Awareness, early intervention needed to reduce impact of breast cancer-related lymphedema

An estimated 10 million Americans suffer from lymphedema or related diseases.

The debilitating and painful chronic condition — caused by collection of fluid in fatty tissue — most often is characterized by swelling of the arms and legs. Swelling also can occur in the head, chest or genitals.

All individuals who undergo cancer treatment are susceptible to lymphedema, but it occurs most frequently among those whose lymph nodes were removed or damaged during therapy.

The risk is particularly high for patients with breast cancer, some of whom require axillary lymph node dissection. An estimated 25% to 30% of women who undergo the procedure develop lymphedema.

Despite this high prevalence, the condition often is unaddressed as a possible long-term side effect of treatment.

Source: Robert Hood, Fred Hutch 2017

“Lymphedema has fallen a bit off the radar, but the problem has not gone away,” Gary H. Lyman, MD, MPH, FASCO, FRCP (Edin), co-director of Hutchinson Institute for Cancer Outcomes Research at Fred Hutchinson Cancer Research Center, told HemOnc Today. “It still, for these affected women, can have a profound impact on their lives.”

The development of less aggressive surgical techniques — such as sentinel lymph node biopsy — have reduced the incidence and severity of lymphedema.

“Breast cancer management has trended toward using fewer surgical interventions, which has led to considerable improvements,” Lyman said. “It’s good news, but I don’t want to downplay the fact that the problem is still there. Ideally, women who are affected find it early and are managed with appropriate interventions.”

HemOnc Today spoke with breast oncologists, surgeons and rehabilitation therapists about lymphedema prevention strategies; the importance of physician and patient education to ensure appropriate surveillance; and the need for timely referral for patients who require surgery, physical or occupational therapy, or other treatment for lymphedema.

Prevalence and risk

A retrospective analysis by Brayton and colleagues — who studied health claims data from a large national insurer — showed lymphedema prevalence among cancer survivors increased from 0.95% in 2007 to 1.24% in 2013. Aggregate total costs for patients with cancer-related lymphedema totaled $62,190 in the 12 months following diagnosing, comprised mostly of inpatient services ($15,458), hospital outpatient services ($21,222) and office visits ($15,278).

Individuals who undergo treatment for head and neck cancer, sarcoma or melanoma are at increased risk for lymphedema, but breast cancer survivors account for the majority of cases.

As breast cancer incidence and the number of survivors increase, the number of women at risk for lymphedema will continue to grow.

Still, there is some reason for optimism.

“The frequency [of lymphedema] has gone down from what was probably half or more of women with breast cancer several decades ago, to perhaps a quarter of women currently,” Lyman said.

Changes in surgical patterns have contributed to this trend.

Axillary lymph node dissection — removal of all the nodes in the axilla — is a known risk factor for lymphedema. The removal of armpit nodes disrupts the normal flow of the lymph from the arm, which can lead to a buildup of fluid and, in turn, tissue swelling.

However, patients with positive lymph nodes at diagnosis who undergo chemotherapy may be candidates for sentinel node surgery, thereby avoiding axillary dissection.

“There have been many advances and changes in surgical management of the axilla so that axillary dissection is performed much less commonly than in the past,” Judy C. Boughey, MD, FACS, professor of surgery and vice chair of surgical research at Mayo Clinic in Rochester, Minnesota, said in an interview. “Minimizing the extent of axillary surgery will hopefully help decrease lymphedema rates.”

ASCO released an updated clinical guideline in February that recommended against axillary lymph node dissection for women with early-stage breast cancer without sentinel lymph node metastases, and for most women with one or two metastatic sentinel lymph nodes who planned to undergo breast-conserving surgery with whole-breast radiotherapy.

Instead, sentinel node biopsy — removal of only the first few affected nodes — is recommended for women who have operable breast cancer, including those undergoing breast conservation or mastectomy; with multicentric tumors; with ductal carcinoma in situ or invasive breast cancer; undergoing or who previously underwent breast or axillary surgery; or who received neoadjuvant systemic therapy.

“The guidelines are clear: Sentinel biopsy is the first step,” said Lyman, the lead author on that guideline. “Unless there are several lymph nodes found affected by the cancer, the woman may not have to have a complete lymph node dissection.”

