. As a result, L-Dex measurements can be used to prospectively manage lymphedema in patients with breast cancer and to monitor patients undergoing treatment for lymphedema. A recent study published by Hayes et al. [22] used bioimpedance as the reference standard to investigate sensitivity and sensitivity of various methods of lymphedema measurement.

Recent media coverage of the scientific basis for this technology and its clinical adoption is available by viewing the following sites:

May 2007

WUSA, Washington D.C.

National Institutes of Health

http://www.wusa9.com/news/news_article.aspx?storyid=57814

May 16, 2008
FOX KTVU, San Francisco, Calif.
Dr. Stan Rockson
Stanford University Medical Center
http://www.impedimed.com/index.php?action=view&view=29268&pid=29267

May 30, 2008

ABC WGGB, Springfield, Mass.
Dr. Steven Schonholz
Mercy Breast Cancer Center, Mercy Medical Center
http://www.impedimed.com/index.php?action=view&view=29266&pid=29262

Lastly, guidelines and consensus statements from NIH, International Society Lymphology (ISL), Northern Ireland, Germany and Canada, strongly endorse the prospective assessment and management of lymphedema in order to provide optimal care of patients at risk for lymphedema. [23-25]

Eventual adoption of this new paradigm of care and use of bioimpedance to detect and treat early signs of secondary lymphedema in cancer patients will promote the reduction in severity of this condition while contributing to the quality of life of many cancer survivors at risk for this chronic and disabling disorder.

Additional information related to lymphedema is available from the NIH at:

http://www.cancer.gov/cancertopics/pdq/supportivecare/lymphedema/
HealthProfessional/page2

References:  

1. Warren A, Brorson H, Borud L, and Slavin S, Lymphedema:  A Comprehensive Review,  Annals of Plastic Surgery • Volume 59, Number 4, 2007

2. Francis WP, Abghari P, Du W, Rymal C, Suna M, Kosir MA. Improving surgical outcomes: standardizing the reporting of incidence and severity of acute lymphedema after sentinel lymph node biopsy and axillary lymph node dissection. Am J Surg 2006;192(5):636-9. Available from http://www.ncbi. .nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&dopt=Citation &list_uids=17071198 <http://www.ncbi.nlm. nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db= PubMed&amp;dopt=Citation&amp;list_uids=17071198>

3. Armer J, Fu MR, Wainstock JM, Zagar E, Jacobs LK. Lymphedema following breast cancer treatment, including sentinel lymph node biopsy. Lymphology 2004;37(2):73-91. Available from PM:15328760

4. Leidenius M, Leivonen M, Vironen J, von Smitten K. The consequences of long-time

arm morbidity in node-negative breast cancer patients with sentinel node biopsy or axillary clearance. J.Surg.Oncol . 2005;92(1):23-31. Available from PM:16180231

5. Langer I, Guller U, Berclaz G, Koechli OR, Schaer G, Fehr MK, et al. Morbidity of sentinel lymph node biopsy (SLN) alone versus SLN and completion axillary lymph node dissection after breast cancer surgery: a prospective Swiss multicenter study on 659 patients. Ann Surg 2007;245(3):452-61. Available from http://www.ncbi..nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=PubMed& dopt=Citation&list_uids=17435553 <http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?cmd= Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17435553>

6. Clark B, Sitzia J, Harlow W. Incidence and risk of arm oedema following treatment for breast cancer: a three-year follow-up study.QJM. 2005;98(5):343-48. Available from PM:15820971

7. Umberto Veronesi, M.D., Giovanni Paganelli, M.D., Giuseppe Viale, F.R.C.Path., Alberto Luini, M.D., Stefano Zurrida, M.D., Viviana Galimberti, M.D., Mattia Intra, M.D., Paolo Veronesi, M.D., Chris Robertson, Ph.D., Patrick Maisonneuve, Eng., Giuseppe Renne, M.D., Concetta De Cicco, M.D., Francesca De Lucia, M.D. and Roberto Gennari, M.D.: A Randomized Comparison of Sentinel-Node Biopsy with Routine Axillary Dissection in Breast Cancer.N Engl J Med Volume 349;6:546-553 August 7, 2003

8. Haid et al: Morbidity of Breast Cancer Patients Following Complete Axillary Dissection or Sentinel Node Biopsy Only: A Comparative Evaluation.Breast Cancer Research and Treatment Volume 73, Number 1 / May, 2002

9. Werngren-Elgstrom, M., & Lidman, D. (1994). Lymphedema of the lower extremities after surgery and radiotherapy for cancer of the cervix. Scandinavian Journal of Plastic Reconstruction Surgery and Hand Surgery, 28, 289-293.

