We’ve got to come to a universal agreement on how to measure and define lymphedema. Then we can begin to determine the threshold for intervention.— Alphonse Taghian, MD, PhD
“Early intervention might prevent lymphedema progression,” Alphonse Taghian, MD, PhD, said at the 18th Annual Lynn Sage Breast Cancer Symposium in Chicago, but the lack of a universal definition of lymphedema and agreement on how to optimally measure it impedes phase III studies to test that hypothesis.1 Dr. Taghian is Professor of Radiation Oncology, Harvard Medical School, and Director, Lymphedema Research Program, Massachusetts General Hospital, Boston.
Up to now, lymphedema management has been based on an impairment model, “which means that we see the problem first and then we deal with it,” Dr. Taghian stated. The problem of lymphedema can be “a devastating condition for patients”—not only in terms of quality of life and body image, but also sometimes associated with decreased upper extremity function, he added.
Moving forward, “I would like to see a screening-based model so we can catch it as early as possible and test the hypothesis that if we treat it early, we can prevent progression. I would like to see oncologists strongly involved upfront,” Dr. Taghian said. “We’ve got to come to a universal agreement on how to measure and define lymphedema,” he stressed. “Then we can begin to determine the threshold for intervention,” he continued, and test interventions in phase III trials to build level I evidence.
Testing the Hypothesis
To test the hypothesis that screening for lymphedema might prevent its progression, members of the Massachusetts General Hospital Lymphedema Team take measurements of both arms of patients before they are treated for breast cancer. After reviewing the different methods of measuring lymphedema, “we decided to go with the Perometer,” Dr. Taghian said.
Perometry is a noninvasive technique involving a Perometer (Pero-System), which uses infrared light to scan a limb and obtain measurements of the limb’s circumference. The volume of fluid in a patient’s arm can be calculated preoperatively by using these measurements to establish a baseline. Any changes in the relative volume of fluid in a patient's arm can be identified on subsequent screening perometry to identify lymphedema subclinically. Dr. Taghian added, “We usually do three measurements on each arm. It takes 2 to 3 minutes, maybe a maximum of 5 minutes, and we measure 70 to 85 patients per week.”
Without preoperative or baseline arm measurements, “you might overtreat or undertreat the patient,” Dr. Taghian said. “Early postoperative measurement is not accurate as a baseline.” A study of 1,028 women with unilateral breast cancer defined thresholds of ≥ 5% relative volume change for subclinical lymphedema and ≥ 10% for clinically significant lymphedema. In preoperative screening by perometry, 28.3% had arm asymmetry > 5%, and 2.9% had arm asymmetry > 10%. The first postoperative measurement was used to simulate not having a baseline. “Without baseline,” the authors reported, “41.6% of patients were underdiagnosed and 40.1% overdiagnosed at relative volume change ≥ 5%, increasing to 50.0% and 54.8% at relative volume change ≥ 10%.”2
Several different methods have been used to measure lymphedema. They include absolute circumference change > 2 cm at 1 or 2 points; absolute volume difference > 10%, and relative volume change > 10%. “Relative volume change is independent of preoperative arm volume, patient weight, and body mass index,” Dr. Taghian said. “We strongly recommend using relative volume change.”
Dr. Taghian presented data from 4,526 newly diagnosed breast cancer patients who were screened, 2,887 with at least 3 measurements. “With these three measurements, we were able to get a survey from the patient every time,” reporting on “symptoms, changes in arm functionality, impact on body image, cording, and fear of developing lymphedema,” Dr. Taghian said. “We wanted to identify patients at high risk, and maybe if we cannot screen all women, we can just keep a closer eye on these women.”
Reviewing the literature revealed that clinical edema occurs in 20% to 25% of patients undergoing axillary node dissection and 5% to 9% of those undergoing sentinel node mapping, whereas subclinical edema occurs in 47% of axillary node patients and 17% of sentinel node patients. Studies aimed at establishing a threshold for intervention indicated that a 5% to 10% increase in arm volume “is probably the right threshold to investigate,” Dr. Taghian said. “We also found that very early swelling—within the first few months—of 3% to 5% was significant for progression, but the smaller swelling after 3 months was not.”
Looking at the data overall, including large phase III clinical trials with lymphedema as an endpoint, Dr. Taghian listed these “lessons learned”:
Impact of Radiation Therapy and Surgery
Two large studies of regional lymph node irradiation—the National Cancer Institute of Canada (NCIC) MA.20 and European Organisation for Research and Treatment of Cancer (EORTC) 22922 trials—randomized patients with breast cancer to radiation therapy to the regional lymph nodes or not based on the number of positive lymph nodes. Before these trials, only patients with four or more positive lymph nodes routinely received regional lymph node radiation, Dr. Taghian explained. After these trials, patients with one to three positive lymph nodes and high-risk negative lymph nodes also began receiving regional radiation. “This would mean that in the next few months or years, we might see more lymphedema coming, because we are treating more patients with regional radiation.”