Lymphedema risk decreases dramatically if treatment does not include full axillary lymph node dissection.

“For women who undergo a sentinel node technique, their lifetime risk for lymphedema is reduced to 6% to 8%,” Stanley G. Rockson, MD, Allan and Tina Neill professor of lymphatic research and medicine at Stanford University School of Medicine, told HemOnc Today. “However, if you’re one out of five women who are treated for breast cancer, that is a significant proportion.”

Factors beyond axillary dissection affect a patient’s risk for lymphedema.

A population-based cohort study by Nguyen, Boughey and others, published this year in Annals of Surgical Oncology, indicated risk for lymphedema is multifactorial. Radiation, chemotherapy, advanced disease stage and higher BMI all played a role.

Researchers evaluated data from 1,794 patients diagnosed with stage I to stage III breast cancer between 1990 and 2010 to assess long-term breast cancer-related lymphedema incidence and risk factors.

The 5-year cumulative incidence of breast cancer-related lymphedema was 9.1% (95% CI, 7.8-10.5). Risk appeared to be lower among women who underwent sentinel node biopsy rather than axillary dissection (5.3% vs. 15.9%; P < .001). Rates also appeared higher among women with BMI of 25 kg/m² or greater than among women with lower BMI (14.3% vs. 8%; P = .002).

However, lymphedema rates appeared comparable between women who underwent axillary dissection or sentinel node biopsy if surgery was the only treatment received (3.5% vs. 4.1%), suggesting other treatments influenced risk.

For instance, receipt of breast or chest wall radiation more than doubled 5-year incidence among patients who underwent axillary dissection (9.5% vs. 3.5%; P = .01). Patients with the highest incidence — greater than 25% — underwent axillary dissection with nodal radiation and/or anthracycline/cyclophosphamide plus taxane chemotherapy.

“Chemotherapy, which hasn’t been thought of as much as a risk factor because very little is published on it, clearly does impact risk for lymphedema,” Boughey said.

Preventive strategies

Because of the clear connection between surgery and lymphedema, researchers have strived to identify patients who can avoid surgery.

Results of the American College of Surgeons Oncology Group Z1071 trial suggested women with lymph node-positive breast cancer treated with neoadjuvant chemotherapy may avoid routine axillary dissection.

The trial included 687 patients with T0-4, N1-2, M0 primary invasive breast cancer. All patients completed neoadjuvant chemotherapy, underwent sentinel lymph node surgery and axillary dissection.

Researchers initially reported a 12.6% false-negative rate — which exceeded the predetermined acceptable rate of 10% — for sentinel lymph node surgery after neoadjuvant chemotherapy among patients with node-positive disease and two or more sentinel nodes removed.

In a subsequent analysis, Boughey and colleagues assessed whether axillary ultrasound after neoadjuvant chemotherapy could identify abnormal nodes, thereby improving patient selection for sentinel lymph node surgery.

After reviewing axillary ultrasound images for 611 patients, researchers found 71.8% with suspicious axillary ultrasound images had positive nodes at surgery, compared with 56.5% of patients with normal axillary ultrasound images (P < .001). Further, patients with suspicious ultrasound images had more positive nodes and larger metastases (P < .001).

If patients enrolled in the Z1071 trial had been “selected for sentinel lymph node surgery based on axillary ultrasound findings and undergone sentinel lymph node surgery with resection of at least two sentinel lymph nodes,” the false-negative rate would have decreased to 9.8% (90% CI, 7.1-13.2).

This method of patient selection could reduce the number of women who experience surgery-related complications.

Still, lymphedema prevention methods are needed for those patients who do require axillary dissection.

Researchers in Europe have evaluated a newer prophylactic surgery that is performed after axillary dissection and is used by a few centers in the United States.

Surgeons utilize the same incision made for the axillary dissection and identify any lymphatic channels — made visible with a dye injected into the arm or hand — that may have been severed during the first procedure. They then connect these severed channels to small blood vessels to create a new flow for the lymphatic channel.

With the procedure, lymphedema risk among patients undergoing axillary lymph node dissection, radiation and chemotherapy declines from 40% to 4%, according to Roman Skoracki, MD, FRCSC, FACS, professor of plastic surgery and division chief of reconstructive oncologic plastic surgery at The Ohio State University Comprehensive Cancer Center, who has performed the surgery.

