Excluding cancer recurrence, lymphedema is considered by many to be the most dreaded consequence of breast cancer.
While often asymptomatic, this abnormal accumulation of protein-rich fluid in the lymphatic system of the arm on the same side of body as the site of the breast cancer may be associated with pain, discomfort, psychological suffering, and a negative impact on quality of life.
Known risk factors include lymphadenectomy and radiation to the lymph nodes. Lymphedema is usually an early consequence of breast cancer treatment—i.e., lymphadenectomy and radiation to the lymph nodes—but it can also occur years later.
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Figure: Hiram S. Cody, MD: “For inflammatory breast cancer, we do SLN biopsy but still with a back-up axillary dissection for validation. The role of SLN biopsy following neoadjuvant therapy is not fully worked out yet, but data from M. D. Anderson and elsewhere suggest that SLN is accurate in this setting as well.”
Neglected for many years, lymphedema has become the focus of attention due to increasing reliance on sentinel lymph node biopsy as the technique of choice to assess lymph node status in women with breast cancer.
Full axillary node dissection, the standard of lymph node assessment for many years, is associated with lymphedema in up to one third of patients while sentinel lymph node biopsy—although not devoid of side effects—has a much lower risk of lymphedema—less than 1%, according to experts interviewed for this article.
“Lymphedema is an independent predictor of decreased quality of life even when other predictive factors, such as socioeconomic status, decreased range of motion, age, and obesity are included in a multivariate analysis,” noted Jeanne A. Petrek, MD, Professor of Surgery at Weill Medical College of Cornell University and an attending surgeon on the Breast Service of Memorial Sloan-Kettering Cancer Center (MSKCC). Dr. Petrek has focused much of her research efforts on lymphedema and is an acknowledged expert in the field.
Although there are no exact statistics for the number of women who develop lymphedema, current estimates are that up to 30% of women who undergo full axillary node dissection will develop some degree of lymphedema.
“Anywhere from 10% to 15% of women who have axillary dissection will have obvious lymphedema and another 10% to 15% will have some evidence of measurable swelling,” said Kelly McMasters, MD, the Sam and Lolita Weakley Professor of Surgical Oncology at the University of Louisville.
Accuracy No Longer an Issue
Sentinel lymph node biopsy has evolved over the past 10 years, and the accuracy of the technique in staging the axillary nodes is no longer an issue at centers with appropriately trained surgeons.
“Sentinel lymph node biopsy is practiced routinely as the standard of care in most major medical centers around the world—for good reason,” Dr. McMasters said. The procedure has reduced complications, side effects, and morbidity compared with standard axillary dissection.
Hiram S. Cody, III, MD, Professor of Clinical Surgery at Cornell Medical School and an attending surgeon on the Breast Service of MSKCC, agreed. “We know SLN biopsy is an accurate technique and we consider it a new standard of care, with the caveat that surgeons need to be well-trained in the technique,” he said.
Dr. Cody pointed out that sentinel lymph node biopsy has given the topic of lymphedema a high profile, and made physicians and patients more aware of this complication. “The rate of side effects with SLN is not zero.” he said.
A study at his institution, however, showed that abnormal sensory side effects from axillary surgery are 50% less with sentinel node biopsy compared with standard axillary dissection.
Figure: Jeanne Petrek, MD: “Many patients dread lymphedema almost as much as a recurrence in the breast. It is disfiguring, painful, and takes a toll on patients' lives.”
“For both procedures, sensory effects diminish over time,” he added.
Most breast cancer patients are candidates for the procedure, even those with multifocal tumors. Age and weight are not relative contraindications. Newer techniques for injection of the radioactive tracer that homes in on the sentinel node have improved the accuracy of detection, explained Dr. McMasters.
“The tracer can be injected into the skin, under the skin, or under the nipple. This allows for more reliable detection of the sentinel lymph node. We can now find the sentinel node 100% of the time, whereas in the past the node was not detected in about 10% or 15% of cases.”
