As many as 170 million people worldwide and 3 to 5 million people in the U.S. suffer from secondary lymphedema.1 Many varied procedures have been developed to try to cure lymphedema without tremendous success. Thus, preventing the development of lymphedema is the key to reducing this disease. The techniques of axillary lymph node dissection (ALND) and even of sentinel lymph node (SLN) surgery have yet to be standardized, likely compromising both accuracy of staging and risk of lymphedema. Operative Standards for Cancer Surgery Volumes I and II have introduced surgical standards for these procedures, some of which are being adopted as Commission on Cancer quality measures in 2020.2,3
A recent pooled analysis of 6,711 breast cancer patients who underwent SLN surgery found the incidence of lymphedema to be 6.3 percent, with a range of 0 to 23 percent. A similar analysis of 5,354 patients undergoing ALND found a pooled incidence of 28 percent, with a range of 11 to 57 percent.4 This wide variation in lymphedema rates with the same surgical procedure is related to patient factors, treatment factors, and technical factors associated with how the axillary surgery was performed. Surgeons have good reason to deescalate surgery in order to decrease postoperative complications. Problematic in the deescalation of surgery is that it often is replaced with escalation of radiation to the undissected axilla, which may result in axillary fibrosis and more lymphedema over time.5
SLN surgery and ALND do not distinguish the lymphatics of the breast from the lymphatics draining the upper extremities (UE), and the possibility of mapping the drainage from the UE into the axilla has only recently been published.6-8 Transection of the major UE lymphatics, which can be up to 6mm in diameter, during axillary lymphadenectomy in patients without significant collaterals is most likely the root cause of lymphedema, which is arguably the most widely published complication of both SLN surgery and of ALND. Some might say the risk from SLN surgery is already reasonably low (0 to 13 percent). However, most patients who undergo SLN surgery have negative nodes and then lymphedema occurs in node-negative patients. We should strive to lower the risk of axillary surgery toward zero.
Adding ARM to the armamentarium
Axillary reverse mapping (ARM) may be one tool that can help further refine the technique of axillary staging, whether performing SLN surgery and/or ALND. ARM uses split mapping of the breast and the UE to distinguish lymphatics draining the breast from those draining the UE and preserve them.
In a single-institution prospective phase II trial, 642 patients underwent 685 ARM procedures with SLN surgery and/or ALND.7 Objective lymphedema rates by volume displacement for SLN surgery and ALND were 0.8 percent and 6.5 percent, respectively, with 26-month median follow-up. Blue lymphatics were identified during SLN surgery in 29.2 percent of patients—indicating they were in harm’s way during the dissection to remove the SLNs—and in 71.8 percent of ALND procedures. Metastases were seen in the blue node in 4.5 percent of the cases and only in patients with advanced N3 disease.8 In the subset of patients in the phase II trial, in which an identified blue lymphatic was transected, the overall lymphedema rate was 18.7 percent (9/48) when the lymphatic was not reanastomosed/reapproximated, and 0 percent (0/33) when the lymphatic was reanastomosed/reapproximated (p = 0.009) over an average follow-up of 14 months (range 3 to 54 months).8
Similarly, Yue and colleagues performed a randomized study in 265 patients undergoing ALND, randomizing patients to ARM versus ALND only. In the control group, 33 percent developed lymphedema, whereas only 6 percent of the patients with UE lymphatic mapping developed lymphedema at 20-month follow-up.9 In this trial, no reapproximation of lymphatics was performed.
To further evaluate the role of axillary reverse mapping in patients undergoing axillary surgery for breast cancer, the Alliance for Clinical Trials in Oncology has launched a prospective trial to address this question.
Study design of A221702
For Alliance A221702: Axillary Reverse Mapping: A Prospective Trial to Study Rates of Lymphedema and Regional Recurrence after Sentinel Lymph Node Biopsy and Sentinel Lymph Node Biopsy Followed by Axillary Lymph Node Dissection with and without ARM, patients with T1-T3, N0-3, M0 disease are eligible for participation if they are undergoing a mastectomy with any axillary surgery (see Figure 1) or if they are having breast conservation therapy with an ALND (see Figure 2). National Comprehensive Cancer Network guidelines recommend an ALND in any patient treated with mastectomy for a node-positive axilla excluding micro-metastases. Patients undergoing breast conservation surgery and not meeting Alliance Z0011 criteria also are eligible for the trial.
Figure 1. A221702: Schema I For patients with clinically negative nodes who are undergoing mastectomy
Figure 2. A221702: Schema II For patients with clinically positive nodes who are undergoing breast conserving surgery or mastectomy, >2 positive nodes—clinical or occult*
The primary objective of the A221702 study is to determine the occurrence of postoperative lymphedema by conical geometric volume measures in clinical T1–3, N0–3, M0 breast cancer patients undergoing axillary surgery and randomized to Group 1 (no ARM) versus Group II (ARM). Secondary objectives will compare the study groups’ lymphedema symptom intensity and distress as measured by the lymphedema symptom intensity and distress survey. The study will evaluate the technical success of performance of ARM procedure, identification of ARM lymphatics and the ability to spare or reapproximate ARM lymphatics, and will compare the rate of regional recurrence between patients randomized to undergo ARM versus patients who are not.
Like the National Surgical Adjuvant Breast and Bowel Project (also known as NSABP)-32 and many surgical trials, the ARM procedure will require training but is easy to learn and apply. Surgeons can watch a YouTube video and perform and submit two training cases. Thus, any practicing surgeon could apply this technique to their present practice of lymphadenectomy with minimal training and cost, with a potentially huge benefit of preventing or mitigating lymphedema in our patients.
Successful completion of the proposed study will likely help standardize technical aspects of axillary surgery and launch a new area in the primary prevention of lymphedema. Future studies may use the knowledge gained to determine who is at risk for lymphedema and guide therapeutic surgical interventions for secondary lymphedema.
Any questions related to the A221702 clinical trial should be directed to Suzanne Klimberg, MD, PhD, FACS, at Klimberg1954@gmail.com.
- Cemal Y, Pusic A, Mehrara BJ. Preventative measures for lymphedema: Separating fact from fiction. J Am Coll Surg. 2011;213(4):543-551.
- Nelson H, Hunt KK, Veeramachaneni N. Operative Standards for Cancer Surgery: Volume I. Philadelphia, PA: Wolters Kluwer Health; 2015.
- Katz MHG, Hunt KK, Veeramachaneni N. Operative Standards for Cancer Surgery: Volume II. Philadelphia, PA: Wolters Kluwer Health; 2019.
- Shaitelman SF, Cromwell KD, Rasmussen JC. Recent progress in the treatment and prevention of cancer-related lymphedema. CA Cancer J Clin. 2015;65(1):55-81.
- 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.
- Thompson M, Korourian S, Henry-Tillman R, et al. Axillary reverse mapping (ARM): A new concept to identify and enhance lymphatic preservation. Ann Surg Onc. 2007;14(6):1890-1895.
- Boneti C, Korourian S, Bland K, Cox K, et al. Axillary reverse mapping: Mapping and preserving arm lymphatics may be important in preventing lymphedema during sentinel lymph node biopsy. J Am Coll Surg. 2008;206(5):1038-1042.
- Tummel E, Ochoa D, Korourian S, et al. Does axillary reverse mapping prevent lymphedema after lymphadenectomy? Ann Surg. 2017;265(5):987-992.
- Yue T, Zhuang D, Zhou P, et al. A prospective study to assess the feasibility of ARM and evaluate its effect on preventing lymphedema in breast cancer patients. Clin Breast Cancer. 2015;15(4):301-306