“It is still a rerouting or bypass from the lymphatic system to the venous system, which is something that we do perform for the treatment of lymphedema,” Skoracki told HemOnc Today. “The difference here is that it is performed before lymphedema develops. We perform the bypass with the hope that the patient will never develop lymphedema.”

Exercise also may reduce lymphedema risk following surgery.

Cynthia J. Shechter, MA, OTR/L, CIMT, CLT-UE, owner and director of rehabilitation at ShechterCare, a rehabilitation facility in New York City that specializes in breast cancer-related lymphedema, works with patients to both prevent and manage lymphedema.

“My focus for a postoperative referral has always been to work with patients to obtain full-range of motion, decrease scar tissue, ensure they know lymphedema precautions and to get them moving and independently performing daily activities,” Shechter told HemOnc Today. “The less patients move, the less the fluid flows.”

Lyman encourages women who might feel early symptoms of lymphedema after surgery to exercise.

“It is not necessarily aerobic-type exercise they should be doing, but just moving the affected areas,” he said. “That may improve not only the blood circulation, but also lymphatic circulation in that arm.”

However, the role of exercise among patients at risk for lymphedema is somewhat controversial. Some patients are advised to avoid heavy lifting, which may deter them from exercise.

In a study published in JAMA, Schmitz and colleagues sought to determine whether a 1-year weightlifting intervention increased lymphedema risk compared with no exercise among breast cancer survivors. Those assigned the intervention underwent 13 weeks of supervised instruction, followed by 9 months of unsupervised weightlifting.

Researchers found 11% of women in the intervention group experienced incident lymphedema onset compared with 17% in the control group (cumulative incidence difference [CID] = 6%; 95% CI, 17.2 to 5.2). This difference widened when researchers evaluated only women who had at least five lymph nodes removed (7% vs. 22%; CID = 15%; 95% CI, 18.6% to 11.4%).

The National Lymphedema Network (NLN) — which maintains that exercise is “essential for effective lymphedema management” — recommends a patient be cleared by a physician before beginning an exercise program. Further, the network recommends patients at risk work with a specialist to perform aerobic and resistance exercise.

“One has to be cautious because any trauma to the arm if lymphedema is present could result in infection, but to not use that arm at all is probably the worst thing they can do,” Lyman said. “Working with a trainer or physical therapist would be the optimal way to approach the appropriate exercise with the affected arm.”

It also may be difficult for women to receive a proper referral for physical therapy and maintain all their appointments.

“There are a lot of ‘have-tos’ for individuals with breast cancer-related lymphedema,” Shechter said. “They have many medical appointments; they may have experienced a great deal of loss already; and they may be going through reconstructive surgery, chemotherapy and radiation therapy after mastectomy. Patients can become overwhelmed at times.

“Some clinicians will say that a patient who is unable to comply with all of the steps of complete decongestive therapy is noncompliant,” Shechter added. “Treatment of lymphedema must be tailored to the patient, considering their work and personal lifestyle.”

Early detection and diagnosis

When lymphedema cannot be prevented, surveillance is key for early detection and treatment.

“Until we can perfect our medical and surgical approaches, lymphedema will persist,” Rockson said. “This is where surveillance becomes so important. If we can catch it at an early stage, we can catch it from blossoming into a whole other problem, which is the best we can do right now.”

However, delayed onset of symptoms and the lack of standardized diagnostic criteria have hindered timely detection.

“People have to be aware that lymphedema is not just something that happens 5 months out from your cancer, but can also happen 5 to 10 years after,” Simona F. Shaitelman, MD, EdM, associate professor in the department of radiation oncology at The University of Texas MD Anderson Cancer Center, told HemOnc Today.

Certain symptoms, such as heaviness or swelling, can be early warning signs.

NLN recommendations for early detection of breast cancer-related lymphedema urge clinicians to inform patients that they should immediately report any heaviness or tightness, swelling, redness or heat in at-risk arms, breast, chest or truncal areas.

“These are also questions we should be asking our patients as a precursor,” Shaitelman said.

Guidelines created by a multidisciplinary panel — assembled by the American Society of Breast Surgeons and published this year in Annals of Surgical Oncology — recommended preoperative assessment and ongoing surveillance at regular intervals.