False Negatives A Concern
There are no false positives with sentinel lymph node biopsy, but false negatives are a concern, because failure to detect positive lymph nodes could lead to recurrence or to undertreatment of the cancer.
A false-negative result refers to a negative finding when there is actually cancer in the lymph nodes that was missed by the sentinel lymph node procedure, Dr. McMasters explained.
Adequate training in performing the procedure is a critical factor for success. Among surgeons who have performed at least 20 sentinel lymph node biopsies with back-up full axillary node dissections, the false-negative rate is less than 5%, Dr. McMasters said.
The rate of false negatives is comparable to what is found with ordinary axillary dissection, not taking out Level 3 lymph nodes (the standard technique is to remove only Level 1 and 2 lymph nodes, he added).
Dr. Cody agreed, noting that as of November 2002, a total of 4,800 sentinel lymph node biopsies had been performed at Sloan Kettering. Of these, among 2,200 patients who had negative sentinel nodes and no further axillary node dissection, only one developed an isolated recurrence in these axillary nodes.
“Recurrences in the axilla when SLN is negative appear to happen at a much lower rate than predicted by a false negative rate of 5%,” he said. “This suggests that adjuvant therapies for breast cancer, including radiation, chemotherapy, and tamoxifen, may act to further reduce local recurrence.”
Not Suitable for Cases of Small Mammographically Detected DCIS
Dr. Cody said that sentinel lymph node dissection is suitable for almost all breast cancer patients, except those with small, mammographically detected ductal carcinoma in situ; SLN should be performed in patients with DCIS when there is clinical suspicion of invasion (based on the presence of a large mass or extensive lesion requiring mastectomy) or when pathology cannot rule out microinvasion.
Kelly McMasters, MD, noted that newer techniques for injection of the radioactive tracer that homes in on the sentinel node have improved the accuracy of detection.
“SLN should be performed for every invasive breast cancer, regardless of tumor size, if the axilla is clinically negative,” he said.
“For inflammatory breast cancer, we do SLN biopsy but still with a back-up axillary dissection for validation. The role of SLN biopsy following neoadjuvant therapy is not fully worked out yet, but data from M. D. Anderson and elsewhere suggest that SLN is accurate in this setting as well.”
No Standardized Measurements
It is hard to determine the true incidence of lymphedema, partly because there are no standardized measurements, Dr. Petrek explained. Studies have utilized different techniques, most of them cumbersome.
“The measures of lymphedema are insufficient and imprecise and fail to differentiate between degree of lymphedema, or even no lymphedema,” she stated in a recent editorial (The Cancer Journal 2004; 10:17–19).
Several scales to measure lymphedema have been proposed and some of them have been used in studies, but they have not been formally validated. “A common language and exact terminology for events such as lymphedema is essential,” so that treatments can be compared and costs estimated, she said.
NCI Conference
A new system for addressing treatment-related events (including lymphedema) was the focus of a conference sponsored by the NCI last April, called Late Effects on Normal Tissue (LENT IV).
The system, developed by the Lymphedema Working Group, is referred to as CTC v 3.0 (Common Toxicity Criteria version 3); it can be easily applied by clinicians without the need for special equipment.
Innovations for the new version of CTC include separate criteria for volumetric increase, dermal changes, and subcutaneous fibrosis. CTC v 3.0 criteria for lymphedema are detailed in a recent article by a team led by Andrea L. Cheville, MD (Seminars in Radiation Oncology 2003;13:214–255).
In parallel with the development of less invasive treatments to assess lymph node status, management of lymphedema has undergone an evolution as well, explained Dr. Cheville, Director of Cancer Rehabilitation at the University of Pennsylvania Health System.
The extent to which sentinel lymph node biopsy reduces lymphedema has not yet been fully established, she said. “SLN is a dramatic advance, but the risk of lymphedema with SLN is not zero.”