10. Nunns, D., Williamson, K., Swaney, L., et al. (2000). The morbidity of surgery and adjuvant radiotherapy in the management of endometrial carcinoma.International Journal of Gynecological Cancer, 10, 233-238.

11. Fujiwara, K., Kigawa, J., Hasegawa, K., et al. (2003). Effect of simple omentoplasty and omentopexy in the prevention of complications after pelvic lymphadenectomy.International Journal of Gynecological Cancer, 13, 61-66.

12. Carlson, J., Kauderer, J., Walker, J., Gold, M., O’Malley, D., et al. (2007). Phase III trial of Tisseel to reduce lymphedema after inguinal lymph node dissection: A gynecologic oncology group study. Proceedings of the 38 th annual meeting on women’s cancer (abstract 228). San Diego, CA.

13. Rockson SG: Addressing the Unmet Needs in Lymphedema Risk management. LYMPHATIC RESEARCH AND BIOLOGY. Mary Ann Liebert Publishers. Vol. 4 No. 1, 42-46.

14. Armer, J.M., & Stewart, B.R. (2005). A comparison of four diagnostic criteria for lymphedema in a post-breast cancer population.Lymphatic Research and Biology , 3(4), 17.

15. Box, R., Hildegard, M., Bullock-Saxton, J., & Furnival, C. (2002). Physiotherapy after breast cancer surgery: Results of a randomized study to minimise lymphoedema.Breast Cancer Research and Treatment , 75, 51-64.

16. Johansson, K., Ohlsson, K., Ingvar, C., Albertsson, M., & Ekdahl, C. (2002). Factors associated with the development of arm lymphedema following breast cancer treatment: A match pair case-control study. Lymphology , 35(2), 59-71.

17. Stout N, Pfalzer L, McGarvey C, Springer B,. Gerber L, Soballe P. Preoperative assessment enables the early diagnosis and successful treatment of lymphedema:

Cancer Volume 112, Issue 12, Pages 2809-2819, 15 June 2008

18. Cornish, B. (2006) Bioimpedance analysis: scientific background.Lymphat Res Biol, 4, 47 50.

19. Cornish, B. H., BunceE, I. H., Ward, L. C., Jones, L. C. & Thomas, B. J. (1996) Bioelectrical impedance for monitoring the efficacy of lymphoedema treatment programmes. Breast Cancer Res Treat, 38, 169-76.

20. Cornish, B. H., Chapman, M., Hirst, C., Mirolo, B., Bunce, I. H., Ward, L. C. & Thomas, B. J. (2001) Early diagnosis of lymphedema using multiple frequency bioimpedance. Lymphology, 34, 2-11.

21. Cornish, B. H., Thomas, B. J., Ward, L. C., Hirst, C. & Bunce, I. H. (2002) A new technique for the quantification of peripheral edema with application in both unilateral and bilateral cases. Angiology 53, 1: 41-47.

• Hayes S, Jana B, Cornish D, and Newman B. Lymphedema secondary to Breast Cancer:

How Choice of measure influences diagnosis, prevalence and identifiable risk factors. Lymphology 41, 2008, 18-28. Angiology, 53, 41-7.

23. The Diagnosis and Treatment of Peripheral Lymphedema: Consensus Document of the International Society of Lymphology.Lymphology 36 (2003) pp 84-91

24. Susan R. Harris, Maria R. Hugi, Ivo A. Olivotto, Mark Levine and the Steering

Committee for Clinical Practice Guidelines for the Care and Treatment of Breast Cancer Clinical practice guidelines for the care and treatment of breast cancer:

Lymphedema CMAJJAN. 23, 2001; 164 (2) 191

25. Gerber LH, Augustine E, McGarvey C and Pflazer L. Preserving and Restoring Function in Breast Cancer Survivors. In Harris J, Lippman M, Morrow M and Osborne C (Eds) Diseases of the Breast 3 rd Ed. Lippincott Williams and Wilkins. Philadelphia 2004. pp. 1405-1417.