However, based on a lack of head-to-head comparisons, the panel did not recommend one method of screening as the gold standard.

“The ideal anthropometric measuring tool should be easy to use, noninvasive, hygienic, cost-effective, reliable, reproducible and quantifiable,” the panel wrote.

Circumferential nonstretch tape measurements are the minimum standard — for which a 2-cm increase in circumference defines lymphedema — followed by arm volume calculations using a frustum, or truncated cone.

The NLN and International Society of Lymphology also recommend bioimpedance spectroscopy, tissue dielectric constants and infrared perometry for subclinical lymphedema.

Akita and colleagues assessed whether measuring subcutaneous fat with perioperative CT could be used as a novel alternative screening method for early detection of lymphedema.

The researchers reviewed data on lymphatic function — measured with indocyanine green lymphography — for 96 patients with gynecological cancer and 189 patients with breast cancer.

Results — published this year in Microsurgery — showed perioperative temporal subcutaneous fat thick index for 180 lower extremities appeared higher in 46 lymphatic dysfunction limbs (1.21 ± 0.08) than in 134 normal lymphatic function limbs (1.03 ± 0.08; P < .01).

Researchers measured postoperative crosswise subcutaneous fat thickness index in 53 upper extremities and found higher levels in 11 lymphatic dysfunction limbs (1.31 ± 0.21) than in 42 normal lymphatic function limbs (1.01 ± 0.06; P < .01).

“If the efficacy of this method is validated, patients worldwide may be assessed using the same criterion,” the researchers wrote.

Still, consensus on ideal surveillance methods is lacking.

“It’s hard to compare across studies and quantify the numbers to see which method is best,” Shaitelman said. “The bottom line is we know who’s at increased risk, so we can tell patients when they should go for prophylactic meetings with physical therapists to learn exercises and behaviors to prevent lymphedema.”

Treatment strategies

Early detection of lymphedema enables timely management with appropriate multimodality interventions by a certified lymphedema therapist.

Current treatments, also known as complete decongestive therapy, include various aspects of bandage application combined with exercise, the use of compression garments, massage and proper skin care maintenance.

Compression has been shown to reduce tissue fluid volume and improve symptoms.

In the study by Brayton and colleagues, researchers found use of pneumatic compression devices over 12 months decreased the rate of hospitalization (45% vs. 32%; P < .001), outpatient hospital visits (95% vs. 90%; P < .0001), cellulitis diagnoses (28% vs. 22%; P = .003) and physical therapy use (50% vs. 41%; P < .0001) compared with baseline.

“The treatment strategies for existing lymphedema revolve around physical treatments that emanate from the European approach to lymphedema; this has been in place as a treatment strategy for the last 60 to 70 years,” Rockson said. “There is also a big self-care piece.”

New surgical techniques present more options for treatment. The most common surgical options include vascularized lymph node transfer, liposuction debulking and lymphovenous bypass.

“Lymphovenous bypass and lymph node transfer are good procedures to try to minimize lifelong impact, with lymphovenous bypass used in early lymphedema and lymph node transfer for more advanced disease,” Boughey said.

Lymphaticovenular anastomosis — in which an anastomosis is created between the lymphatic and venous systems — is another surgical technique being investigated for the treatment of breast cancer-related lymphedema.

In a study published this year in Breast Cancer Research and Treatment, Winters and colleagues showed 29 women with unilateral breast cancer-related lymphedema who underwent lymphaticovenular anastomosis had a reduced mean difference in arm volumes of 24.7% at 6-month follow-up and 23.5% at 1-year follow-up compared with preoperative mean volume (P = .02). Overall quality of life — as measured on a 10-point scale using the LymphQoL arm questionnaire, a validated questionnaire for patients with lymphedema of the arm — increased from 5.8 ± 1.1 to 7.4 ± 0.7.

Beyond surgery and physical therapy, no pharmaceutical interventions are approved for lymphedema treatment.

However, extensive preclinical research conducted by Rockson and colleagues identified inflammatory mediator leukotriene B₄ as a potential target for lymphedema treatment.

Study results published this year in Science Translational Medicine showed the painkiller ketoprofen inhibits leukotriene B₄. This inhibition reversed edema, improved lymphatic function and restored lymphatic architecture in mouse models of lymphedema.