To try to quantify the impact of regional radiation, Dr. Taghian and colleagues at Massachusetts General Hospital used a Perometer to collect arm volume measurements preoperatively from 1,476 women diagnosed with breast cancer (1,501 breasts) during postoperative visits. Lymphedema was defined as ≥ 10% increase in arm volume occurring > 3 months postoperatively.
At 2 years, the overall cumulative incidence of lymphedema was 6.8%. “Cumulative incidence by radiation therapy type was as follows: 3.0% no radiation therapy, 3.1% breast or chest wall alone, 21.9% supraclavicular, and 21.1% supraclavicular and posterior axillary boost,” the authors reported.3 “On multivariate analysis, the hazard ratio [HR] for regional lymph node radiation (supraclavicular with or without posterior axillary boost) was 1.7 (P = .025) compared with breast/chest wall radiation alone.”
The lesson learned from this study, Dr. Taghian said, was that patients who undergo regional lymph node radiation after sentinel lymph node or axillary node dissection should be more closely monitored for changes in arm volume.
Impact of Breast Reconstruction
A study aimed at determining the risk of lymphedema associated with immediate breast reconstruction compared to mastectomy alone “suggests that in patients for whom implant-based reconstruction is available, immediate implant reconstruction does not increase the risk of lymphedema compared to mastectomy alone,” the authors reported.4 Among 616 patients (891 mastectomies), 65% had immediate implant procedures, 11% had immediate autologous reconstruction, and 24% had no reconstruction. Arm measurements were performed with a Perometer preoperatively and during postoperative follow-up. At 2 years, the lymphedema rates were 4.08% with implants, 9.89% with autologous reconstruction, and 26.7% with no reconstruction.
“In multivariate analysis, body mass index, axillary lymph node dissection, and number of lymph nodes dissected were all associated with significantly different lymphedema rates,” Dr. Taghian said. “No reconstruction vs immediate implant was highly significant, with a hazard ratio of 0.35. No reconstruction vs autologous procedure was not significant.”
The lessons learned from this study, he remarked, are to counsel patients regarding the benefit from immediate reconstruction and to closely monitor patients who do not have reconstruction.
Neoadjuvant vs Adjuvant Chemotherapy
A study to determine whether neoadjuvant chemotherapy reduced the risk of lymphedema in patients undergoing unilateral axillary lymph node dissection for node-positive breast cancer compared patients who had adjuvant vs neoadjuvant chemotherapy. “Prospective arm volumes were measured via perometry preoperatively and at 3- to 7-month intervals after surgery. Lymphedema was defined as relative volume change ≥ 10%, > 3 months from surgery,” the authors explained.5
The total number of patients was 229, with 68 (30%) receiving neoadjuvant chemotherapy and 161 (70%) receiving adjuvant chemotherapy. Lymphedema occurred in 15% of the neoadjuvant group vs 23% of the adjuvant group. “This was not significant,” Dr. Taghian said, “but what we found that was very strongly significant was that women who had residual positive lymph nodes after neoadjuvant chemotherapy had a significant, almost ninefold, increase for the development of lymphedema. So patients with residual positive lymph nodes after neoadjuvant chemotherapy should be closely monitored for lymphedema and possible early intervention for the condition.”
Conventional Precautionary Guidelines
Dr. Taghian also presented a review of studies of conventional precautionary guidelines for avoiding lymphedema.6 Recommendations include the avoidance of blood pressure readings, blood draws, infusions, or injections in the at-risk arm, as well as not flying a long distance without a compression sleeve and no repetitive movements.
“There is a paucity of high-level scientific evidence supporting or refuting these precautionary measures and conflicting results among the studies that have been published,” he said. In addition, most of the published data are based on populations with a majority of patients receiving axillary lymph node dissection, but “nowadays, only 20% of patients have lymph node dissection,” he noted.
Lymphedema Risk Factors
Dr. Taghian concluded by listing 5 risk factors for the development of lymphedema identified by the Massachusetts General Lymphedema Studies Team among a modern, prospectively followed cohort of more than 4,000 patients:
Disclosure: Dr. Taghian has received research funding from ImpediMed L-Dex.
3. Warren LE, Miller CL, Horick N, et al: The impact of radiation therapy on the risk of lymphedema after treatment for breast cancer: A prospective cohort study. Int J Radiat Oncol Biol Phys 88:565-571, 2014.
4. Miller CL, Colwell AS, Horick N, et al: Immediate implant reconstruction is associated with a reduced risk of lymphedema compared to mastectomy alone: A prospective cohort study. Ann Surg 263:399-405, 2016.
5. Specht MC, Miller CL, Skolny MN, et al: Residual lymph node disease after neoadjuvant chemotherapy predicts an increased risk of lymphedema in node-positive breast cancer patients. Ann Surg Oncol 20:2835-2841, 2013.
6. Asdourian MS, Skolny MN, Brunelle C, et al: Precautions for breast cancer-related lymphedema: Risk from air travel, ipsilateral arm blood pressure measurements, skin puncture, extreme temperatures, and cellulitis. Lancet Oncol 17:e392-e405, 2016.