It is becoming increasingly appreciated that radiation to the chest can injure the lymphatics appreciably, causing lymphedema, depending on the patient's overall health status and the robustness of premorbid lymphatic function,” Dr. Cheville said.
‘Lymphedemic Overload’
“Many breast cancer patients are vulnerable to developing a state of lymphedemic overload,” she continued. “This may initially give rise to subclinical lymphatic congestion with no visible alteration in soft tissue volume.
“If lymphatic overload is protracted and progressive, volumetric increase will eventually develop. Radiation may cause progressive lymphedematic compromise due to subdermal fibrosis, which produces extrinsic compression of lymph vessels.”
Specifics of Complete Decongestive Therapy: 2 Phases
Regarding treatment, Dr. Cheville said that the current international standard of management is complete decongestive therapy (CDT), which comprises two phases. In the first, the patient is treated with compression therapy, skin care, manual lymphatic drainage (MLD), and short-stretch compression bandaging.
MLD, or Vodder-type massage, is a technique developed in Austria that requires special training for optimal efficacy. In order to achieve successful lymphatic decongestion, the stagnant lymph that has accumulated in a section of the body due to lymph node or vessel compromise (the lymphotome) is “gently and deliberately” moved to an adjacent lymphotome with intact drainage, Dr. Cheville explained.
It is important to keep the skin clean and use topical antibiotics and antifungal creams when there is a wound or abrasion to reduce risk of infection.
“The success of this therapy is highly dependent on the training and skill level of the therapist,” she emphasized. “The therapy is only as effective as the therapist who performs it.”
Dr. Cheville pointed out that currently there are no enforced qualifications for lymphedema therapists. Essentially any physical/occupational therapist, nurse, or physician can present himself or herself as a lymphedema specialist. The Lymphology Association of North America (LANA) has developed standards for lymphedema therapists.
The goal of the first phase of treatment is to achieve lymphatic decongestion and reduce limb volume. If the volume is not being reduced, the therapist needs to troubleshoot and adapt the therapy accordingly.
Although there are no exact statistics for the number of women who develop lymphedema, current estimates are that up to 30% of women who undergo full axillary node dissection will develop some degree of lymphedema.
The second phase of treatment, Dr. Cheville related, is aimed at maintaining the reduction in volume achieved by the four maneuvers in phase I and consists mainly of nocturnal short-stretch compression bandaging, use of a compression garment (wearing a sleeve on the affected arm) and exercise.
The bandages function as a soft, indistensible cast, with a low resting pressure but a high working pressure. As the muscles within the bandaged limb contract, tissue pressure increases, while muscle relaxation reduces tissue pressure.
Currently there are no enforced qualifications for lymphedema therapists, and essentially any physical/occupational therapist, nurse, or physician can present himself or herself as a lymphedema specialist. The Lymphology Association of North America has developed standards for lymphedema therapists.
This appears to stimulate the lymphatic vessels, enabling them to sequester protein, which has been implicated in the formation of scar tissue. Without exercise, the benefits of bandaging are significantly less, she explained.
Skin care should be continued as needed during phase II.
Challenges to Delivering Appropriate Therapy
The major challenge in delivering optimal therapy for lymphedema, as noted, is the appropriate level of expertise needed. Temporal and fiscal constraints are other challenges. MLD requires one-on-one attention for 35 to 45 minutes per session. Often insufficient time is spent on MLD, Dr. Cheville said.
“Ideally, MLD should involve the entire trunk, preparing the adjacent lymph node beds to receive congestive lymph. Only when the trunk has been decongested, should the therapist move to the affected limb to reduce congestion.”
Another challenge is the limited ability of some therapists to adapt their bandaging technique to break down accumulated fibrosis optimally and to meet the unique requirements of each patient's lymphedema.
Exercise is essential for optimal decongestion, she emphasized, and too often patients are not taught appropriate exercises.
Use of pumps is still controversial for several reasons, Dr. Cheville said. In the past pumps were used at very high pressures with resultant damage to the extant lymphatics and exacerbation of lymphedema.