Bestatin (Ubenimex, Eiger BioPharmaceuticals, Inc.) — an anticancer therapy approved in Japan but not in the United States — has shown more selective inhibition of leukotriene B₄,thus lowering toxicity. The ULTRA trial is recruiting patients to compare bestatin with placebo for patients with leg lymphedema.

“A phase 2 clinical trial is underway and, at the moment, we are examining the impact in leg lymphedema,” Rockson said. “It is our expectation there will be a breast cancer trial in the future.”

Despite these efforts, prevention is the best approach to reduce the impact of lymphedema, Lyman said.

“There are trials with medicines looking to try to improve the flow of lymphatics,” he said. “However, I haven’t seen anything in the literature that says they are very effective. The prevention approach with less surgery and monitoring is the most tried and true way to minimize risk for severity.”

Lack of awareness, support

Despite its prevalence, lymphedema is not given top priority in medical training programs. This lack of provider education translates into disparate information and support for patients.

In a report published in Lymphatic Research and Biology,Neil Granger, PhD, Boyd professor and head of the department of molecular and cellular physiology at Louisiana State University Health Sciences Center, discussed survey findings that evaluated medical curriculum for lymphatic biology among members of the Association of Chairs of Departments of Physiology.

Slightly more than half of survey respondents said they devoted 30 minutes or less to teaching lymphatic function during the first 2 years of medical school.

“Of interest is the fact that nearly 40% responded that 1 to 3 hours of time was devoted to the lymphatic system,” Granger wrote. “Thus, there are some great disparities, with nearly one-fourth of the responses indicating 15 minutes or less and slightly more than one-fourth indicating 1 to 2 hours.”

The lack of medical education has a direct effect on patients.

“The center of all of this is how much time universities spend teaching the lymphatic system to new medical students,” William Repicci, president and CEO at Lymphatic Education & Research Network, said in an interview. “As a result of the lack of education, I routinely find that patients are being undiagnosed, misdiagnosed, offered poor treatments for their disease, or are simply told to go find a therapist to help maintain their health.”

Without proper education, clinicians cannot discuss signs and symptoms of which patients at risk for lymphedema should be aware.

“The biggest challenge still is the fact patients have been so isolated for a variety of reasons and have not gotten the kind of support from the medical community that they deserve,” Repicci said.

“I’ve talked to breast cancer surgeons about whether they tell patients about lymphedema prior to surgery and some do, but I also have received responses like, ‘Why would I do that? I don’t want to scare them even more and they have enough on their minds,’” Repicci added. “But it’s the patient’s decision, not theirs.”

Clinicians may be wary that discussions about lymphedema risk may dissuade patients from undergoing effective treatment.

“You don’t want to tell a patient you will do some harm in addition to the good a treatment might do,” Lyman said. “It maybe isn’t discussed as openly and transparently as it should be. But the discussion, in fact, should be had with patients before they consent to surgery, and certainly as they are monitored postoperatively.”

Patients also may not receive timely referrals to therapy.

“If referrals were readily made, there could be a decrease in the number of patients because we could work on the tissue prior to the issue developing,” Shechter said. “The more opportunity we have to work on tissue postoperatively, the less likely someone will develop lymphatic dysfunction.”

It is often unknown that a community of specialized lymphedema certified therapists exist to care for these patients, Shaitelman said.

“It’s a different skill than that of the average physical therapist,” she said. “Most members of the oncology community don’t have quite the amount of detailed knowledge and time that the therapist can give.”

However, patient awareness of lymphedema appears strong.

“Most of our patients with breast cancer are concerned with the possibility of developing lymphedema and surgeons at Mayo Clinic routinely discuss the risks for lymphedema associated with axillary surgery,” Boughey said. “Many women are aware because breast cancer is so common and lymphedema used to be more common and severe.”

Lack of insurance coverage for lymphedema-related care, though, remains a challenge for patients.

“Unfortunately, this is a huge problem,” Shaitelman said. “The compression garments tend to get worn out over time and then need to be remeasured and replaced, but insurance doesn’t always pay for this.”

Insurance companies have not yet recognized the dramatic impact lymphedema can have on a patient’s life after cancer, Lyman said.

