Considering Lymphedema Is Key for Multimodality Therapy of Breast Cancer

When considering management of the axilla in patients undergoing surgical procedures for breast cancer, it is important to consider lymphedema, particularly when one considers the growing number of breast cancer survivors.¹

“Lymphedema results from the multimodality therapy that we utilize for treatment of breast cancer, and I would say that until recently, lymphedema was dismissed or forgotten as just the collateral damage of breast cancer treatment,” Susan B. Kesmodel, MD, FACS, of the University of Miami, said during her presentation at the 38th Annual Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC (PER®). “But we know that lymphedema has a significant impact on quality of life, and also that management of lymphedema increases health care costs, and this could really be a significant financial burden for patients.”

Kesmodel went on to say that the likelihood of lymphedema developing depends on interventions on the axilla, with the incidence being lowest in patients having sentinel lymph node biopsy alone and highest in those with axillary lymph node dissection (ALND), at 4% to 8% versus 30% to 35%, respectively.

Considerations for reducing lymphedema is a 3-step process, said Kesmodel, involving a reduction in the need for axillary surgery; reduction in ALDN; and, when necessary, better performance of axillary surgery.

Reducing Axillary Surgery

When discussing the reduction of axillary surgery, Kesmodel focused on patients with ductal carcinoma in situ (DCIS) and in older patients with hormone receptor (HR)–positive early breast cancer.

“Current [National Comprehensive Cancer Network] guidelines do not recommend routine use of axillary surgery in patients with [DCIS] undergoing breast-conserving surgery,” Kesmodel said. “And in this setting, the risk of having a sentinel lymph node biopsy is less than 5%.”

She went on to detail studies of several databases showing that sentinel lymph node biopsy is performed in the range of 15% to 20% of patients with DCIS undergoing breast-conserving surgery. And while there may be potential indications for this in this patient group—including features that are concerning for invasive cancer, plans for mastectomy, or location which may preclude future sentinel lymph node biopsy—it does appear that, in general, the procedure is over utilized.

Patients with HR-positive disease who are over the age of 70 years have been examined in studies that specifically investigated omission of axillary surgery. In the CALGB 9343 trial, which looked at older women with ER-positive breast cancer who underwent lumpectomy plus either tamoxifen and radiotherapy or tamoxifen monotherapy, about 60% of the patients had no axillary surgery. In those patients who were randomized to the tamoxifen alone arm without axillary surgery, the regional recurrence rate was only 3%.²

Kesmodel said data from additional studies conducted in Europe support the findings from CALGB 9343, with slightly broader inclusion criteria including younger age and HR-negative tumors.

“I’m not advocating that we completely abandon sentinel lymph node biopsy in women who are over the age of 70,” Kesmodel said. “I just think it’s something that should be discussed with the patient and together, you can make a joint decision about how that surgery may affect treatment decisions.”

Reducing Axillary Lymph Node Dissection

Kesmodel began by talking about ALND saying that significant progress has been made in this area in the past 20 years, with ample data in the literature supporting its omission in the majority of patients with early-stage breast cancer undergoing breast-conserving surgery and in many of those undergoing mastectomy.

“An alternative approach for patients who have a slightly greater burden of the disease in the axilla would you be to consider regional nodal irradiation per the AMAROS [NCT00014612]³ or OTOASAR⁴ trials,” said Kesmodel. Both trials indicated that in select patients, ALND can be avoided in favor of radiotherapy approaches.

Despite the available clinical evidence, real-world data indicate that practicing surgeons are likely to perform lymph node dissection with just 1 positive node. Changes to the treatment paradigm that involves using sentinel lymph node biopsy to guide de-escalation of surgery after neoadjuvant chemotherapy may be promising. And to reduce this method being hindered by false negativity rates, Kesmodel said it is recommended to use dual-tracer sentinel lymph node biopsy.

In addition, the use of neoadjuvant therapy to eradicate occult nodal disease, especially in patients with HER2-positive or triple-negative early breast cancer undergoing mastectomy, may be another viable method by which to reduce the need for ALND in this population.

“I think that the timing of treatment is very important to try and avoid axillary lymph node dissection,” Kesmodel said. I think this is definitely something that should be considered in patients undergoing mastectomy…because the likelihood of performing an axillary lymph node dissection in those patients with a positive node is higher.”

Better Axillary Surgery

In those cases where ALND is necessary, Kesmodel promoted the ARM approach, or axillary reverse mapping.

“Axillary reverse lymphatic mapping, which is a technique to identify and preserve the arm lymphatics, can be performed with sentinel lymph node biopsy or axillary lymph node dissection and can be easily incorporated into surgical practice,” she said.

There are several options for the management of lymphatics with the ARM procedure. One involves preserving the lymphatics, a process that is difficult in many cases because there is some variability in the drainage of the lymphatics. Another is to do a lymphatic re-approximation by a formal microvascular lymphaticovenous anastomosis, known as a LYMPHA (LYmphatic Microsurgical Preventive Healing Approach); or a simplified lymphaticovenous anastomosis, known as simplified LYMPHA (S-LYMPHA).

“The major issue with the LYMPHA procedure is that it requires microvascular surgery, said Kesmodel. “Because of this, it’s not going to be accessible to all breast surgeons.”

Recognizing this limitation, a modification to the LYMPHA technique, called S-LYMPHA, was developed that does not require microsurgery, it can be performed by any breast surgeon. It uses the ARM procedure to identify the lymphatics straining from the arm, and the procedure utilizes an invagination of the lymphatics into the vein which are then secured with nonabsorbable sutures.

In one study of 380 patients undergoing ALND with or without S-LYMPHA, lymphedema rates were significantly lower by both univariate and multivariate analyses (3% vs 19%; OR, 0.12; 95% CI, 0.03-0.50; P = .001).⁵

“ARM is clearly a feasible procedure which can readily be incorporated into a breast surgeon's practice and you can try and preserve the lymphatics,” Kesmodel concluded.

References:

1. Kesmodel SB. Reducing lymphedema: surgical considerations. Presented at: 38th Annual Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC (PER®). March 4-7, 2021.

2. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013;31(19):2382-2387. doi: 10.1200/JCO.2012.45.2615

3. Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 2014;15(12):1303-1310. doi: 10.1016/S1470-2045(14)70460-7

4. Sávolt Á, Péley G, Polgár C, et al. Eight-year follow up result of the OTOASOR trial: The Optimal Treatment Of the Axilla - Surgery Or Radiotherapy after positive sentinel lymph node biopsy in early-stage breast cancer: A randomized, single centre, phase III, non-inferiority trial. Eur J Surg Oncol. 2017;43(4):672-679. doi: 10.1016/j.ejso.2016.12.011

5. Ozmen T, Lazaro M, Zhou Y, Vinyard A, Avisar E. Evaluation of Simplified Lymphatic Microsurgical Preventing Healing Approach (S-LYMPHA) for the Prevention of Breast Cancer-Related Clinical Lymphedema After Axillary Lymph Node Dissection. Ann Surg. 2019;270(6):1156-1160. doi: 10.1097/SLA.0000000000002827