Pump use has also been criticized because of its putative failure to eliminate accumulated interstitial protein. While effective at mobilizing fluid, pumping alone fails to mobilize the solid constituents of lymph adequately.
The persistence of these macromolecules in tissue has been implicated in causing low-grade inflammation and progressive fibrosis, she said. “In addition, pumps and compression garments were used as exclusive lymphedema therapy for many years with little benefit. Now, however, the pendulum is beginning to swing the other way.”
A recent small trial showed that use of a pump in conjunction with CDT achieved more rapid reduction in lymphedema than CDT alone. “This study, though small, reopens the question of pump use,” Dr. Cheville said.
“My fear is that pumps will be overused, because it is much easier and economical for a therapist to put a patient on a pump without devoting the time and energy required for successful multimodal therapy.”
Figure. Debbie: Saslow, PhD, of the American Cancer Society, said doctors should take blood pressure readings and do blood tests on the unaffected
arm—i.e., the contralateral arm. They should also advise patients to avoid using the ipsilateral arm for heavy lifting and not to engage in heavy weight-lifting for exercise.
Compliance
Compliance is another hurdle, she said. Many patients are reluctant to face the problem of lymphedema and the rigors of appropriate treatment. Effective CDT is arduous, time-consuming, and costly.
After negotiating primary breast cancer therapy, many patients have little residual stamina to expend on CDT. Effective therapy demands acknowledging and working within the constraints of each patient's limitations.
Other treatments for lymphedema remain experimental, Dr. Cheville said. These include coumarin (not shown to be beneficial in lymphedema of breast cancer), hyperbaric oxygen therapy, and laser therapy.
Quality of Life
There is no doubt that lymphedema has a negative impact on quality of life. Dr. Petrek said, “Many patients dread lymphedema almost as much as a recurrence in the breast. It is disfiguring, painful, and takes a toll on patients' lives.”
Any level of lymphedema has a negative effect on quality of life, agreed Debbie Saslow, PhD, the American Cancer Society's Director of Breast and Gynecologic Cancer.
In addition to the physical discomfort and the distortion that occurs with lymphedema, there are also psychological effects. Lymphedema is a constant reminder of breast cancer, and even mild lymphedema has a negative impact.
For example, the presence of lymphedema may contribute to a poor self image. Adding to the fear is that lymphedema can occur at any time, even as late as 20 years following treatment.
Triggers
A number of “triggers” for lymphedema have been reported anecdotally, she said, noting, however, that no scientific data validate any of these theories. For example, tight clothing or a scratch, burn, or infection on the arm. Flying on an airplane, insect bites, and lifting with the affected arm have also been reported to be causally related.
Even so, many oncologists give their patients a long list of instructions on how to supposedly avoid lymphedema. The American Cancer Society's Web site also provides a list of risk-reducing measures for patients “in a non-threatening context,” Dr. Saslow noted.
“We really don't know if any of these measures work,” Dr. Cody said. “There are no data to show that any of them makes a difference. My own feeling is that most lymphedema occurs as a result of treatment and not as a result of anything patients did or did not do later on.”
While Dr. Cody believes that most surgeons discuss lymphedema with breast cancer patients, Dr. Saslow says that a major complaint from patients is that lymphedema is not commonly discussed until it occurs.
Dr. Saslow emphasized that oncologists and family physicians need to address lymphedema proactively with breast cancer patients and be familiar with certain caveats.
“Doctors should take blood pressure readings and do blood tests on the unaffected arm [i.e., the contralateral arm],” she said. “They should also advise patients to avoid using the ipsilateral arm for heavy lifting [as in lifting a child or a heavy bag of groceries] and not to engage in heavy weight-lifting for exercise.”
Check www.oncology-times.com for basic information about OT. Although the articles are available as yet only in the print edition, the Web site does have a Table of Con-tents list of all articles starting in January 2001.