“Patients have additional health care costs upward of between $10,000 and $20,000 a year in some cases,” he said. “For any management of infection or chronic illness, additional procedures or treatments might be called for but are consistently out of coverage range. We keep encouraging insurers to consider this as part of managing the cancer treatment in many women, particularly those who have had to have all their lymph nodes removed.”

Because Medicare does not reimburse for compression garments, many third-party payers follow suit, Rockson said.

“This becomes a significant cost burden of several thousand dollars per year for patients,” he added.

Congressman David Reichert, R-Washington, introduced the Lymphedema Treatment Act in the House of Representatives in February. The proposed federal legislation aims to improve insurance coverage for medically necessary, doctor-prescribed compression supplies essential for treatment of lymphedema.

“The group supporting this act has done a great job,” Repicci said. “Something like this should be automatic, but it has taken years for the bill to even make it this far.”

Sen. Kirsten Gillibrand, D-N.Y., is the lead sponsor on another request — brought forth by the Lymphatic Education & Research Network — to include $70 million in lymphatic and lymphedema research funding to the NIH in fiscal year 2018.

“This is what we are currently fighting for,” Repicci said. “When we succeeded in getting our request in, I got 12 phone calls, seven of which were people telling me what a waste of time it was. This is what we are up against, but we need to give patients hope and encouragement that things can change.”

The fact that a growing proportion of patients with breast cancer are younger women — who may have had less health care coverage — compounds this problem.

“A young woman with a breast cancer diagnosis is less likely to have an insurance policy to cover rehabilitation for the sequella that can occur after breast cancer treatment, like lymphedema,” Shechter said. “Reality comes back hard because we don’t anticipate a diagnosis like breast cancer, nor do young women anticipate developing an incurable condition that will require rehabilitation treatment on an ongoing basis, let alone insurance not covering treatment for it.”

Apart from improved education and insurance coverage, more research is the key to improving the diagnosis and treatment of lymphedema.

“The advancement of research and science will put more in the physician’s toolkit to deal with the disease and help the patient,” Repicci said. “But, if you really want to create change in the field, you need patients to embrace the cause, and patients still face obstacles to finding their voice and building a strong community.” – by Melinda Stevens

Click here to read the , “Should prophylactic antibiotic therapy be used to prevent recurrent infection in patients with lymphedema?”

References:

Akita S, et al. Microsurgery. 2017;doi:10.1002/micr.30188.

Boughey JC, et al. JAMA. 2013;doi:10.1001/jama.2013.278932.

Boughey JC, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.57.8401.

Brayton KM, et al. PLoS One. 2014;doi:10.1371/journal.pone.0114597.

Lyman GH, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.71.0947.

McLaughlin SA, et al. Ann Surg Oncol. 2017;doi:10.1245/s10434-017-5982-4.

Nguyen TT, et al. Ann Surg Oncol. 2017;doi:10.1245/s10434-017-5960-x.

Rockson SG, et al. Lymphat Res Biol. 2004;2(2):86-95.

Schmitz KH, et al. JAMA. 2010;doi:10.1001/jama.2010.1837.

Shaitelman SF, et al. CA Cancer J Clin. 2015;doi:10.3322/caac.21253.

Tian W, et al. Sci Transl Med. 2017;doi:10.1126/scitranslmed.aal3920.

Winters H, et al. Breast Cancer Res Treat. 2017;doi:10.1007/s10549-017-4335-0.

For more information:

Judy C. Boughey, MD, FACS, can be reached at boughey.judy@mayo.edu.

Gary H. Lyman, MD, MPH, FASCO, FRCP (Edin), can be reached at glyman@fredhutch.org.

William Repicci can be reached at wrepicci@lymphaticnetwork.org.

Stanley G. Rockson, MD, can be reached at rockson@stanford.edu.

Simona F. Shaitelman, MD, EdM, can be reached at sfshaitelman@mdanderson.org.

Cynthia J. Shechter MA, OTR/L, CIMT, CLT-UE, can be reached at cynthia@shechtercare.com.

Disclosures: Repicci reports employment with the Lymphatic Education & Research Network. Shaitelman reports grant support from the NIH for lymphedema-related research. Boughey, Lyman, Rockson and Shechter report no relevant financial disclosures.